Conditional Deletion of Smad1 and Smad5 in Somatic Cells of Male and Female Gonads Leads to Metastatic Tumor Development in Mice
- 1 January 2008
- journal article
- Published by Informa UK Limited in Molecular and Cellular Biology
- Vol. 28 (1), 248-257
- https://doi.org/10.1128/mcb.01404-07
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.Keywords
This publication has 56 references indexed in Scilit:
- Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cellsNature, 2006
- Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferationProceedings of the National Academy of Sciences of the United States of America, 2006
- Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryoDevelopmental Biology, 2006
- Misexpression of Full-length HMGA2 Induces Benign Mesenchymal Tumors in MiceCancer Research, 2006
- Bone morphogenetic protein signaling and growth suppression in colon cancerAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2006
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cellsOncogene, 2004
- Nuclear phosphoproteins HMGA and their relationship with chromatin structure and cancerFEBS Letters, 2004
- Induction and expression of βig-h3 in pancreatic cancer cellsBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2002
- Requirement of Bmpr1a for Müllerian duct regression during male sexual developmentNature Genetics, 2002