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natural variants of the beta isoform of the human glucocorticoid receptor do not alter sensitivity to glucocorticoids.the beta isoform of the human glucocorticoid receptor, hgrbeta, is a product of alternative splicing of the hgr gene. the physiological function of this isoform is unknown up to now. recent data are contradictory in that they either favor or argue against a role of hgrbeta as a repressor of the functional hgralpha isoform. in the present study hgrbeta did not inhibit transcriptional activation of the mmtv-driven luciferase reporter gene by dexamethasone-activated hgralpha in cos-1 cells. in addi ...199910459864
rescue of an mmtv transgene by co-integration reveals novel locus control properties of the ovine beta-lactoglobulin gene that confer locus commitment to heterogeneous tissues.in an attempt to enhance the frequency and level of expression of a poor-performing mmtv-driven transgene, we co-integrated this construct with the ovine beta-lactoglobulin (blg) gene in transgenic mice. seven lines of transgenic mice possessing co-integrated blg and mmtv-rz5 transgenes were compared with 12 lines of mice that possessed only the mmtv-rz5 construct. co-integration enhanced the frequency of expression in the mammary gland from two out of 12 lines for the mmtv-rz5 transgene alone, ...199810461392
double pronuclei injection of dna into zygotes increases yields of transgenic mouse lines.transgenic mice are increasingly used for gene function and regulation studies of mammalian genes. a major limitation is the necessity to produce a large number of founder animals to obtain one line with the desired expression pattern. we developed a method, the 'double pronuclei injection', that doubles the yield of transgenic mouse lines obtained from each injection session, thereby reducing the time, effort and costs of generating transgenic mice. three transgenic vectors were microinjected i ...199810461393
t cell response in malaria pathogenesis: selective increase in t cells carrying the tcr v(beta)8 during experimental cerebral malaria.to characterize the t cells involved in the pathogenesis of cerebral malaria (cm) induced by infection with plasmodium berghei anka clone 1.49l (pba 1.49l), the occurrence of the disease was assessed in mice lacking t cells of either the alphabeta or gammadelta lineage (tcralphabeta(-/-) or tcrgammadelta(-/-)). tcrgammadelta(-/-) mice were susceptible to cm, whereas all tcralphabeta(-/-) mice were resistant, suggesting that t cells of the alphabeta lineage are important in the genesis of cm. the ...199910464176
the proinflammatory cytokine, interleukin-1alpha, reduces glucocorticoid receptor translocation and function.proinflammatory cytokines have been shown to influence the expression and function of the glucocorticoid receptor (gr). specifically, several studies have found that cytokines induce a decrease in gr function, as evidenced by reduced sensitivity to glucocorticoid effects on functional end points. to investigate the potential mechanism(s) involved, we examined the impact of the proinflammatory cytokine, interleukin-1alpha (il-1alpha), on 1) gr translocation from cytoplasm to nucleus using gr immu ...199910465310
induction of mammary gland hyperplasia in transgenic mice over-expressing human cdc25b.cdc25 a and b are dual-specificity phosphatases which have been implicated in neoplastic transformation. although cdc25a and cdc25b have been found to be over-expressed in many cancer cell lines and primary tumors, the physiological roles of cdc25a and b in vivo are largely undefined. to investigate the roles of these proteins in the oncogenic transformation of the mammary gland we used the mouse mammary tumor virus (mmtv) promoter to target over-expression of the cdc25b transgene in the mammary ...199910467401
many human endogenous retrovirus k (herv-k) proviruses are unique to humans.endogenous retroviruses contribute to the evolution of the host genome and can be associated with disease. human endogenous retrovirus k (herv-k) is related to the mouse mammary tumor virus and is present in the genomes of humans, apes and cercopithecoids (old world monkeys). it is unknown how long ago in primate evolution the full-length herv-k proviruses that are in the human genome today were formed.199910469592
possible etiology of human breast cancer: comment. 199910472435
sequences homologous to the mouse mammary tumor virus env gene in human breast carcinoma correlate with overexpression of laminin receptor.we previously reported that a 660-bp sequence that is homologous to the env gene of the mouse mammary tumor virus (mmtv) but not to endogenous retroviruses or to other known genes was present in 38% of human breast cancers and in some breast cancer cell lines studied (y. wang et al., cancer res., 55: 5173-5179, 1995). here, we have investigated whether the mmtv-like sequences were associated with the clinical, pathological, and molecular parameters that have been reported to define two subsets o ...199910473094
selective binding of steroid hormone receptors to octamer transcription factors determines transcriptional synergism at the mouse mammary tumor virus promoter.transcriptional synergism between glucocorticoid receptor (gr) and octamer transcription factors 1 and 2 (oct-1 and oct-2) in the induction of mouse mammary tumor virus (mmtv) transcription has been proposed to be mediated through directed recruitment of the octamer factors to their binding sites in the viral long terminal repeat. this recruitment correlates with direct binding between the gr dna binding domain and the pou domain of the octamer factors. in present study, in vitro experiments ide ...199910480874
role of dendritic cells in the immune response induced by mouse mammary tumor virus superantigen.after mouse mammary tumor virus (mmtv) infection, b lymphocytes present a superantigen (sag) and receive help from the unlimited number of cd4(+) t cells expressing sag-specific t-cell receptor vbeta elements. the infected b cells divide and differentiate, similarly to what occurs in classical b-cell responses. the amplification of sag-reactive t cells can be considered a primary immune response. since b cells are usually not efficient in the activation of naive t cells, we addressed the questio ...199910482591
transcription originating in the long terminal repeats of the endogenous mouse mammary tumor virus mtv-3 is activated in stat5a-null mice and picks up hitchhiking exons.the enhancer within the long terminal repeats (ltrs) of acquired somatic mouse mammary tumor viruses (mmtv) can activate juxtaposed genes and induce mammary tumors. in contrast, germ line proviral mmtv genomes are integrated in the host genome and considered to be genetically confined transcription units. here we demonstrate that transcription initiated in an mmtv provirus proceeds into flanking host sequences. we discovered multiple polyadenylated transcripts which are induced in stat5a null mi ...199910482620
the dominant negative activity of the human glucocorticoid receptor beta isoform. specificity and mechanisms of action.alternative splicing of the human glucocorticoid receptor gene generates a nonhormone binding splice variant (hgrbeta) that differs from the wild-type receptor (hgralpha) only at the carboxyl terminus. previously we have shown that hgrbeta inhibits the transcriptional activity of hgralpha, which is consistent with reports of elevated hgrbeta expression in patients with generalized and tissue-specific glucocorticoid resistance. the potential role of hgrbeta in the regulation of target cell sensit ...199910488132
