Opposing roles of pRB and p107 in adipocyte differentiation

The retinoblastoma (RB) family of proteins, pRB, p107. and p130, have been postulated to be partially redundant in their ability to regulate progressi on through the G(1) phase of the cell cycle. However, pRB appears to be uni que in its capacity as a classical tumor suppressor, possibly because of a specialized role in maintaining the balance between proliferation and diffe rentiation. A variety of studies have in fact revealed an apparent role for pRB in cellular differentiation and development. However, roles for p107 a nd p130 in differentiation have not yet been established, and knockout mous e studies have indicated that they may be functionally redundant during dev elopment, and possibly perform a role in differentiation distinct from that of pRB. Using adipogenesis as a model, we have indeed found distinct roles for the pRB family proteins in regulating differentiation. 3T3 fibroblasts deficient in p107 and p130 differentiate with high efficiency, whereas pRB (-/-) 3T3 cells exhibit defects in their differentiation potential. Moreove r. over-expression of pRB in wild-type cells promotes differentiation, wher eas over-expression of p107 antagonizes differentiation. The seemingly oppo sing roles of pRB family members in adipocyte differentiation can be explai ned, at least in part, by a requirement for pRB in maintaining cell cycle e xit as well as potentiating the activity of the differentiation-associated transcription factor. C/EBP alpha. p107 does not affect C/EBP alpha-driven transcription and is not required for cell cycle exit, but instead, loss of p107 lowers the requirement for the differentiation factor PPAR gamma. The se findings suggest contrasting biological roles for individual members of the pRB family of proteins that may explain why pRB, but not p107, is commo nly mutated during human tumor development.