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fk506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor a isoform.fk506-binding protein 52 (fkbp52) is a tetratricopeptide repeat protein that associates with steroid receptors in complexes containing heat shock protein 90. to investigate the role of fkbp52 in steroid-regulated physiology, we generated fkbp52-deficient mice. fkbp52 (-/-) females are sterile due to a complete failure of implantation, a process that requires estrogen (er) and progesterone receptors (pr). because the uterus expresses two forms of pr, pr-a and pr-b, we investigated all three recep ...200616873445
kit and pdgfr-alpha activities are necessary for notch4/int3-induced tumorigenesis.transgenic mice overexpressing notch4 intracellular domain (int3) under the control of the whey acidic protein (wap) or mouse mammary tumor virus-long terminal repeat promoters, develop mammary tumors. microarray analysis of these tumors revealed high levels of c-kit expression. gleevec is a tyrosine kinase inhibitor that targets c-kit, platelet-derived growth factor receptors (pdgfrs) and c-abl. this led us to speculate that tyrosine kinase receptor activity might be a driving force in the deve ...200716878155
structurally distinct ligand-binding or ligand-independent notch1 mutants are leukemogenic but affect thymocyte development, apoptosis, and metastasis differently.we previously found that provirus insertion in t cell tumors of mouse mammary tumor virus/c-myc transgenic (tg) mice induced two forms of notch1 mutations. type i mutations generated two truncated molecules, one intracellular (ic) (notch1(ic)) and one extracellular (notch1(ec)), while in type ii mutations notch1 was deleted of its c terminus (notch1(deltact)). we expressed these mutants in tg mice using the cd4 promoter. both notch1(ic) and notch1(deltact), but not notch1(ec), tg mice developed ...200616887975
determination of androgen bioactivity in human serum samples using a recombinant cell based in vitro bioassay.the present study describes the development and optimization of a cell-based reporter assay for the determination of androgen bioactivity levels in human serum samples. towards this end, human embryonic kidney (hek) 293 cells were cotransfected with two plasmids, one encoding the mouse mammary tumor virus (mmtv)-driven luciferase reporter gene and the other the sv40 promoter-driven human androgen receptor (ar), and a stable cell line, expressing human ar and androgen-responsive luciferase was es ...200616893644
epithelial-specific and stage-specific functions of insulin-like growth factor-i during postnatal mammary development.postnatal development of the mammary gland requires interactions between the epithelial and stromal compartments, which regulate actions of hormones and growth factors. igf-i is expressed in both epithelial and stromal compartments during postnatal development of the mammary gland. however, little is known about how local expression of igf-i in epithelium or stroma regulates mammary growth and differentiation during puberty and pregnancy-induced alveolar development. the goal of this study was t ...200616901968
an immunoreceptor tyrosine activation motif in the mouse mammary tumor virus envelope protein plays a role in virus-induced mammary tumors.mouse mammary tumor virus (mmtv) induces breast cancer with almost 100% efficiency in susceptible strains through insertional activation of protooncogenes, such as members of the wnt and fibroblast growth factor (fgf) families. we previously showed that expression of the mmtv envelope protein (env) in normal immortalized mammary epithelial cells grown in three-dimensional cultures caused their morphological transformation, and that this phenotype depended on an immunoreceptor tyrosine-based acti ...200616940512
cross-talk of wnt and fgf signaling pathways at gsk3beta to regulate beta-catenin and snail signaling cascades.wnt and fgf signaling pathways cross-talk during a variety of cellular processes, such as human colorectal carcinogenesis, mouse mammary tumor virus (mmtv)-induced carcinogenesis, e2a-pbx-induced leukemogenesis, early embryogenesis, body-axis formation, limb-bud formation, and neurogenesis. canonical wnt signals are transduced through frizzled receptor and lrp5/6 coreceptor to downregulate gsk3beta (gsk3b) activity not depending on ser 9 phosphorylation. fgf signals are transduced through fgf re ...200616940750
gadd45a suppresses ras-driven mammary tumorigenesis by activation of c-jun nh2-terminal kinase and p38 stress signaling resulting in apoptosis and senescence.the gadd45 family of proteins is known to play a central role as cellular stress sensors that modulate the response of mammalian cells to stress inflicted by physiologic and environmental stressors. gadd45a was shown to be a direct target to the p53 and brca1 tumor suppressor genes, whose loss of function is known to play a vital role in breast carcinogenesis; however, the role of gadd45a in the suppression of breast cancer remains unclear. to address this issue, gadd45a-deficient mice were cros ...200616951155
comparison of the specificity of interaction of cellular and viral zinc-binding domains with 2-mercaptobenzamide thioesters.the interactions of two 2-mercaptobenzamide thioester compounds with six diverse zinc-binding domains (zbds) have been analyzed by uv/visible spectroscopy, nmr spectroscopy, and nucleic acid binding assays. these thioester compounds serve as useful tools for probing the intrinsic chemical stability of zbds that exist within a variety of cellular and viral proteins. in our studies, the classical (cys(2)his(2)) zinc finger zbds, the interleaved ring like zbds of protein kinase c delta (cys(2)hiscy ...200616953638
selection of early-occurring mutations dictates hormone-independent progression in mouse mammary tumor lines.mice harboring three mouse mammary tumor virus (mmtv) variants develop pregnancy-dependent (pd) tumors that progress to pregnancy-independent (pi) behavior through successive passages. herein, we identified 10 predominant insertions in pi transplants from 8 independent tumor lines. these mutations were also detected in small cell populations in the early pd passages. in addition, we identified a new viral insertion upstream of the gene rspo3, which is overexpressed in three of the eight independ ...200616971449
differentiation-induced cleavage of cutl1/cdp generates a novel dominant-negative isoform that regulates mammary gene expression.cutl1/ccaat displacement protein (cdp) is a transcriptional repressor of mouse mammary tumor virus (mmtv), a betaretrovirus that is a paradigm for mammary-specific gene regulation. virgin mammary glands have high levels of full-length cdp (200 kda) that binds to negative regulatory elements (nres) to repress mmtv transcription. during late pregnancy, full-length cdp levels decline, and a 150-kda form of cdp (cdp150) appears concomitantly with a decline in dna-binding activity for the mmtv nres a ...200617015474
transgenic mice expressing the p75 ccaat-displacement protein/cut homeobox isoform develop a myeloproliferative disease-like myeloid leukemia.the p75 ccaat-displacement protein/cut homeobox (cdp/cux) isoform was previously reported to be overexpressed in human breast cancers. to investigate its oncogenic potential, we engineered two transgenic mouse lines expressing p75 cdp/cux under the control of the mouse mammary tumor virus-long terminal repeat. the fvb strain of mouse is generally used in the generation of mouse models for breast cancer. the transgene was introduced into the hprt locus of 129/ola embryonic stem cells and, followi ...200617018605
a common polymorphism in the mineralocorticoid receptor modulates stress responsiveness.mineralocorticoid receptors (mr) mediate the action of aldosterone on sodium resorption in kidney tubular cells, but in brain they respond to the glucocorticoid cortisol in stress regulation and cognitive processes.200617018659
the combination of the rexinoid, lg100268, and a selective estrogen receptor modulator, either arzoxifene or acolbifene, synergizes in the prevention and treatment of mammary tumors in an estrogen receptor-negative model of breast cancer.we tested whether a selective estrogen receptor modulator (serm) and a rexinoid are active for prevention and treatment in the mouse mammary tumor virus-neu mouse model of estrogen receptor-negative breast cancer.200617020999
expression of constitutively active notch1 in male genital tracts results in ectopic growth and blockage of efferent ducts, epididymal hyperplasia and sterility.the notch signaling pathway is involved in a variety of developmental processes. here, we characterize the phenotypes developing in the reproductive organs of male transgenic (tg) mice constitutively expressing the activated mouse notch1 intracellular domain (notch1(intra)) under the regulatory control of the mouse mammary tumor virus (mmtv) long terminal repeat (ltr). tg expression was detected in testis, vas deferens and epididymis by northern blot analysis. in situ hybridization with a notch1 ...200617046738
stromal and epithelial caveolin-1 both confer a protective effect against mammary hyperplasia and tumorigenesis: caveolin-1 antagonizes cyclin d1 function in mammary epithelial cells.here, we investigate the role of caveolin-1 (cav-1) in breast cancer onset and progression, with a focus on epithelial-stromal interactions, ie, the tumor microenvironment. cav-1 is highly expressed in adipocytes and is abundant in mammary fat pads (stroma), but it remains unknown whether loss of cav-1 within mammary stromal cells affects the differentiated state of mammary epithelia via paracrine signaling. to address this issue, we characterized the development of the mammary ductal system in ...200617071600
development of leiomyosarcoma of the uterus in mmtv-cr-1 transgenic mice.overexpression of cripto-1 (cr-1) in fvb/n mice using the mmtv-ltr promoter results in increased mammary tumourigenesis in these female transgenic mice (mmtv-cr-1). here, we characterize uterine tumours that developed in 15/76 (19.7%) of mmtv-cr-1 female nulliparous or multiparous mice during 24 months of observation compared with 0/33 (0%) of fvb/n normal control mice observed during the same time period (p < 0.01). the uterine tumours collected from the mmtv-cr-1 mice were classified as leiomy ...200717072826
induction of progesterone target genes requires activation of erk and msk kinases and phosphorylation of histone h3.how genes are regulated in the context of chromatin is a central question of biology. steroid hormones control gene expression via interaction of their receptors with target sequences on dna but can also activate cytoplasmic signaling cascades. here we report that rapid erk activation by progestins participates in induction of target genes by preparing the chromatin for transcription. five minutes after hormone treatment, erk activation leads to phosphorylation of the progesterone receptor (pr), ...200617081988
activin and glucocorticoids synergistically activate follicle-stimulating hormone beta-subunit gene expression in the immortalized lbetat2 gonadotrope cell line.fsh is produced by the pituitary gonadotrope to regulate gametogenesis. production of the beta-subunit of fsh is the rate-limiting step in fsh synthesis, and a number of peptide and steroid hormones within the reproductive axis have been found to regulate transcription of the fsh beta-subunit gene. although both activin and glucocorticoids are notable regulators of fshbeta by themselves, we find that cotreatment results in a synergistic interaction on the mouse fshbeta promoter at the level of t ...200717082263
introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models.we have adapted the avian leukosis virus rcas (replication-competent avian sarcoma-leukosis virus ltr splice acceptor)-mediated somatic gene transfer technique to introduce oncogenes into mammary cells in mice transgenic for the avian subgroup a receptor gene, tva, under control of the mouse mammary tumor virus (mmtv) promoter. intraductal instillation of an rcas vector carrying the polyoma middle t antigen (pymt) gene (rcas-pymt) induced multiple, oligoclonal tumors within 3 weeks in infected m ...200617090666
wnt-1 is dominant over neu in specifying mammary tumor expression profiles.wnt-1 and neu collaborate to induce mammary tumors in bitransgenic mice carrying both mmtv-wnt-1 and mmtv-neu. in this report, gene expression profiles were determined for tumors from these bitransgenic mice, and compared with expression profiles of tumors from mice singly transgenic for mmtv-wnt-1 or mmtv-neu. while very different from tumors arising in mmtv-neu transgenic mice, tumors from these bitransgenic mice were found not to have identifiable differences from tumors from mmtv-wnt-1 trans ...200617121432
immune response to mmtv infection.mouse mammary tumor virus (mmtv) has developed a strategy of exploitation of the immune response. it infects dendritic cells and b cells and requires this infection to establish an efficient chronic infection. this allows transmission of infection to the mammary gland, production in milk and infection of the next generation via lactation. the elaborate strategy developed by mmtv utilizes several key elements of the normal immune response. starting with the infection and activation of dendritic c ...200717127406
endogenous mmtv proviruses induce susceptibility to both viral and bacterial pathogens.most inbred mice carry germline proviruses of the retrovirus, mouse mammary tumor virus (mmtv) (called mtvs), which have multiple replication defects. a balb/c congenic mouse strain lacking all endogenous mtvs (mtv-null) was resistant to mmtv oral and intraperitoneal infection and tumorigenesis compared to wild-type balb/c mice. infection of mtv-null mice with an mmtv-related retrovirus, type b leukemogenic virus, also resulted in severely reduced viral loads and failure to induce t-cell lymphom ...200617140288
stem cells and mammary cancer in mice.i have used the paradigm of mammary cancer induction by the mouse mammary tumor virus (mmtv) to illustrate the body of evidence that supports the hypothesis that mammary epithelial stem/progenitor cells represent targets for oncogenic transformation. further, it is argued that this is not a special case applicable only to mmtv-induced mammary cancer, because mmtv acts as an environmental mutagen producing random interruptions in the somatic dna of infected cells by insertion of proviral dna copi ...200517142858