transport and metabolic characterization of caco-2 cells expressing cyp3a4 and cyp3a4 plus oxidoreductase.to further characterize cyp3a4-transfected caco-2 cells with regard to morphological, transport, and metabolic properties, and to evaluate a different caco-2 cell strain transfected with both cyp3a4 and oxidoreductase (or).199910496649
transcriptional state of the mouse mammary tumor virus promoter can affect topological domain size in vivo.unrestrained dna supercoiling and the number of topological domains were measured within a 1.8 megabase pair chromosomal region consisting of about 200 tandem repeats of a mouse mammary tumor virus promoter-driven ha-v-ras gene. when uninduced, unrestrained negative supercoiling was organized into 32-kilobase pair (kb) topological domains. upon induction, dna supercoiling throughout the region was completely relaxed. supercoiling was detected, however, when elongation was blocked before or follo ...199910497225
increased susceptibility to carcinogen-induced mammary tumors in mmtv-cdc25b transgenic mice.cdc25 phosphatases activate cyclin-dependent kinases (cdks) by dephosphorylating critical phospho-tyrosine and phospho-threonine residues on these proteins. several types of studies indicate that cdc25s can enhance cell proliferation and oncogenesis. furthermore, overexpression of cdc25a and/or b have been detected in several types of primary human cancers, including breast cancers. to further assess the oncogenic capacity of cdc25b in vivo, we have generated transgenic mice that overexpress cdc ...199910498865
interaction between the ret finger protein and the int-6 gene product and co-localisation into nuclear bodies.the mouse int-6 gene was identified in mammary tumors as an integration site for the mouse mammary tumor virus. its human counterpart encodes a product that interacts with the tax viral oncoprotein of the human t cell leukaemia virus type 1. this interaction impedes the localisation of over-expressed int-6 in nuclear bodies containing the promyelocytic leukaemia gene product (pml). in this study, int-6 is characterised as a 52 kda protein that is localised within nuclear bodies in primary lympho ...199910504338
in vivo expression of prostate-specific adenoviral vectors in a canine model.the activity and expression of transgene beta-galactosidase (lacz) by replication-deficient adenoviral vectors (ad-lacz) containing prostate-specific promoters were compared using an in vivo canine model. the prostate tissue-specific promoters were prostate-specific antigen, probasin, and mouse mammary tumor virus long-terminal repeat, which were fused separately to an escherichia coli lacz gene. dogs underwent laparotomy, and adenoviral vectors were delivered by direct intraprostatic injection. ...199910505856
conditionally adherent growth of serum-independent cho cells for automated drug screening and biopharmaceutical production.ssf3 is a cho cell line adapted for growth in protein-free medium. it grows in suspension unless serum-derived attachment factors such as vitronectin are added to the medium. serum-independent cell lines, which adhere to the substrate after induction with dexamethasone or constitutively, were created by transfection with a human vitronectin gene under control of the mouse mammary tumor-virus promoter. substrate attachment and ssf3vn-cell spreading could be prevented with an rgd peptide (arginine ...199910516577
rfg (ara70, ele1) interacts with the human androgen receptor in a ligand-dependent fashion, but functions only weakly as a coactivator in cotransfection assays.abnormalities of the human androgen receptor (har) cause a range of clinical defects in male development. a large proportion of these mutations are single amino acid substitutions in the hormone-binding domain (hbd) that alter ar function by interfering with the capacity of the ar to bind androgen or to form stable hormone-receptor complexes. prior studies have suggested that the formation of such stable, active hormone-receptor complexes is a crucial step in the modulation of genes by the ar. i ...199910517667
inhibition of histone deacetylation augments dihydrotestosterone induction of androgen receptor levels: an explanation for trichostatin a effects on androgen-induced chromatin remodeling and transcription of the mouse mammary tumor virus promoter.the integrated mouse mammary tumor virus (mmtv) promoter has provided an excellent model system with which to study the impact of steroid hormones on transcriptional activation in the context of a defined chromatin structure. the hormone response element (hre) of this promoter is positioned on a phased nucleosome which becomes remodeled in response to steroids. one possible mechanism of chromatin remodeling by steroid receptors could involve recruitment of coactivators which alter the histone ac ...199910527637
conditional modulation of glucocorticoid receptor activities by creb-binding protein (cbp) and p300.coactivators of nuclear receptors are integral components of the signal transduction pathways of steroid hormones. here, we show that one of the major coactivators of the glucocorticoid receptor (gr), creb-binding protein (cbp), can also function conditionally as a negative regulator of its activities. indeed, cbp suppressed the responsiveness of the mouse mammary tumor virus (mmtv) promoter to dexamethasone in a dose-dependent fashion in hela and a204 cells. similarly, this protein suppressed t ...199910528999
expression of mouse mammary tumor virus envelope protein does not prevent superinfection in vivo or in vitro.inbred mice expressing endogenous mouse mammary tumor virus envelope proteins can be infected with exogenous virus, and the mammary tumors that develop in these mice usually have many proviruses integrated in their genomes, indicating that this virus is not subject to receptor interference. we show here that transgenic mice expressing an exogenous mouse mammary tumor virus (c3h) envelope protein can still be infected with this virus. moreover, cultured mammary gland cells expressing the mouse ma ...199910544114
identification of a protein that recognizes a distal negative regulatory element within the mouse mammary tumor virus long terminal repeat.the mouse mammary tumor virus (mmtv) long terminal repeat contains a distal negative regulatory element (dnre) that selectively represses activity of the proviral promoter in the absence of steroid hormone receptor-mediated activation. a protein, termed mmtv nre-binding protein 1 (mnbp-1), that recognizes long terminal repeat sequences between -433 and -418 was identified by gel electrophoresis mobility shift assays and methylation interference footprinting in nuclear extracts of hela and ltk(-) ...199910544147
