Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumor development in mice

被引：177

作者：

Pangas, Stephanie A. ^{[1
]}

Li, Xiaohui ^{[1
]}

Umans, Lieve ^{[4
,5
]}

Zwijsen, An ^{[4
,5
]}

Huylebroeck, Danny ^{[4
,5
]}

Gutierrez, Carolina ^{[1
]}

Wang, Degang ^{[6
]}

Martin, James F. ^{[6
]}

Jamin, Soazik P. ^{[7
]}

Behringer, Richard R. ^{[7
]}

Robertson, Elizabeth J. ^{[8
]}

Matzuk, Martin M. ^{[1
,2
,3
]}

机构：

[1] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA

[2] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[4] VIB, Dept Dev Biol VIB7, Louvain, Belgium

[5] VIB, Div Mol & Dev Genet, Lab Mol Biol CELGEN, Dept Human Genet DME, Louvain, Belgium

[6] Texas A&M Univ Syst, Hlth Sci Ctr, Inst Biosci & Technol, Houston, TX 77030 USA

[7] Univ Texas Houston, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA

[8] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2008年 / 28卷 / 01期

关键词：

D O I：

10.1128/MCB.01404-07

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The transforming growth factor beta (TGF beta) family has critical roles in the regulation of fertility. In addition, the pathogenesis of some human cancers is attributed to misregulation of TGF beta 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 TGF beta 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.

引用

页码：248 / 257

页数：10

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