rank overexpression in transgenic mice with mouse mammary tumor virus promoter-controlled rank increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formation in cultured epithelial acini.rank and rankl, the key regulators of osteoclast differentiation and activation, also play an important role in the control of proliferation and differentiation of mammary epithelial cells during pregnancy. here, we show that rank protein expression is strictly regulated in a spatial and temporal manner during mammary gland development. rank overexpression under the control of the mouse mammary tumor virus (mmtv) promoter in a transgenic mouse model results in increased mammary epithelial cell p ...200717145767
mouse mammary tumour-like virus gene sequences and specific breast cancer morphology. 200717158634
osmotic stress-dependent repression is mediated by histone h3 phosphorylation and chromatin structure.histone h3 phosphorylation has been linked to various environmental stress responses and specific chromatin structure. the role of h3 phosphorylation in the osmotic stress response was investigated on the mouse mammary tumor virus (mmtv) promoter in different chromatin configurations. hormone-dependent transcription from the mmtv promoter is repressed by osmotic stress when the promoter is integrated and has a normal chromatin structure. however, when the mmtv promoter is transiently transfected ...200717158874
chromatin-dependent cooperativity between site-specific transcription factors in vivo.accessing binding sites in dna wrapped around histones in condensed chromatin is an obstacle that transcription factors must overcome to regulate gene expression. here we demonstrate cooperativity between two transcription factors, the glucocorticoid receptor (gr) and nuclear factor 1 (nf1) to bind the mouse mammary tumor virus promoter organized as regular chromatin in vivo. this cooperativity is not observed when the promoter is introduced transiently into cells. using rna interference to depl ...200717186943
ligand-specific dynamics of the androgen receptor at its response element in living cells.androgens have key roles in normal physiology and in male sexual differentiation as well as in pathological conditions such as prostate cancer. androgens act through the androgen receptor (ar), which is a ligand-modulated transcription factor. antiandrogens block ar function and are widely used in disease states, but little is known about their mechanism of action in vivo. here, we describe a rapid differential interaction of ar with target genomic sites in living cells in the presence of agonis ...200717189428
prevention of mammary tumorigenesis by intermittent caloric restriction: does caloric intake during refeeding modulate the response?chronic caloric restriction (ccr) prevents mammary tumorigenesis in rodents, but a protective effect for intermittent caloric restriction (icr) is less well documented. we recently reported that icr reduced mammary tumor (mt) incidence of mouse mammary tumor virus-transforming growth factor (mmtv-tgf)-alpha mice to a greater extent than did ccr. here, we repeated this protocol and obtained serum and tissue samples. ad libitum (al) mmtv-tgf-alpha mice were fed ain-93m diet. beginning at 10 weeks ...200717202587
mechanism of histone h1-stimulated glucocorticoid receptor dna binding in vivo.xenopus oocytes lack somatic linker histone h1 but contain an oocyte-specific variant, b4. the glucocorticoid receptor (gr) inducible mouse mammary tumor virus (mmtv) promoter was reconstituted in xenopus oocytes to address the effects of histone h1. the expression of xenopus h1o [corrected] (h1) via cytoplasmic mrna injection resulted in h1 incorporation into in vivo assembled chromatin based on (i) the appearance of a chromatosome stop, (ii) the increased nucleosome repeat length (nrl), and (i ...200717210632
transcriptional cooperation between the transforming growth factor-beta and wnt pathways in mammary and intestinal tumorigenesis.transforming growth factor-beta (tgf-beta) and wnt ligands function in numerous developmental processes, and alterations of both signaling pathways are associated with common pathologic conditions, including cancer. to obtain insight into the extent of interdependence of the two signaling cascades in regulating biological responses, we used an oligonucleotide microarray approach to identify wnt and tgf-beta target genes using normal murine mammary gland epithelial cells as a model. combination t ...200717210685
bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression.genes that modify oncogenesis may influence dormancy versus progression in cancer, thereby affecting clinical outcomes. the bin1 gene encodes a nucleocytosolic adapter protein that interacts with and suppresses the cell transforming activity of myc. bin1 is often attenuated in breast cancer but its ability to negatively modify oncogenesis or progression in this context has not been gauged directly. in this study, we investigated the effects of mammary gland-specific deletion of bin1 on initiatio ...200717210688
akt1 ablation inhibits, whereas akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (mmtv)-erbb2/neu and mmtv-polyoma middle t transgenic mice.ample evidence to date links the phosphatidylinositol 3-kinase-regulated protein kinase akt with the induction and progression of human cancer, including breast cancer. however, there are three akt isoforms with limited information about their specificity during oncogenesis. this study addresses the role of the three isoforms in polyoma middle t (pymt) and erbb2/neu-driven mammary adenocarcinomas in mice. the effects of ablation of akt1, akt2, and akt3 on the induction and the biology of these t ...200717210696
imaging tumors with an albumin-binding fab, a novel tumor-targeting agent.association with albumin as a means to improve biodistribution and tumor deposition of a fab was investigated using ab.fab4d5, a bifunctional molecule derived from trastuzumab (herceptin) capable of binding albumin and tumor antigen her2 (erbb2) simultaneously. ab.fab4d5 was compared with trastuzumab and a trastuzumab-derived fab (fab4d5) for the ability to target tumors overexpressing her2 in mouse mammary tumor virus/her2 allograft models. biodistribution was monitored using intravital microsc ...200717210705
inhibition of estrogen-induced mammary tumor formation in mmtv-aromatase transgenic mice by 4-chlorophenylacetate.treatment of estrogen-sensitive breast cancer with selective estrogen selective modulators (serms) and, more recently, aromatase inhibitors has met with wide success. however, antagonism of estrogen receptor (er) activity in breast carcinomas by serms such as tamoxifen has been associated with increased risk of cancer in other tissue such as the endometrium. furthermore, current therapies using aromatase inhibitors have side effects on bone resulting in development of osteoporosis in some patien ...200717215075
dynamic histone acetylation/deacetylation with progesterone receptor-mediated transcription.histone acetylation is a highly dynamic posttranslational modification that plays an important role in gene expression. previous work showed that promoter histone deacetylation is accompanied by progesterone receptor (pr)-mediated activation of the mouse mammary tumor virus (mmtv) promoter. we investigated the role of this deacetylation and found that this histone deacetylation is not a singular event. in fact, histone acetylation at the mmtv promoter is highly dynamic, with an initial increase ...200717227884
aly is a common coactivator of runx1 and c-myb on the type b leukemogenic virus enhancer.type b leukemogenic virus (tblv), a mouse mammary tumor virus (mmtv) variant, often induces t-cell leukemias and lymphomas by c-myc activation following viral dna integration. transfection assays using a c-myc reporter plasmid indicated that the tblv long terminal repeat (ltr) enhancer is necessary for t-cell-specific increases in basal reporter activity. the sequence requirements for this effect were studied using mutations of the 62-bp enhancer region in an mmtv ltr reporter vector. deletion o ...200717229714
[study of mouse mammary tumor virus-like gene sequences expressing in breast tumors of chinese women].to analyse the expression of mouse mammary tumor virus-like (mmtv-like) gene sequencesin breast cancer of chinese women.200617236577
apobec3 inhibits mouse mammary tumour virus replication in vivo.genomes of all mammals encode apobec3 genes, which are thought to have a function in intrinsic cellular immunity to several viruses including human immunodeficiency virus type 1 (hiv-1). apobec3 (a3) proteins are packaged into virions and inhibit retroviral replication in newly infected cells, at least in part by deaminating cytidines on the negative strand dna intermediates. however, the role of a3 in innate resistance to mouse retroviruses is not understood. here we show that a3 functions duri ...200717259974
chromatin remodeling and control of cell proliferation by progestins via cross talk of progesterone receptor with the estrogen receptors and kinase signaling pathways.transcription from the mouse mammary tumor virus (mmtv) promoter can be induced by glucocorticoids or progestins. progesterone treatment of cultured cells carrying an integrated single copy of an mmtv transgene leads to recruitment of progesterone receptor (pr), swi/snf, and snf2h-related complexes to mmtv promoter. recruitment is accompanied by selective displacement of histones h2a and h2b from the nucleosome b. in nucleosomes assembled on promoter sequences, swi/snf displaces histones h2a and ...200617261755
critical role of dendritic cells in mouse mammary tumor virus in vivo infection.mouse mammary tumor virus (mmtv) is a milk-transmitted betaretrovirus that causes mammary tumors in mice. although mammary epithelial cells are the ultimate targets of mmtv, the virus utilizes components of the host immune system to establish infection. previous studies indicated that dendritic cells play a role in mmtv infection. here we show that dendritic cells are the first cells to be infected by mmtv in vivo and that they are capable of producing infectious virus that can be transmitted to ...200717267484
sequence-dependent nucleosome structure and stability variations detected by förster resonance energy transfer.nucleosomes, the basic unit of eukaryotic chromosome structure, cover most of the dna in eukaryotes, including regulatory sequences. here, a recently developed förster resonance energy transfer approach is used to compare structure and stability features of sea urchin 5s nucleosomes and nucleosomes reconstituted on two promoter sequences that are nucleosomal in vivo, containing the yeast gal10 tata or the major transcription response elements from the mouse mammary tumor virus promoter. all thre ...200717269656
constitutive activation of smoothened (smo) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia.the hedgehog signaling network regulates pattern formation, proliferation, cell fate and stem/progenitor cell self-renewal in many organs. altered hedgehog signaling is implicated in 20-25% of all cancers, including breast cancer. we demonstrated previously that heterozygous disruption of the gene encoding the patched-1 (ptch1) hedgehog receptor, a negative regulator of smoothened (smo) in the absence of ligand, led to mammary ductal dysplasia in virgin mice. we now show that expression of activ ...200717287253
human int6 interacts with mcm7 and regulates its stability during s phase of the cell cycle.the mouse int6 gene is a frequent integration site of the mouse mammary tumor virus and int6 silencing by rna interference in hela cells causes an increased number of cells in the g2/m phases of the cell cycle, along with mitotic defects. in this report, we investigated the functional significance of the interaction between int6 and mcm7, which was observed in a two-hybrid screen performed with int6 as bait. it was found that proteasome inhibition strengthens interaction between both proteins an ...200717310990
sumoylation and proteasomal activity determine the transactivation properties of the mineralocorticoid receptor.mr is a hormone-activated transcription factor that carries a strong synergy inhibitory function at its n-terminus. using this region as bait in a yeast two-hybrid screening, we isolated major components of the sumoylation pathway, including the sumo-1-conjugating enzyme ubc9, and sumo-1 itself. we found that mr interacts with both, ubc9 and sumo-1 in mammalian cells, and that the receptor is sumoylated at four acceptor sites which are clustered within its af-1 domain. we observed that mr can be ...200717314004
an active nuclear retention signal in the glucocorticoid receptor functions as a strong inducer of transcriptional activation.the glucocorticoid receptor (gr) cycles between a naive chaperone-complexed form in the cytoplasm and a transcriptionally active steroid-bound nuclear form. nuclear import of gr occurs rapidly and is mediated through the importin alpha/beta karyopherin import pathway. by contrast, nuclear export of gr occurs only slowly under most conditions, despite a dependence on active signaling. in this study we have defined a nuclear retention signal (nrs) in the hinge region of gr that actively opposes th ...200717314103
hyperproduction of hyaluronan in neu-induced mammary tumor accelerates angiogenesis through stromal cell recruitment: possible involvement of versican/pg-m.elevated concentrations of hyaluronan are often associated with human breast cancer malignancy. here, we investigated the roles of hyaluronan in carcinogenesis and cancer progression using the mouse mammary tumor virus (mmtv)-neu transgenic model of spontaneous breast cancer. conditional transgenic mice that express murine hyaluronan synthase 2 (has2) by cre-mediated recombination were generated and crossed with the mmtv-neu mice. in expressing cre recombinase under the control of the mmtv promo ...200717322391
mammalian tumor suppressor int6 specifically targets hypoxia inducible factor 2 alpha for degradation by hypoxia- and pvhl-independent regulation.the hypoxia-inducible factors hif-1 alpha and hif-2 alpha are structurally similar as regards their dna-binding and dimerization domains, but differ in their transactivation domains and, as is shown by experiments using hif-1 alpha(-/-) and hif-2 alpha(-/-) mice, in their functions. this implies that hif-1 alpha and hif-2 alpha may have unique target genes. to address this discrepancy and identify hif-2 alpha-specific target genes, we performed yeast two-hybrid analysis and identified the tumor ...200717324924
protein-tyrosine phosphatase 1b is required for her2/neu-induced breast cancer.the protein-tyrosine phosphatase 1b (ptp1b; ptpn1) is an important regulator of mammalian metabolism and also helps control signaling by growth factors, cytokines, and extracellular matrix. gene knockout studies in mice established ptp1b as a key negative regulator of the insulin and leptin receptors. experiments using ptp1b(-/-) fibroblast lines, dominant-negative mutants, or small interfering rnas indicate that ptp1b contributes to dephosphorylation of the epidermal growth factor receptor and ...200717347513
fhit expression protects against her2-driven breast tumor development: unraveling the molecular interconnections.the tumor suppressor gene fhit is inactivated by genetic and epigenetic changes, i.e., loss of heterozygosity or promoter hypermethylation, in common human cancers. we recently showed that fhit protein levels can be regulated by fhit proteasome degradation mediated by egf-dependent activation of egfr family members, including her2, whose overexpression is linked to poor prognosis in breast cancer. analysis of a series of 384 human primary breast carcinomas revealed low/absent fhit protein levels ...200717374991
tumors initiated by constitutive cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression.cyclin d1/cyclin-dependent kinase 2 (cdk2) complexes are present at high frequency in human breast cancer cell lines, but the significance of this observation is unknown. this report shows that expression of a cyclin d1-cdk2 fusion protein under the control of the mouse mammary tumor virus (mmtv) promoter results in mammary gland hyperplasia and fibrosis, and mammary tumors. cell lines isolated from mmtv-cyclin d1-cdk2 (mmtv-d1k2) tumors exhibit rb and p130 hyperphosphorylation and up-regulation ...200717409420
inhibition of tgf-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression.we investigated whether tgf-beta induced by anticancer therapies accelerates tumor progression. using the mmtv/pyvmt transgenic model of metastatic breast cancer, we show that administration of ionizing radiation or doxorubicin caused increased circulating levels of tgf-beta1 as well as increased circulating tumor cells and lung metastases. these effects were abrogated by administration of a neutralizing pan-tgf-beta antibody. circulating polyomavirus middle t antigen-expressing tumor cells did ...200717415413
mouse mammary tumor biology: a short history.for over a century, mouse mammary tumor biology and the associated mouse mammary tumor virus (mmtv) have served as the foundation for experimental cancer research, in general, and, in particular, experimental breast cancer research. spontaneous mouse mammary tumors were the basis for studies of the natural history of neoplasia, oncogenic viruses, host responses, endocrinology, and neoplastic progression. however, lacking formal proof of a human mammary tumor virus, the preeminence of the mouse m ...200717433908
proteasome activity modulates chromatin modifications and rna polymerase ii phosphorylation to enhance glucocorticoid receptor-mediated transcription.the 26s proteasome modulates steroid hormone receptor-dependent gene transcription at least in part by regulating turnover and recycling of receptor/transcriptional dna complexes, thereby ensuring continued hormone response. for the glucocorticoid receptor (gr), inhibition of proteasome-mediated proteolysis or rna interference-mediated depletion of specific proteasome subunits results in an increase in gene expression. to facilitate transcription, proteasome inhibition alters at least two featur ...200717438138
properties of nucleosomes in acetylated mouse mammary tumor virus versus 5s arrays.acetylation is one of the most abundant histone modifications found in nucleosomes. although such modifications are thought to function mainly in recognition, acetylation is known to produce nucleosome structural alterations. these could be of functional significance in vivo. here, the basic features of mouse mammary tumor virus (mmtv) promoter nucleosomal arrays reconstituted with highly acetylated histones prepared from butyrate-treated hela cells are characterized by atomic force microscopy. ...200717444617
mmtv insertional mutagenesis identifies genes, gene families and pathways involved in mammary cancer.we performed a high-throughput retroviral insertional mutagenesis screen in mouse mammary tumor virus (mmtv)-induced mammary tumors and identified 33 common insertion sites, of which 17 genes were previously not known to be associated with mammary cancer and 13 had not previously been linked to cancer in general. although members of the wnt and fibroblast growth factors (fgf) families were frequently tagged, our exhaustive screening for mmtv insertion sites uncovered a new repertoire of candidat ...200717468756
search for dna of exogenous mouse mammary tumor virus-related virus in human breast cancer samples.earlier reports of a human exogenous retrovirus (hmtv) related closely to mouse mammary tumor virus (mmtv) led us to search for these viral sequences in breast cancer tissues and normal tissues. a real-time pcr was developed based on mmtv and published hmtv envelope sequences. the real-time pcr method can detect one to ten copies of mmtv target dna. tissue samples were collected prospectively from 18 breast cancer patients and 11 non-malignant control cases, as well as peripheral blood leukocyte ...200717485542
neu-mediated phosphorylation of protein tyrosine phosphatase epsilon is critical for activation of src in mammary tumor cells.the receptor-type protein tyrosine phosphatase epsilon (rptpepsilon) activates c-src in mammary tumor cells induced in vivo by neu. tumor cells lacking rptpepsilon exhibit reduced c-src activity, appear less transformed morphologically and proliferate slower in vitro and in vivo. expression of src rescues most of these phenotypes, indicating that c-src activity is important for maintaining the transformed phenotype. however, the molecular mechanisms that control activation of c-src by rptpepsilo ...200717486066
effects of brca1 transgene expression on murine mammary gland development and mutagen-induced mammary neoplasia.to characterize the role of brca1 in mammary gland development and tumor suppression, a transgenic mouse model of brca1 overexpression was developed. using the mouse mammary tumor virus (mmtv) promoter/enhancer, transgenic mice expressing human brca1 or select mutant controls were generated. transgenic animals examined during adolescence were shown to express the human transgene in their mammary glands. the mammary glands of 13-week-old virgin homozygous mmtv-brca1 mice presented the morphology ...200717505536
recirculating cd4 memory t cells mount rapid secondary responses without major contributions from follicular cd4 effectors and b cells.for weeks after primary immunization with thymus-dependent antigens the responding lymph nodes contain effector cd4 t cells in t zones and germinal centers as well as recirculating memory t cells. conversely, remote nodes, not exposed to antigen, only receive recirculating memory cells. we assessed whether lymph nodes with follicular effector cd4 t cells in addition to recirculating memory cd4 t cells mount a more rapid secondary response than nodes that only contain recirculating memory cells. ...200717506034
androgen receptor co-activator hic-5/ara55 as a molecular regulator of androgen sensitivity in dermal papilla cells of human hair follicles.androgen site-specifically affects human hair growth after puberty through androgen receptors in the dermal papilla, which transactivate target genes acting in conjunction with co-activators. to examine the regulation of androgen sensitivity in hair follicles, we focused on androgen receptor co-activator hic-5/ara55. its interaction with transfected androgen receptor in beard dermal papilla cells was confirmed with mammalian two-hybrid assays. the semiquantitative reverse transcriptase-polymeras ...200717508020
female mice are more susceptible to developing inflammatory disorders due to impaired transforming growth factor beta signaling in salivary glands.transforming growth factor beta (tgfbeta) plays a key role in the onset and resolution of autoimmune diseases and chronic inflammation. the aim of this study was to delineate the precise function of tgfbeta signaling in salivary gland inflammation.200717530708
endothelial akt signaling is rate-limiting for rapamycin inhibition of mouse mammary tumor progression.chronic activation of akt signaling in the endothelium recapitulates the salient features of a tumor vasculature and can be inhibited by rapamycin, an inhibitor of mammalian target of rapamycin. this led to the hypothesis that the antitumor efficacy of rapamycin may be partially dependent on its ability to inhibit endothelial akt signaling, making rapamycin an antiangiogenic agent and endothelial akt pathway inhibitor. dose-response studies with rapamycin showed that primary human endothelial ce ...200717545582
the soluble wnt receptor frizzled8crd-hfc inhibits the growth of teratocarcinomas in vivo.wnt signaling is important for normal cell proliferation and differentiation, and mutations in pathway components are associated with human cancers. recent studies suggest that altered wnt ligand/receptor interactions might also contribute to human tumorigenesis. therefore, agents that antagonize wnt signaling at the extracellular level would be attractive therapeutics for these cancers. we have generated a soluble wnt receptor comprising the frizzled8 cysteine-rich domain (crd) fused to the hum ...200717545618
independent and complementary methods for large-scale structural analysis of mammalian chromatin.the fundamental building block of chromatin, the nucleosome, occupies 150 bp of dna in a spaced arrangement that is a primary determinant in regulation of the genome. the nucleosomal organization of some regions of the human genome has been described, but mapping of these regions has been limited to a few kilobases. we have explored two independent and complementary methods for the high-throughput analysis of mammalian chromatin structure. through adaptations to a protocol used to map yeast chro ...200717568008
secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment.pleiotrophin (ptn, ptn) is an 18-kda secretory cytokine expressed in many breast cancers; however, the significance of ptn expression in breast cancer has not been established. we have now tested three models to determine the role of inappropriate expression of ptn in breast cancer. mouse mammary tumor virus (mmtv) promoter-driven ptn expressed in mmtv-polyoma virus middle t antigen (pymt)-ptn mouse breast cancers was first shown to induce rapid growth of morphologically identified foci of "scir ...200717578909
subcellular localization modulates activation function 1 domain phosphorylation in the androgen receptor.although the steady-state distribution of the androgen receptor (ar) is predominantly nuclear in androgen-treated cells, androgen-bound ar shuttles between the nucleus and the cytoplasm. in the present study we have addressed how nucleocytoplasmic shuttling contributes to the regulation of ar. nuclear transport signal fusions were used to force ar localization to the nucleus or cytoplasm of prostate cancer cells, and the effect of localization on shuttling, transcription, androgen binding, and p ...200717579212
retroviral transduction of dt40.retroviral transduction of dt40 provides an easy way to obtain population of cells stably expressing a transgene without causing cellular stress or the levels of cell death seen in transfection protocols. by employing moloney murine leukemia virus based constructs and pseudotyping the viral particles with vsv envelope glycoprotein, it is a highly efficient procedure, routinely resulting in transgene expression in the majority of cells. it is also rapid. from production of the transgene-containin ...200617623925
no evidence of human papillomavirus dna sequences in invasive breast carcinoma.breast cancer is one of the most frequently diagnosed cancers in women in france, but its aetiology remains unknown. viruses including epstein-barr virus (ebv), a human equivalent of murine mammary tumour virus (mmtv) and human papillomavirus (hpv) have been detected in benign breast tissues and breast tumours and are considered to be involved in the aetiology of breast cancer. the aim of this study was to determine the prevalence of high-risk oncogenic hpvs in breast carcinoma from french patie ...200817624590
expression of truncated int6/eif3e in mammary alveolar epithelium leads to persistent hyperplasia and tumorigenesis.int6 has been shown to be an interactive participant with the protein translation initiation complex eif3, the cop9 signalosome and the regulatory lid of the 26s proteasome. insertion of mouse mammary tumor virus into the int6 locus creates a c-terminally truncated form of the protein. expression of the truncated form of int6 (int6sh) in stably transfected human and mouse mammary epithelial cell lines leads to cellular transformation. in addition, decreased expression of int6/eif3e is observed i ...200717626637
a novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance.generalized glucocorticoid resistance is a rare condition characterized by partial, end-organ insensitivity to glucocorticoids, compensatory elevations in adrenocorticotropic hormone and cortisol secretion, and increased production of adrenal steroids with androgenic and/or mineralocorticoid activity. we have identified a new case of glucocorticoid resistance caused by a novel mutation of the human glucocorticoid receptor (hgr) gene and studied the molecular mechanisms through which the mutant r ...200717635946
promotion of breast cancer by beta-hexachlorocyclohexane in mcf10at1 cells and mmtv-neu mice.exposure to beta-hexachlorocyclohexane (beta-hch), a contaminant of the hexachlorohexane pesticide lindane, has been implicated as a risk factor in the development of breast cancers in epidemiological studies. previous studies in our laboratory have demonstrated the ability of beta-hch to elicit its actions via a ligand-independent activation of the estrogen receptor through increased c-neu (= erbb2 or her-2) expression and kinase activation in both the bg-1 and mcf-7 cell lines. in addition, lo ...200717640349
viruses and human breast cancer.there are well-established risk factors for breast cancer, most of which relate to estrogens and growth hormones in females. these include early-age menarche, late-age menopause, postmenopausal obesity and use of hormone therapy. however, these factors do not account for the sixfold difference in breast cancer incidence and mortality between countries and the fact that these differences dramatically lessen after migration; nor do they account for male breast cancer. accordingly, hormone-responsi ...200617661684
incorporation of high levels of chimeric human immunodeficiency virus envelope glycoproteins into virus-like particles.the human immunodeficiency virus (hiv) envelope (env) protein is incorporated into hiv virions or virus-like particles (vlps) at very low levels compared to the glycoproteins of most other enveloped viruses. to test factors that influence hiv env particle incorporation, we generated a series of chimeric gene constructs in which the coding sequences for the signal peptide (sp), transmembrane (tm), and cytoplasmic tail (ct) domains of hiv-1 env were replaced with those of other viral or cellular p ...200717670815
overexpression of the low molecular weight cyclin e in transgenic mice induces metastatic mammary carcinomas through the disruption of the arf-p53 pathway.in tumor cells, cyclin e deregulation results in the appearance of five low molecular weight (lmw) isoforms. when overexpressed in breast cancer cells, these forms of cyclin e induce genomic instability, resistance to inhibition by p21 and p27, and resistance to antiestrogen therapy. additionally, the lmw forms of cyclin e strongly correlate with decreased survival in patients with breast cancer. however, the oncologic role of the lmw forms of cyclin e in breast cancer tumorigenesis is yet to be ...200717671189
promoter complex in the central part of the mouse mammary tumor virus long terminal repeat.unique among the retroviruses, mouse mammary tumor virus (mmtv) carries, in addition to the usual long terminal repeat (ltr) promoter, another promoter, p2, which is located in the central part of the proviral u3 sequence, within the ltr open reading frame (orf). using an in vitro reporter system based on a sensitive luciferase expression assay, we investigated the regulation of the p2 promoter in the context of the mtv-2 and mtv-8 genomes. irrespective of the genomic source, the activity of the ...200717686873
effects of il-12 gene therapy on spontaneous transgenic and transplanted breast tumors.cytokines are promising agents for cancer therapy due to their activity at low concentrations. we used a naked il-12 dna expression vector to achieve long-term systemic cytokine expression to inhibit breast tumor growth in mmtvneu transgenic and transplanted models. constant low levels of il-12 produced by this protocol provided effective tumor growth inhibition of both tumor models without adverse effects.200817687642
molecular mechanisms of paclitaxel and nm-3 on human gastric cancer in a severe combined immune deficiency mice orthotopic implantation model.to explore the molecular mechanisms of action of paclitaxel and nm-3 on human gastric cancer in severe combined immune deficiency (scid) mice.200717696236
rapamycin inhibits multiple stages of c-neu/erbb2 induced tumor progression in a transgenic mouse model of her2-positive breast cancer.amplification of the her2 (erbb2, c-neu) proto-oncogene in breast cancer is associated with poor prognosis and high relapse rates. her2/erbb2, in conjunction with erbb3, signals through the akt/phosphatidylinositol 3-kinase pathway and leads to the activation of mammalian target of rapamycin (mtor), a critical mrna translation regulator that controls cell growth. gene expression analysis of mammary tumors collected from mouse mammary tumor virus-c-neu transgenic mice revealed that mrna levels of ...200717699716
disruption of cyclin d1 nuclear export and proteolysis accelerates mammary carcinogenesis.cyclin d1 levels are maintained at steady state by phosphorylation-dependent nuclear export and polyubiquitination by scf(fbx4-alphab crystallin). inhibition of cyclin d1 proteolysis has been implicated as a causative factor leading to its overexpression in breast and esophageal carcinomas; however, the contribution of stable cyclin d1 to the genesis of such carcinomas has not been evaluated. we therefore generated transgenic mice wherein expression of either wild-type or a stable cyclin d1 alle ...200817724472
mouse mammary tumor virus. 196217740814
estrogen receptor-alpha expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice.the estrogen receptor-alpha (eralpha) is a critical transcription factor that regulates epithelial cell proliferation and ductal morphogenesis during postnatal mammary gland development. tissue recombination and transplantation studies using the first generation of eralpha knockout (erko) mice suggested that this steroid hormone receptor is required in the mammary stroma that subsequently exerts its effect on the epithelium through additional paracrine signaling events. a more detailed analysis ...200717785410
skp2b stimulates mammary gland development by inhibiting rea, the repressor of the estrogen receptor.skp2b, an f-box protein of unknown function, is frequently overexpressed in breast cancer. in order to determine the function of skp2b and whether it has a role in breast cancer, we performed a two-hybrid screen and established transgenic mice expressing skp2b in the mammary glands. we found that skp2b interacts with the repressor of estrogen receptor activity (rea) and that overexpression of skp2b leads to a reduction in rea levels. in the mammary glands of mmtv-skp2b mice, rea levels are also ...200717785450
identification of tumorsphere- and tumor-initiating cells in her2/neu-induced mammary tumors.a variety of human malignancies, including breast cancer, are thought to be organized in a hierarchy, whereby a relatively minor population of tumor initiating cells (tic) is responsible for tumor growth and the vast majority of remaining cells is nontumorigenic. analysis of tics in model systems of breast cancer would offer uniform and accessible source of tumor cells and the power of mouse genetics to dissect these rare cells. the her2/neu proto-oncogene is overexpressed in an aggressive form ...200717875707
characterization of viral particles isolated from primary cultures of human breast cancer cells.the association of human breast cancer with sequences similar to the mouse mammary tumor virus (mmtv) has been shown, but convincing evidence for the presence of viral particles in breast tumors has been lacking. we have described the complete proviral structure of a retrovirus in human breast cancer. this provirus, designated as human mammary tumor virus (hmtv), was 95% homologous to mmtv and revealed features of a replication-competent virus. we have therefore investigated the production of vi ...200717875739
hypoxia modulation and radiosensitization by the novel dual egfr and vegfr inhibitor aee788 in spontaneous and related allograft tumor models.concomitant inhibition of erbb1/2- and vegf receptor-signaling synergizes when used in combination with dna-damaging agents. here, we investigated for the first time the combined treatment modality of the novel dual specific receptor tyrosine kinase inhibitor aee788 with ionizing radiation and analyzed treatment-induced end points in situ as indicators for a potential sensitizing mechanism. furthermore, we assessed tumor hypoxia in response to different antiangiogenic and antiproliferative treat ...200717876047
a mouse model for luminal epithelial like er positive subtype of human breast cancer.generation of novel spontaneous er positive mammary tumor animal model from heterozygous nih nude mice.200717880731
jaagsiekte sheep retrovirus is not detected in human lung adenocarcinomas expressing antigens related to the gag polyprotein of betaretroviruses.a proportion of human lung adenocarcinomas (hlacs) express an antigen related to the major capsid protein (ca) of jaagsiekte sheep retrovirus (jsrv), a betaretrovirus that causes a transmissible lung cancer in sheep. in this study, we have investigated whether jsrv or related betaretroviruses are expressed in hlacs. results obtained indicate that jsrv is not associated with human lung adenocarcinomas. however, a proportion of hlacs reacted positively in immunohistochemistry with antibodies speci ...200717889995
the int6 cancer gene and mek signaling pathways converge during zebrafish development.int-6 (integration site 6) was identified as an oncogene in a screen of tumorigenic mouse mammary tumor virus (mmtv) insertions. int6 expression is altered in human cancers, but the precise role of disrupted int6 in tumorigenesis remains unclear, and an animal model to study int-6 physiological function has been lacking.200717895999
rapid spread of mouse mammary tumor virus in cultured human breast cells.the role of mouse mammary tumor virus (mmtv) as a causative agent in human breast carcinogenesis has recently been the subject of renewed interest. the proposed model is based on the detection of mmtv sequences in human breast cancer but not in healthy breast tissue. one of the main drawbacks to this model, however, was that until now human cells had not been demonstrated to sustain productive mmtv infection.200717931409
sequence-dependent variations associated with h2a/h2b depletion of nucleosomes.mechanisms that can alter nucleosome structure to enhance dna accessibility are of great interest because of their potential involvement in genomic processes. one such mechanism is h2a/h2b release from nucleosomes; it occurs in vivo and is involved in the in vitro activities of several transcription-associated complexes. using fluorescence approaches based on förster resonance energy transfer, we previously detected sequence-dependent structure/stability variations between 5s and two types of pr ...200817933873
an egr2/cited1 transcription factor complex and the 14-3-3sigma tumor suppressor are involved in regulating erbb2 expression in a transgenic-mouse model of human breast cancer.amplification and elevated expression of the erbb2 receptor tyrosine kinase occurs in 20% of human breast cancers and is associated with a poor prognosis. we have previously demonstrated that mammary tissue-specific expression of activated erbb2 under the control of its endogenous promoter results in mammary tumor formation. tumor development was associated with amplification and overexpression of erbb2 at both the transcript and protein levels. here we demonstrate that the egr2/krox20 transcrip ...200717938205
the rexinoid lg100268 prevents the development of preinvasive and invasive estrogen receptor negative tumors in mmtv-erbb2 mice.to test whether a novel rexinoid, lg100268, prevents the development of preinvasive and invasive estrogen receptor-negative mammary tumorigenesis in mmtv-erbb2 mice.200717947490
a new rexinoid, nrx194204, prevents carcinogenesis in both the lung and mammary gland.we evaluated the anti-inflammatory and growth-inhibitory properties of the novel rexinoid nrx194204 (4204) in vitro and then tested its ability to prevent and/or treat experimental lung and estrogen receptor (er)-negative breast cancer in vivo.200717947492
mmtv-egf receptor transgene promotes preneoplastic conversion of multiple steroid hormone-responsive tissues.correlative analyses of tumors and patient-derived cell lines of the human reproductive system suggest that overexpression of egf contributes to the oncogenic phenotype. however, it is unclear at what stage in disease overexpression of the egfr is most critical. to assess its role as an initiator of reproductive tissue tumor development, transgenic mice were derived with mouse mammary tumor virus (mmtv)-regulated overexpression of the human egfr. although elevated expression of the egfr in hormo ...200817960555
iron accumulation in mammary tumor suggests a tug of war between tumor and host for the microelement.iron is indispensable for the metabolism and proliferation of both normal and malignant cells. recycling from senescent erythrocytes in the liver and spleen is critical for iron supply to all tissues. in the liver and spleen from mmtv-neu (erbb-2) mice bearing a mammary carcinoma, we noticed the scarcity of hemosiderin pigment and its abundance in the stroma of the tumor. thus iron (iii) was investigated with the perls' reaction in tissues from normal and mmtv-neu mice. with respect to normal an ...200717970045
isolation and molecular characterization of cancer stem cells in mmtv-wnt-1 murine breast tumors.in human breast cancers, a phenotypically distinct minority population of tumorigenic (tg) cancer cells (sometimes referred to as cancer stem cells) drives tumor growth when transplanted into immunodeficient mice. our objective was to identify a mouse model of breast cancer stem cells that could have relevance to the study of human breast cancer. to do so, we used breast tumors of the mouse mammary tumor virus (mmtv)-wnt-1 mice. mmtv-wnt-1 breast tumors were harvested, dissociated into single-ce ...200817975224
mouse mammary tumor virus-like gene sequences in breast cancer samples of mexican women.previous reports related the presence of mouse mammary tumor virus (mmtv)-like gene sequences to human breast carcinoma. the aim of this study was to determine whether mmtv-like env gene sequences are present in breast cancer samples of mexican women and in breast and lung cancer cell lines.200717975321
wnt4 inhibits beta-catenin/tcf signalling by redirecting beta-catenin to the cell membrane.during embryonic development, beta-catenin is central both to the transcriptional activation of wnt [wingless-type mmtv (murine-mammary-tumour virus) integration site family] target genes and as a mediator of cell-cell adhesion. signals that regulate its levels and subcellular localization are critical. one mechanism of wnt signalling results in stabilization of beta-catenin protein, which leads to its translocation into the nucleus, where it interacts with tcf (t-cell factor, hmg box) and activ ...200817976036
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