polycitone a, a novel and potent general inhibitor of retroviral reverse transcriptases and cellular dna polymerases.polycitone a, an aromatic alkaloid isolated from the ascidian polycitor sp. exhibits potent inhibitory capacity of both rna- and dna-directed dna polymerases. the drug inhibits retroviral reverse transcriptase (rt) [i.e. of human immunodeficiency virus type 1 (hiv), murine leukaemia virus (mlv) and mouse mammary tumour virus (mmtv)] as efficiently as cellular dna polymerases (i.e. of both dna polymerases alpha and beta and escherichia coli dna polymerase i). the mode and mechanism of inhibition ...199910548537
structure/function of the human glucocorticoid receptor: tyrosine 735 is important for transactivation.ligand-induced activation of the glucocorticoid receptor (gr) is not well understood. the gr ligand-binding domain was modeled, based on homology with the progesterone receptor. tyrosine 735 interacts with the d ring of dexamethasone, and substitution of d ring functional groups results in partial agonist steroids with reduced ability to direct transactivation. loss of the tyr735 hydroxyl group by substitution to phenylalanine (tyr735phe) did not reduce ligand binding affinity [dissociation cons ...199910551779
cd4+ t cell responses to cd40-deficient apcs: defects in proliferation and negative selection apply only with b cells as apcs.during t-apc interactions in vivo, interfering with cd40-cd154 interactions leads to reduced t cell priming, defects in effector function, and, in some cases, t cell tolerance. as shown here, however, presentation of conventional peptide ags by cd40-deficient spleen apc in vitro leads to normal cd4+ t cell proliferative responses. by contrast, responses to the same peptides presented by purified b cells were markedly reduced in the absence of cd40. thus, the requirement for cd40-cd154 interactio ...199910553046
involvement of notch1 in the development of mouse mammary tumors.the mmtv/neu transgenic (tg) mice spontaneously develop mammary tumors stochastically after a long latent period, suggesting that the c-neu/erbb2 oncogene is not sufficient for tumor formation. to identify putative collaborator(s) of the c-neu/erbb2, we used the provirus insertional mutagenesis approach with mammary tumors arising in mmtv/neu tg mice infected with the mouse mammary tumor virus (mmtv). the notch1 gene was identified as a novel target for mmtv provirus insertional activation. in n ...199910557086
mouse mammary tumor virus carrying a bacterial supf gene has wild-type pathogenicity and enables rapid isolation of proviral integration sites.mouse mammary tumor virus (mmtv) has frequently been used as an insertional mutagen to identify provirally activated mammary proto-oncogenes. to expedite and facilitate the process of cloning mmtv insertion sites, we have introduced a bacterial supf suppressor trna gene into the long terminal repeat (ltr) of mmtv, thus allowing selection of clones containing it in lambda vectors bearing amber mutations. the presence of supf in the ltr should circumvent the screening process for proviral insertio ...199910559292
wild-derived inbred mice have a novel basis of susceptibility to polyomavirus-induced tumors.polyomavirus induces a broad array of tumors when introduced into newborn mice of certain standard inbred strains, notably those bearing the h-2(k) haplotype. susceptibility in these mice is conferred by an endogenous mouse mammary tumor virus superantigen (mtv-7 sag) that acts to delete t cells required for polyomavirus-induced tumor immunosurveillance. in the present study we show that mice of two wild-derived inbred strains, pera/ei (pe) and czech ii/ei (cz), are highly susceptible to polyoma ...199910559322
a ligand binding domain mutation in the mouse glucocorticoid receptor functionally links chromatin remodeling and transcription initiation.we utilized the mouse mammary tumor virus (mmtv) long terminal repeat (ltr) in vivo to understand how the interaction of the glucocorticoid receptor (gr) with a nucleosome-assembled promoter allows access of factors required for the transition from a repressed promoter to a derepressed, transcriptionally competent promoter. a mutation (c644g) in the ligand binding domain (lbd) of the mouse gr has provided information regarding the steps required in the derepression/activation process and in the ...199910567540
accelerated mammary tumor development in mutant polyomavirus middle t transgenic mice expressing elevated levels of either the shc or grb2 adapter protein.the grb2 and shc adapter proteins play critical roles in coupling activated growth factor receptors to several cellular signaling pathways. to assess the role of these molecules in mammary epithelial development and tumorigenesis, we have generated transgenic mice which individually express the grb2 and shc proteins in the mammary epithelium. although mammary epithelial cell-specific expression of grb2 or shc accelerated ductal morphogenesis, mammary tumors were rarely observed in these strains. ...199910567542
expression of cre recombinase as a reporter of signal transduction in mammalian cells.cell-based reporter assays, which rely on a reporter gene under the control of a regulated promoter, are widely used to screen chemical libraries for novel receptor ligands. here, we describe a reporter system that is based on ligand-induced dna recombination to express the reporter gene. this system converts a transient activation of a signal transduction pathway into an amplified, constitutive and heritable expression of the reporter gene.199910574783
organogenic role of b lymphocytes in mucosal immunity.follicle-associated epithelium (fae) in the intestinal peyer's patches contains m cells that deliver pathogens to organized lymphoid tissue. development of peyer's patches, fae, and m cells was found to be impaired in mice that had no b cells. transgenic expression of membrane-bound immunoglobulin m restored b cells and fae development. the lack of m cells abrogated infection with a milk-borne retrovirus. thus, in addition to secretion of antibodies and presentation of antigens, b cells are impo ...199910583962
inhibition of heat shock factor activity prevents heat shock potentiation of glucocorticoid receptor-mediated gene expression.using mouse l929 cells stably transfected with a glucocorticoid receptor (gr)-responsive murine mammary tumor virus-chloramphenicol acetyltransferase (mmtv-cat) reporter gene (lmcat2 cells), we have shown that cellular stress (heat or chemical shock) can cause a dramatic increase in the levels of dexamethasone (dex)-induced cat gene expression. we refer to this response as the heat shock potentiation effect, or hspe. as the cellular heat shock response also involves the activation of heat shock ...199910590836
engineering cho cells to overexpress a secreted reporter protein upon induction from mouse mammary tumor virus promoter.the mouse mammary tumor virus (mmtv) promoter is induced by the addition of a glucocorticoid hormone or analog such as dexamethasone. the hormone binds to its specific transcription factor, glucocorticoid receptor (gr), and the activated complex then binds to the glucocorticoid response elements (gres) in the enhancer region of the mmtv promoter to induce the overexpression of downstream genes. we have constructed an expression vector for a reporter protein, secreted alkaline phosphatase (seap), ...200010592510
