Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mol Cell Biol
2008 Jan 01;281:248-57. doi: 10.1128/MCB.01404-07.
Show Gene links
Show Anatomy links
Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumor development in mice.
Pangas SA
,
Li X
,
Umans L
,
Zwijsen A
,
Huylebroeck D
,
Gutierrez C
,
Wang D
,
Martin JF
,
Jamin SP
,
Behringer RR
,
Robertson EJ
,
Matzuk MM
.
Abstract
The transforming growth factor beta (TGFbeta) family has critical roles in the regulation of fertility. In addition, the pathogenesis of some human cancers is attributed to misregulation of TGFbeta function and SMAD2 or SMAD4 mutations. There are limited mouse models for the BMP signaling SMADs (BR-SMADs) 1, 5, and 8 because of embryonic lethality and suspected genetic redundancy. Using tissue-specific ablation in mice, we deleted the BR-SMADs from somatic cells of ovaries and testes. Single conditional knockouts for Smad1 or Smad5 or mice homozygous null for Smad8 are viable and fertile. Female double Smad1 Smad5 and triple Smad1 Smad5 Smad8 conditional knockout mice become infertile and develop metastatic granulosa cell tumors. Male double Smad1 Smad5 conditional knockout mice are fertile but demonstrate metastatic testicular tumor development. Microarray analysis indicated significant alterations in expression of genes related to the TGFbeta pathway, as well as genes involved in infertility and extracellular matrix production. These data strongly implicate the BR-SMADs as part of a critical developmental pathway in ovaries and testis that, when disrupted, leads to malignant transformation.
Arnold,
Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryo.
2006, Pubmed,
Xenbase
Arnold,
Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryo.
2006,
Pubmed
,
Xenbase
Beck,
Bone morphogenetic protein signaling and growth suppression in colon cancer.
2006,
Pubmed
Bevan,
Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome.
1999,
Pubmed
Boerboom,
Misregulated Wnt/beta-catenin signaling leads to ovarian granulosa cell tumor development.
2005,
Pubmed
Brubaker,
Bone morphogenetic protein signaling in prostate cancer cell lines.
2004,
Pubmed
Buckhaults,
Secreted and cell surface genes expressed in benign and malignant colorectal tumors.
2001,
Pubmed
Chang,
Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects.
1999,
Pubmed
Chang,
Genetic analysis of the mammalian transforming growth factor-beta superfamily.
2002,
Pubmed
Cheng,
Elucidation of epigenetic inactivation of SMAD8 in cancer using targeted expressed gene display.
2004,
Pubmed
Coerver,
Activin signaling through activin receptor type II causes the cachexia-like symptoms in inhibin-deficient mice.
1996,
Pubmed
David,
Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells.
2007,
Pubmed
Dennis,
DAVID: Database for Annotation, Visualization, and Integrated Discovery.
2003,
Pubmed
Derynck,
TGF-beta signaling in tumor suppression and cancer progression.
2001,
Pubmed
Durlinger,
Control of primordial follicle recruitment by anti-Müllerian hormone in the mouse ovary.
1999,
Pubmed
Feng,
Specificity and versatility in tgf-beta signaling through Smads.
2005,
Pubmed
Gemma,
hSmad5 gene, a human hSmad family member: its full length cDNA, genomic structure, promoter region and mutation analysis in human tumors.
1998,
Pubmed
Goumans,
Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors.
2002,
Pubmed
He,
BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.
2004,
Pubmed
Horvath,
Loss of BMP2, Smad8, and Smad4 expression in prostate cancer progression.
2004,
Pubmed
Howe,
Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis.
2001,
Pubmed
Huang,
Conditional knockout of the Smad1 gene.
2002,
Pubmed
Jamin,
Requirement of Bmpr1a for Müllerian duct regression during male sexual development.
2002,
Pubmed
Jeyasuria,
Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function.
2004,
Pubmed
Jorgez,
Granulosa cell-specific inactivation of follistatin causes female fertility defects.
2004,
Pubmed
Järvinen,
Familial juvenile polyposis coli; increased risk of colorectal cancer.
1984,
Pubmed
Kowanetz,
Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor beta and bone morphogenetic protein.
2004,
Pubmed
Li,
SMAD3 regulates gonadal tumorigenesis.
2007,
Pubmed
Looyenga,
Genetic removal of Smad3 from inhibin-null mice attenuates tumor progression by uncoupling extracellular mitogenic signals from the cell cycle machinery.
2007,
Pubmed
Massagué,
TGFbeta signaling in growth control, cancer, and heritable disorders.
2000,
Pubmed
Massagué,
Smad transcription factors.
2005,
Pubmed
Matzuk,
Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice.
1992,
Pubmed
Minn,
Genes that mediate breast cancer metastasis to lung.
2005,
Pubmed
Miyazaki,
BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cells.
2004,
Pubmed
Miyazono,
BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk.
2005,
Pubmed
Monsivais,
The TGF-β Family in the Reproductive Tract.
2017,
Pubmed
Naora,
Ovarian cancer metastasis: integrating insights from disparate model organisms.
2005,
Pubmed
Pangas,
Intraovarian activins are required for female fertility.
2007,
Pubmed
Pangas,
Premature luteinization and cumulus cell defects in ovarian-specific Smad4 knockout mice.
2006,
Pubmed
Pangas,
Growth differentiation factor 9 regulates expression of the bone morphogenetic protein antagonist gremlin.
2004,
Pubmed
Pardali,
Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer.
2007,
Pubmed
Piccirillo,
Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells.
2006,
Pubmed
Pouliot,
Role of Smad1 and Smad4 proteins in the induction of p21WAF1,Cip1 during bone morphogenetic protein-induced growth arrest in human breast cancer cells.
2002,
Pubmed
Risma,
Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors.
1995,
Pubmed
Roberts,
The two faces of transforming growth factor beta in carcinogenesis.
2003,
Pubmed
Rose,
Metastatic patterns in histologic variants of ovarian cancer. An autopsy study.
1989,
Pubmed
Schneider,
Induction and expression of betaig-h3 in pancreatic cancer cells.
2002,
Pubmed
Sgarra,
Nuclear phosphoproteins HMGA and their relationship with chromatin structure and cancer.
2004,
Pubmed
Shim,
Profiling of differentially expressed genes in human primary cervical cancer by complementary DNA expression array.
1998,
Pubmed
Singbrant,
Smad5 is dispensable for adult murine hematopoiesis.
2006,
Pubmed
Sneddon,
Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation.
2006,
Pubmed
Steeg,
Tumor metastasis: mechanistic insights and clinical challenges.
2006,
Pubmed
Subramanian,
Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
2005,
Pubmed
Tremblay,
Mouse embryos lacking Smad1 signals display defects in extra-embryonic tissues and germ cell formation.
2001,
Pubmed
,
Xenbase
Umans,
Generation of a floxed allele of Smad5 for cre-mediated conditional knockout in the mouse.
2003,
Pubmed
Zaidi,
Misexpression of full-length HMGA2 induces benign mesenchymal tumors in mice.
2006,
Pubmed
Zeisberg,
BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.
2003,
Pubmed
Zhan,
Müllerian inhibiting substance regulates its receptor/SMAD signaling and causes mesenchymal transition of the coelomic epithelial cells early in Müllerian duct regression.
2006,
Pubmed
