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Molecular and Cellular Biology, August 2009, p. 4455-4466, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00473-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Sarah M. Francis,1,3 Jacqueline Bergsied,6 Christian E. Isaac,1,3 Courtney H. Coschi,1,3 Alison L. Martens,1,3 Carlo V. Hojilla,5 Subrata Chakrabarti,4 Gabriel E. DiMattia,1,3 Rama Khoka,5 Jean Y. J. Wang,6 and Frederick A. Dick1,2,3*

London Regional Cancer Program,1 Children's Health Research Institute,2 Department of Biochemistry,3 Department of Pathology, University of Western Ontario, London, Ontario N6A 4L6, Canada,4 Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada,5 Division of Biological Sciences and Cancer Institute, University of California, San Diego, California 920936

Received 12 April 2009/ Returned for modification 5 May 2009/ Accepted 31 May 2009

Transforming growth factor β (TGF-β) is a crucial mediator of breast development, and loss of TGF-β-induced growth arrest is a hallmark of breast cancer. TGF-β has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-β 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 Rb1NF), 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-β growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-β signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-β cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-β in growth control and mammary gland development.

* Corresponding author. Mailing address: Cancer Research Labs, University of Western Ontario, 790 Commissioners Rd. East, London, Ontario N6A 4L6, Canada. Phone: (519) 685-8620. Fax: (519) 685-8616. E-mail: fdick{at}uwo.ca

{triangledown} Published ahead of print on 8 June 2009.

Molecular and Cellular Biology, August 2009, p. 4455-4466, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00473-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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