structural determinants of aldosterone binding selectivity in the mineralocorticoid receptor.the structural determinants of aldosterone binding specificity in the mineralocorticoid receptor (mr) have not been determined. the mr has greatest sequence identity with the better characterized glucocorticoid receptor (gr), which is reflected in their overlapping ligand binding specificities. there must be subtle sequence differences that can account for the mr-specific binding of aldosterone and the shared binding of cortisol. to characterize ligand binding specificity, chimeras were made bet ...199910593921
gene switching: analyzing a broad range of mutations using steric block antisense oligonucleotides. 200010595356
nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription.a contemporary view of hormone action at the transcriptional level requires knowledge of the transcription factors including the hormone receptor that may bind to promoters or enhancers, together with the chromosomal context within which these regulatory proteins function. nuclear receptors provide the best examples of transcriptional control through the targeted recruitment of large protein complexes that modify chromosomal components and reversibly stabilize or destabilize chromatin. ligand-de ...199910601972
protein tyrosine phosphatase epsilon increases the risk of mammary hyperplasia and mammary tumors in transgenic mice.accurate phosphorylation of tyrosine residues in proteins plays a central role in regulation of cellular function. although connections between aberrant tyrosine kinase activity and malignancy are well-established, significantly less is known about the roles of protein tyrosine phosphatases (ptpases) in tumorigenesis. we have previously shown that the transmembranal form of ptpase epsilon (ptpepsilon) is upregulated in mouse mammary tumors initiated specifically by ras or neu, suggesting that pt ...199910602512
inhibition of the putative tumor suppressor gene timp-3 by tumor-derived p53 mutants and wild type p53.the p53 gene is a tumor suppressor that regulates the expression of genes required for cell cycle arrest or apoptosis. mutations in p53 have been observed in over 60% of all human cancers. certain classes of mutant p53 proteins maintain some of their activities or acquire novel activities and thus may contribute to the transformed phenotype. by carrying out an analysis of differential gene expression using cdna expression arrays, we compared the expression patterns of cells expressing no p53 to ...199910602522
a method for efficient extraction of bovine papilloma virus-based minichromosomes that preserves native chromatin structure.aiming to create an adequate model for investigation of the molecular mechanisms involved in transcriptional regulation by steroid hormones, a number of cell lines carrying bovine papilloma virus (bpv) based constructs containing the mouse mammary tumor virus long terminal repeat (ltr) were established (ostrowski et al., mol. cell. biol. 3, 2945-2957, 1983). however, all our attempts to extract from the cells such minichromosomes as nucleoprotein complexes using a method previously described (os ...199910619601
protein inhibitor of activated stat-1 (signal transducer and activator of transcription-1) is a nuclear receptor coregulator expressed in human testis.an androgen receptor (ar) interacting protein was isolated from a hela cell cdna library by two-hybrid screening in yeast using the ar dna+ligand binding domains as bait. the protein has sequence identity with human protein inhibitor of activated signal transducer and activator of transcription (pias1) and human gu rna helicase ii binding protein (gbp). binding of pias1 to human ar dna+ligand binding domains was androgen dependent in the yeast liquid beta-galactosidase assay. activation of bindi ...200010628744
expression of the cytoplasmic domain of e-cadherin induces precocious mammary epithelial alveolar formation and affects cell polarity and cell-matrix integrity.cadherins are cell adhesion molecules involved in cell-cell adhesion, signalling, and cellular proliferation and differentiation. e-cadherin is required for the formation of epithelium in vivo. we investigated the contribution of the cytoplasmic domain of e-cadherin to adhesion, signalling, and differentiation during murine mammary gland development, by in vivo expression of a gene encoding a truncated form of e-cadherin lacking the extracellular domain. the expression of this gene in mammary ep ...199910642788
characterization of the interaction between the interferon-induced protein p56 and the int6 protein encoded by a locus of insertion of the mouse mammary tumor virus.for determining cellular functions of the interferon-inducible human cytoplasmic protein p56, we undertook a saccharomyces cerevisiae two-hybrid screen that identified int6 as a p56-interacting protein. that the interaction also occurs in human cells was confirmed by coimmunoprecipitation and the observed cytoplasmic displacement of nuclear int6 upon coexpression of p56. because int6 has been claimed to be both a cytoplasmic and a nuclear protein, we investigated the structural basis of this dis ...200010644362
breast cancer incidence highest in the range of one species of house mouse, mus domesticus.incidence of human breast cancer (hbc) varies geographically, but to date no environmental factor has explained this variation. previously, we reported a 44% reduction in the incidence of breast cancer in women fully immunosuppressed following organ transplantation (stewart et al (1995) lancet 346: 796-798). in mice infected with the mouse mammary tumour virus (mmtv), immunosuppression also reduces the incidence of mammary tumours. dna with 95% identity to mmtv is detected in 40% of human breast ...200010646903
stresgenin b, an inhibitor of heat-induced heat shock protein gene expression, produced by streptomyces sp. as-9.stresgenin b was isolated as an inhibitor of heat-induced heat shock protein (hsp) gene expression from a culture broth of streptomyces sp. as-9 by silica gel chromatography and hplc. the molecular formula of the novel compound was determined as c11h13no5 by high resolution fab-ms analysis, and the structure was determined by uv, 1h nmr, 13c nmr, hmqc, hmbc, and noesy spectra. stresgenin b inhibited heat-induced luciferase reporter-gene expression directed by the human hsp70b promoter in chinese ...199910656568
ras signaling in the inner medullary cell response to urea and nacl.the small guanine nucleotide-binding protein ras, activated by peptide mitogens and other stimuli, regulates downstream signaling events to influence transcription. the role of ras in solute signaling to gene regulation was investigated in the murine inner medullary collecting duct (mimcd3) cell line. urea treatment (100-200 mm), but not sham treatment, increased ras activation 124% at 2 min; the effect of nacl did not achieve statistical significance. to determine the contribution of ras activa ...200010666033
sint1, a common integration site in sl3-3-induced t-cell lymphomas, harbors a putative proto-oncogene with homology to the septin gene family.the murine retrovirus sl3-3 is a potent inducer of t-cell lymphomas when inoculated into susceptible newborn mice. previously, dnas from twenty sl3-3-induced tumors were screened by pcr for provirus integration sites. two out of 20 tumors demonstrated clonal provirus insertion into a common region. this region has now been isolated and characterized. the region, named sl3-3 integration site 1 (sint1), maps to the distal end of mouse chromosome 11, corresponding to human chromosome 17q25, and may ...200010666245
tamoxifen chemoprevention of a hormone-independent tumor in the proto-neu transgenic mice model.we evaluated the effect of tamoxifen (tam) on tumor development in proto-neu transgenic mice that spontaneously develop mammary carcinomas overexpressing the neu protein. these mammary carcinomas are hormone independent because superimposable growth of transplants was observed in females and males. virgin transgenic mice treated with tam from 24 weeks of age, ie., when subclinical mammary tumors are already present, showed a slightly accelerated tumor development. in contrast, transgenic mice tr ...200010667575
ability of systemic interleukin-12 to hamper progressive stages of mammary carcinogenesis in her2/neu transgenic mice.previous studies in mice have shown that chronic administration of recombinant interleukin-12 (il-12) hampers the progression of both chemical- and oncogene-dependent carcinogenesis. this suggests that a new preventive strategy may be envisaged for individuals with a genetic risk of cancer or carrying preneoplastic lesions. starting at progressive stages of mammary carcinogenesis, female balb/c and fvb mice carrying the activated rat her2/neu oncogene (balb-neut) or the proto-oncogene (fvb-neun) ...200010667588
the nmr structure of the nucleocapsid protein from the mouse mammary tumor virus reveals unusual folding of the c-terminal zinc knuckle.the nucleocapsid protein (nc) from the mouse mammary tumor virus (mmtv) has been overexpressed in escherichia coli and purified to homogeneity for structural studies by nuclear magnetic resonance (nmr) spectroscopy. the protein contains two copies of a conserved zinc-coordinating "cchc array" or "zinc knuckle" motif common to the nucleocapsid proteins of nearly all known retroviruses. the residues comprising and adjacent to the zinc knuckles were assigned by standard two-dimensional (1)h and thr ...200010677209
the glucocorticoid receptor: rapid exchange with regulatory sites in living cells.steroid receptors bind to site-specific response elements in chromatin and modulate gene expression in a hormone-dependent fashion. with the use of a tandem array of mouse mammary tumor virus reporter elements and a form of glucocorticoid receptor labeled with green fluorescent protein, targeting of the receptor to response elements in live mouse cells was observed. photobleaching experiments provide direct evidence that the hormone-occupied receptor undergoes rapid exchange between chromatin an ...200010678832
a novel mechanism of resistance to mouse mammary tumor virus infection.exogenous mouse mammary tumor virus (mmtv) is carried from the gut of suckling pups to the mammary glands by lymphocytes and induces mammary gland tumors. mmtv-induced tumor incidence in inbred mice of different strains ranges from 0 to as high as 100%. for example, mice of the c3h/hen strain are highly susceptible, whereas mice of the i/lnj strain are highly resistant. of the different factors that together determine the susceptibility of mice to development of mmtv-induced mammary tumors, gene ...200010684291
superantigen expression is driven by both mouse mammary tumor virus long terminal repeat-associated promoters in transgenic mice.in addition to the usual retroviral promoter, the mouse mammary tumor virus (mmtv) long terminal repeat carries a second promoter located in the u3 region. here we show that both of these promoters are independently able to give rise to superantigen activity in transgenic mice. the ability of multiple mmtv promoters to drive superantigen expression underscores its importance in the virus life cycle.200010684308
superantigens - powerful modifiers of the immune system.superantigens are powerful microbial toxins that activate the immune system by binding to class ii major histocompatibility complex and t-cell receptor molecules. they cause a number of diseases characterized by fever and shock and are important virulence factors for two human commensal organisms, staphylococcus aureus and streptococcus pyogenes, as well as for some viruses. their mode of action and variation around the common theme of over-stimulating t cells, provides a rich insight into the c ...200010689316
hormone activation induces nucleosome positioning in vivo.the mouse mammary tumor virus (mmtv) promoter is induced by glucocorticoid hormone. a robust hormone- and receptor-dependent activation could be reproduced in xenopus laevis oocytes. the homogeneous response in this system allowed a detailed analysis of the transition in chromatin structure following hormone activation. this revealed two novel findings: hormone activation led to the establishment of specific translational positioning of nucleosomes despite the lack of significant positioning in ...200010698943
over-expression of erbb-2/neu is paralleled by inhibition of mouse-mammary-epithelial-cell differentiation and developmental apoptosis.the erbb-2/neu oncogene is frequently over-expressed in many different tumors in humans, including those of breast and ovary. the oncogene encodes a receptor tyrosine kinase closely related to the epidermal-growth-factor receptor. we studied effects on differentiation and cell death of erbb-2/neu during mammary-gland development in transgenic mice expressing an activated, oncogenic rat erbb-2/neu gene controlled by the mammary-gland-specific promoter from mouse-mammary-tumor virus (mmtv-ltr). tr ...200010699933
tcr v(beta) repertoire restriction and lack of cdr3 conservation implicate tcr-superantigen interactions in promoting the clonal evolution of murine thymic lymphomas.thymic lymphoma development is a multistage process in which genetic and epigenetic events cooperate in the emergence of a malignant clone. the notion that signaling via tcr-ligand interactions plays a role in promoting the expansion of developing neoplastic clones is a matter of debate. to investigate this issue, we determined the tcr v(beta) repertoire of thymic lymphomas induced in akr/j mice by either endogenous retroviruses or the carcinogen, n-methyl-n-nitrosourea (mnu). both spontaneous a ...200010700461
alternative proteolytic processing of mouse mammary tumor virus superantigens.mouse mammary tumor viruses express a superantigen essential for their life cycle. it has been proposed that viral superantigens (vsags) require processing by prohormone convertases (pcs) for activity. we now observe, using a panel of mutant forms of potential pc cleavage sites and in vitro cleavage assays, that only the cs1 (position 68 to 71) and cs2 (position 169 to 172) sites are utilized by furin and pc5. other members of the convertase family that are expressed in lymphocytes are not endow ...200010708421
mouse models for breast cancer. 200010713679
mmtv-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways.the study of the mouse mammary tumor virus (mmtv) has provided important insights into the mechanisms of gene transcription regulation by steroid hormones, the mode of action of heritable super antigens and the progressive nature of neoplastic transformation in the mammary gland. here we describe the current situation with respect to the latter aspect of mmtv biology and the prospects for further advance in our understanding of breast cancer in humans that may be expected from a continued study ...200010713682
use of mmtv-wnt-1 transgenic mice for studying the genetic basis of breast cancer.wnt-1 was first identified as a protooncogene activated by viral insertion in mouse mammary tumors. transgenic expression of this gene using a mouse mammary tumor virus ltr enhancer causes extensive ductal hyperplasia early in life and mammary adenocarcinomas in approximately 50% of the female transgenic (tg) mice by 6 months of age. metastasis to the lung and proximal lymph nodes is rare at the time tumors are detected but frequent after the removal of the primary neoplasm. the potent mitogenic ...200010713683
genetic determinants of response to chemotherapy in transgenic mouse mammary and salivary tumors.several transgenic mouse tumor models were utilized to explore how specific genetic alterations affect the tumor cell response to chemotherapeutic agents in vivo. specifically, mmtv-ras transgenic mice were interbred to p53 knock-out mice to create a model for assessing the role of p53 in chemotherapeutic responses. in addition, mmtv-ras tumors were compared to mmtv-myc and mmtv-ras/myc tumors. mice of each genotype reproducibly develop mammary and/or salivary tumors, but tumor growth dynamics v ...200010713698
a stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects.we developed a new stable prostatic cell line expressing the human androgen receptor (ar) and the ar-responsive reporter gene to generate a powerful tool for investigating androgen action and for rapid screening of agonists and antagonists. the ar-deficient pc-3 cells were stably transfected with psg(5)-puro-har and pmmtv-neo-luc. after selection with puromycin and neomycin, one highly inducible clone was isolated and named palm, for pc-3-androgen receptor-luciferase-mmtv. the expression of har ...200010715537
comparison of nucleosome remodeling by the yeast transcription factor pho4 and the glucocorticoid receptor.chromatin reorganization of the pho5 and murine mammary tumor virus (mmtv) promoters is triggered by binding of either pho4 or the glucocorticoid receptor (gr), respectively. in order to compare the ability of pho4 and gr to remodel chromatin and activate transcription, hybrid promoter constructs were created by insertion of the mmtv b nucleosome sequence into the pho5 promoter and then transformed into a yeast strain expressing gr. activation of either pho4 (by phosphate depletion) or gr (by ho ...200010722753
hiv gp120 plus specific peptides are recognized in a similar manner to specific hla plus peptide by hla-restricted antigen-specific t-cell lines.hiv induces disease only following chronic activation of the immune system. other retroviruses such as the mouse mammary tumour virus (mmtv) activate a large percentage of t cells by encoding a superantigen (sag). to date there is no evidence that hiv encodes a sag. an alternative way to induce pan-activation of the immune system is by allogeneic stimulation, which occurs following transplantation. here we extend previous work which demonstrated that hivpg120 could bind peptides in a similar man ...200010733164
contribution of the intercalated adenosine at the helical junction to the stability of the gag-pro frameshifting pseudoknot from mouse mammary tumor virus.the mouse mammary tumor virus (mmtv) gag-pro frameshifting pseudoknot is an h-type rna pseudoknot that contains an unpaired adenosine (a14) at the junction of the two helical stems required for efficient frameshifting activity. the thermodynamics of folding of the mmtv vpk pseudoknot have been compared with a structurally homologous mutant rna containing a g x u to g-c substitution at the helical junction (u13c rna), and an a14 deletion mutation in that context (u13cdeltaa14 rna). dual wavelengt ...200010744025
strength and specificity of different gene promoters in oral cancer cells.gene therapy of oral cancer will require expression of genes by promoters that are both powerful and relatively tumor specific. we compared the level of expression of a reporter gene from promoters of human cytomegalovirus (cmv), sv40 virus, mouse mammary tumor virus (mmtv), human papillomaviruses (hpv) types 16 and 18, and the human multi-drug-resistance gene (mdr1), in several lines of oral cancer cells. in the oral cancer cell line 686ln the rank order of expression levels was: cmv > sv40 > h ...200010745175
selective activation of the glucocorticoid receptor by steroid antagonists in human breast cancer and osteosarcoma cells.steroid hormones regulate the transcription of numerous genes via high affinity receptors that act in concert with chromatin remodeling complexes, coactivators and corepressors. we have compared the activities of a variety of glucocorticoid receptor (gr) antagonists in breast cancer and osteosarcoma cell lines engineered to stably maintain the mouse mammary tumor virus promoter. in both cell types, gr activation by dexamethasone occurs via the disruption of mouse mammary tumor virus chromatin st ...200010748103
the mouse mammary tumor virus promoter adopts distinct chromatin structures in human breast cancer cells with and without glucocorticoid receptor.steroid receptors represent a class of transcription regulators that act in part by overcoming the often repressive nature of chromatin to modulate gene activity. the mouse mammary tumor virus (mmtv) promoter is a useful model for studying transcriptional regulation by steroid hormone receptors in the context of chromatin. the chromatin architecture of the promoter prevents the assembly of basal transcription machinery and binding of ubiquitous transcription factors. however, in human breast car ...200010751396
structure, stability and function of rna pseudoknots involved in stimulating ribosomal frameshifting.programmed -1 ribosomal frameshifting has become the subject of increasing interest over the last several years, due in part to the ubiquitous nature of this translational recoding mechanism in pathogenic animal and plant viruses. all cis-acting frameshift signals encoded in mrnas are minimally composed of two functional elements: a heptanucleotide "slippery sequence" conforming to the general form x xxy yyz, followed by an rna structural element, usually an h-type rna pseudoknot, positioned an ...200010764589
esophagogastric adenocarcinoma in an e1a/e1b transgenic model involves p53 disruption.we studied tumorigenesis and p53 immunostaining in a murine transgenic model introducing e1a/e1b under the control of the mouse mammary tumor virus-long terminal repeat (mmtv-ltr) promoter in which adenocarcinoma occurs at the squamocolumnar junction in the foregut, predominantly in males, and at no other site. mutations of p53 are frequent in human esophageal adenocarcinoma and the e1b gene product interferes with p53-mediated apoptosis, inhibiting tumor suppression at the g(1)/s checkpoint. tr ...200010769092
mouse mammary tumor virus-like env gene sequences in human breast tumors and in a lymphoma of a breast cancer patient.dna sequences with very high similarity (95-98%) to the mouse mammary tumor virus (mmtv) env gene have been amplified by pcr in 38.5% of human breast tumors and in <2% of normal breast tissue (wang et al., cancer res., 55: 5173-5179, 1995). intrigued by these findings, which suggested an exogenous viral etiology for a certain percentage of human breast tumors, we have screened a panel of human breast tumors and normal breast tissue for the presence of mmtv-like dna sequences. using similar pcr p ...200010778951
fgf4 and int2 oncogenes are amplified and expressed in kaposi's sarcoma.kaposi's sarcoma (ks) is a vascular tumor, the pathogenesis of which has been suggested to include human herpesvirus 8 (hhv-8) as well as various cytokines and growth factors. very little is known about cytogenetic and molecular genetic changes in ks. we studied dna copy number changes in ks and found a recurrent gain at 11q13. we then analyzed the amplification and expression status of two known oncogenes, fgf4 and int2, residing at 11q13. comparative genomic hybridization, interphase fluoresce ...200010786811
engineering viral promoters for gene transfer to human neuroblasts.1. the strength and activity of several viral promoters in human neuroblasts were evaluated in vitro. 2. several luciferase reporter gene constructs under the control of different viral promoters (hiv-1 ltr, htlv-i ltr, mmtv ltr, rsv ltr, cmv, sv40), in the presence or in the absence of the viral sv40 enhancer, were transfected into two well-established human neural cell lines, including one derived from human embryonic olfactory cells (b4) and one derived from an adrenal neuroblastoma (sh-sy-5y ...200010789837
a locus closely linked to mtv7 on mouse chromosome 1 influences development of acute versus chronic graft-versus-host disease in a murine model.the relationship between acute and chronic graft-versus-host disease (gvhd) is not well understood. a murine model of acute and chronic gvhd is the b6d2f1 parent-->f1 model in which transfer of c57bl/6 parental strain lymphoid cells to b6d2f1 recipients results in development of th1-mediated acute gvhd, whereas transfer of dba/2 parental strain lymphoid cells to b6d2f1 recipients results in development of th2-mediated chronic gvhd. numerous studies have investigated the reason for the differenti ...200010794427
endocrine host responses during early and late phases of tumor development.it is well established that hormones affect tumor growth. conversely, inoculation of cells obtained from tumors that had been transplanted for many generations causes changes in the concentration of different hormones before and after tumor detection. we aimed at answering the question of whether hormonal alterations also occur during the development of primary tumors and following transplantation of tumors from early generations. primary tumors were induced in mice by either the carcinogenic ag ...200010797255
synergistic action of ga-binding protein and glucocorticoid receptor in transcription from the mouse mammary tumor virus promoter.b lymphocytes are among the first cells to be infected by mouse mammary tumor virus (mmtv), and they play a crucial role in its life cycle. to study transcriptional regulation of mmtv in b cells, we have analyzed two areas of the long terminal repeat (ltr) next to the glucocorticoid receptor binding site, fp1 (at position -139 to -146 from the cap site) and fp2 (at -157 to -164). both showed b-cell-specific protection in dnase i in vitro footprinting assays and contain binding sites for ets tran ...200010799572
lack of androgen receptor transcriptional activity in human keratinocytes.since detection of androgen receptor (ar) expression in keratinocytes by immunostaining is controversial, we investigated whether keratinocytes can act as androgen target cells using transient transfection assays. chloramphenicol acetyltransferase (cat) assays for the endogenous ar transcriptional activity in hacat keratinocytes indicated that dht (10(-9)-10(-8) m) can induce less than 1.5-fold of mouse mammary tumor virus cat, which is quite low, compared with 38-fold induction by 10(-7) m 1,25 ...200010808125
glucocorticosteroids stimulate the activity of the promoters of peripheral myelin protein-22 and protein zero genes in schwann cells.to better understand the mechanism by which glucocorticosteroids (gluc) could enhance myelination in the pns, cultured rat schwann cells were transiently transfected with reporter constructs in which luciferase expression was controlled by the promoter region of either the peripheral myelin protein-22 (pmp22) or the protein zero (p(0)) genes. gluc stimulated the activity of the p(0) promoter and the pmp22 promoters 1 and 2. the effect of gluc was specific as estradiol and testosterone did not ac ...200010814728
mouse mammary tumor virus-ki-rasb transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor.for ras oncoproteins to transform mammalian cells, they must be posttranslationally modified with a farnesyl group in a reaction catalyzed by the enzyme farnesyl:protein transferase (fptase). inhibitors of fptase have therefore been developed as potential anticancer agents. these compounds reverse many of the malignant phenotypes of ras-transformed cells in culture and inhibit the growth of tumor xenografts in nude mice. furthermore, the fptase inhibitor (fti) l-744,832 causes tumor regression i ...200010825141
the oncoprotein kinase chaperone cdc37 functions as an oncogene in mice and collaborates with both c-myc and cyclin d1 in transformation of multiple tissues.cdc37 encodes a 50-kda protein that targets intrinsically unstable oncoprotein kinases including cdk4, raf-1, and v-src to the molecular chaperone hsp90, an interaction that is thought to be important for the establishment of signaling pathways. cdc37 is required for proliferation in budding yeast and is coexpressed with cyclin d1 in proliferative zones during mouse development, a finding consistent with a positive role in cell proliferation. cdc37 expression may not only be required to support ...200010825210
elevated glucocorticoid receptor transactivation and down-regulation of alpha 1 integrin are associated with loss of plasma membrane ca2+-atpase isoform 1.we have previously shown that inhibition of expression of the plasma membrane ca(2+)-atpase isoform 1 in pc6 cells leads to loss of nerve growth factor-mediated neurite extension (brandt, p.c., sisken, j.e., neve, r.l., and vanaman, t.c. (1996) proc. natl. acad. sci. u.s.a. 93, 13843-13848). cells lacking plasma membrane ca(2+)-atpase 1 did not attach to collagen-coated plates as tightly as controls, suggesting that a defect in adhesion might be underlying the inability to extend neurites. we re ...200010827194
differential regulation of testosterone vs. 5alpha-dihydrotestosterone by selective androgen response elements.there are two major physiological androgens, testosterone (t), and 5alpha-dihydrotestosterone (dht), which induce different responses in mammals. these androgens regulate the target gene transcription via binding to and activating the same androgen receptor (ar). the molecular mechanisms that differ between these two very close androgens through the same ar protein to target the distinct genomic responses remain unknown. using yeast genetic selection, we identified two kinds of androgen response ...200010839207
