A functional connection between pRB and transforming growth factor beta in growth inhibition and mammary gland development.
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(DeltaL) 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.
Francis
Sarah M
SM
London Regional Cancer Program, University of Western Ontario, London, Ontario N6A4L6, Canada.
Bergsied
Jacqueline
J
Isaac
Christian E
CE
Coschi
Courtney H
CH
Martens
Alison L
AL
Hojilla
Carlo V
CV
Chakrabarti
Subrata
S
Dimattia
Gabriel E
GE
Khoka
Rama
R
Wang
Jean Y J
JY
Dick
Frederick A
FA
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D055879:Gene Knock-In Techniques; D005838:Genotype; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D007774:Lactation; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D010641:Phenotype; D011487:Protein Conformation; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016378:Tissue Transplantation; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta