A Functional Connection between pRB and Transforming Growth Factor β in Growth Inhibition and Mammary Gland Development

被引：23

作者：

Francis, Sarah M. ^{[3
]}

Bergsied, Jacqueline ^{[6
,7
]}

Isaac, Christian E. ^{[3
]}

Coschi, Courtney H. ^{[3
]}

Martens, Alison L. ^{[3
]}

Hojilla, Carlo V. ^{[5
]}

Chakrabarti, Subrata ^{[4
]}

DiMattia, Gabriel E. ^{[3
]}

Khokha, Rama ^{[5
]}

Wang, Jean Y. J. ^{[6
,7
]}

Dick, Frederick A. ^{[1
,2
,3
]}

机构：

[1] Univ Western Ontario, Canc Res Labs, London Reg Canc Program, London, ON N6A 4L6, Canada

[2] Univ Western Ontario, Childrens Hlth Res Inst, London, ON N6A 4L6, Canada

[3] Univ Western Ontario, Dept Biochem, London, ON N6A 4L6, Canada

[4] Univ Western Ontario, Dept Pathol, London, ON N6A 4L6, Canada

[5] Univ Toronto, Dept Med Biophys, Ontario Canc Inst, Toronto, ON M5G 2M9, Canada

[6] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA

[7] Univ Calif San Diego, Inst Canc, La Jolla, CA 92093 USA

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2009年 / 29卷 / 16期

关键词：

CELL-CYCLE ARREST; RETINOBLASTOMA SUSCEPTIBILITY GENE; TGF-BETA; REPRESSES TRANSCRIPTION; HISTONE DEACETYLASE; MURINE DEVELOPMENT; EPITHELIAL-CELLS; FAMILY PROTEINS; TUMOR-FORMATION; ADENOVIRUS E1A;

D O I：

10.1128/MCB.00473-09

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Transforming growth factor beta (TGF-beta) is a crucial mediator of breast development, and loss of TGF-beta-induced growth arrest is a hallmark of breast cancer. TGF-beta has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-beta cytostatic signaling, pRB is thought to be dispensable for mammary development. Using gene-targeted mice carrying subtle missense changes in pRB (Rb1(Delta L) and Rb1(NF)), we have discovered that pRB plays a critical role in mammary gland development. In particular, Rb1 mutant female mice have hyperplastic mammary epithelium and defects in nursing due to insensitivity to TGF-beta growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-beta signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-beta cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-beta in growth control and mammary gland development.

引用

页码：4455 / 4466

页数：12

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