adaptive variation in lactate dehydrogenase-b gene expression: role of a stress-responsive regulatory element.although changes in gene regulation may play an important role in adaptive evolution, there have been few attempts to investigate the molecular mechanisms responsible for adaptively significant variation in gene expression. here we describe the mechanism underlying an adaptive difference in the expression of the lactate dehydrogenase-b gene (ldh-b) between northern and southern populations of the fish fundulus heteroclitus. ldh-b regulatory sequences from northern and southern individuals, coupl ...200010841559
[the gene of human prion: reassessment of its features and pathogenic role].after a detailed examination of some features of the human prion gene, we propose a reassessment of its role in the pathogenicity of the derived neurodegenerative diseases e.g. creutzfeldt-jakob's disease. the particular resistance of this gene towards physico-chemical agents is related to the relative abundance of the guanine and cytosine bases. other features such as the paucity of cpg sequences, gc box, polyadenylic tail, direct and inverted repeats, all evoke those of retroviral ltrs. finall ...200010844280
transcriptionally regulated adenoviruses for prostate-specific gene therapy.most virally based vectors for gene therapy contain viral promoters that are tissue-nonspecific. consequently, unintended expression of toxic therapeutic genes in normal tissues may potentially occur. we have constructed adenoviruses that contain a bacterial beta-galactosidase (beta-gal) gene (lacz) under the control of three different prostate-specific promoters: prostate-specific antigen (psa), probasin, and the mouse mammary-tumor-virus long terminal repeat (mmtv; prostate-specific ad-lacz). ...200010854143
p185(neu) protein is required for tumor and anchorage-independent growth, not for cell proliferation of transgenic mammary carcinoma.transgenic fvb-neun mice (n202) bearing the rat neu protooncogene driven by the mouse mammary tumor virus promoter/enhancer develop focal mammary carcinomas overexpressing the neu-encoded p185(neu) protein. in vitro expression of p185(neu) among mammary carcinoma cultures was heterogeneous, and we could establish some cell lines and clones displaying a complete loss of p185(neu) expression, along with others with very high p185(neu) protein level. upon in vivo injection, p185(neu)-positive cells ...200010861472
cdp is a repressor of mouse mammary tumor virus expression in the mammary gland.mouse mammary tumor virus (mmtv) transcription is highest in the lactating mammary gland but is detectable in a variety of other tissues. previous results have shown that mmtv expression is suppressed in lymphoid and other tissues through the binding of the homeodomain-containing repressor special at-rich binding protein 1 to a negative regulatory element (nre) in the mmtv long terminal repeat (ltr). another homeoprotein repressor, ccaat displacement protein (cdp), also binds to the mmtv nre, bu ...200010864645
functional analysis of the env open reading frame in human endogenous retrovirus iddmk(1,2)22 encoding superantigen activity.mice harbor a family of endogenous retroviruses, the mouse mammary tumor viruses (mmtv), which encode superantigens. these superantigens are responsible for the deletion of t cells expressing certain vbeta chains of the t-cell receptor in the thymus. human t cells are able to recognize mmtv-encoded superantigens presented by human major histocompatibility complex class ii-positive cells. owing to this and to the similarity of the human and murine immune systems, it was speculated that human endo ...200010864649
glucocorticoid regulation of mouse mammary tumor virus: identification of a short essential dna region.transcription of mouse mammary tumor virus (mmtv) dna is stimulated by steroid hormones. to determine the dna sequences involved in this regulation, we constructed a plasmid containing the mmtv long terminal repeat (ltr) in front of the coding region of the herpes simplex thymidine kinase gene, from which the promoter had been removed. portions of the ltr were removed by the nuclease ba/31, and the deleted molecules were recloned and tested for transcriptional activity in transfections of ltk-ap ...198310872340
mammary tumorigenesis through irradiation of mice. 197410874963
border patrols and secret passageways across the intestinal epithelium. 200010878756
reproductive factors are crucial in the aetiology of breast cancer. 200010883681
tumor viruses and endogenous retrotransposons in mammary tumorigenesis.much of our knowledge about the intricate pathways and molecular mechanisms involved in the conversion of a normal mammary epithelial cell to malignancy derives from studies on mammary tumorigenesis induced by the retrovirus mouse mammary tumor virus. in addition, three dna tumor viruses, simian virus 40, polyomavirus, and human papillomavirus, have been instrumental in dissecting the series of steps comprising neoplastic progression of mammary epithelium, particularly with cultured human breast ...199610887480
characterization of transiently and constitutively expressed progesterone receptors: evidence for two functional states.activated steroid receptors induce chromatin remodeling events in the promoters of some target genes. we previously reported that transiently expressed progesterone receptor (pr) cannot activate mouse mammary tumor virus (mmtv) promoter when it adopts the form of ordered chromatin. however, when expressed continuously, the pr acquires this ability. in this study we explored whether this gain of function occurs through alterations in nucleoprotein structure at the mmtv promoter or through changes ...200010894147
discrete promoter elements affect specific properties of rna polymerase ii transcription complexes.the frequency of transcription initiation at specific rna polymerase ii promoters is, in many cases, related to the ability of the promoter to recruit the transcription machinery to a specific site. however, there may also be functional differences in the properties of assembled transcription complexes that are promoter-specific or regulator-dependent and affect their activity. transcription complexes formed on variants of the adenovirus major late (adml) promoter were found to differ in several ...200010908329
cloning of an infectious milk-borne mouse mammary tumor virus (mmtv) dna from a mammary tumor that developed in an endogenous mmtv-free wild mouse.molecular characterization of infectious mouse mammary tumor viruses (mmtvs) has been hampered due to the problem of cloning a full-length exogenous virus into a plasmid. the present report describes our strategy for obtaining a full-length clone of an exogenous mmtv from a mouse mammary tumor that arose spontaneously in a wild chinese mouse free of endogenous mmtv and shows that the cloned virus (jyg-mmtv) is expressed in rat rba cells. four-week-old c58/j x cba/caj female mice, free of both en ...200010915603
cooperative induction of mammary tumorigenesis by tgfalpha and wnts.we previously reported that multiparous wap-tgfalpha transgenic mice develop mammary gland carcinomas with complete incidence. tgfalpha-induced tumors appear stochastically and with relatively long latency, indicating an additional requirement for other genetic alterations. to identify genes that cooperate with tgfalpha in mammary tumorigenesis, we used a retroviral insertion approach featuring a cloned and infectious hybrid mmtv (c3h/mtv-1; (shackleford and varmus, 1988)). tumor latency was dec ...200010918574
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