The Mad Protein Family Links Transcriptional Repression to Cell Differentiation

The ability of proliferating cells to exit the cell cycle isan important aspect of the ordered growth and development of tissues and organisms (for review, see Raff1996). Many normal cells cease proliferation in responseto a number of external cues including withdrawal of mitogens, cell-cell contact, specific soluble ligands (e.g.,transforming growth factor-β, TGF-β), and damage. Cessation of proliferation is also a critical element in the terminal differentiation of diverse cell types. Importantly,failure to exit the cell cycle in response to appropriate signals is likely to play a key role in oncogenesis. Until recently, there has been scant information on the mechanisms and pathways involved in cell cycle exit. However,work within the last several years delineating the majormolecular components of the cell cycle has revealed aplethora of both positive and negative regulators of cellcycle progression. The negative regulators comprise awide range of proteins including tumor suppressors,checkpoint control proteins, and cyclin-dependent kinaseinhibitors (CKIs) (for reviews, see Hartwell and Kastan1994; Sherr 1996). Although many of these proteins appear to regulate the orderly progression of the cell cycle,several have also been linked to cell cycle exit related todifferentiation. These include proteins in the retinoblastoma (RB) family and the CKIs p21Cip1/WAF1, p27Kip1,and p57Kip2 (Lee et al. 1994; Halevy et al. 1995; Parker etal. 1995; de Nooij et al. 1996; Missero et al. 1996; Casaccia-Bonnefil et al. 1997; Yan et al. 1997; Di Cunto et al.1998)...