The Rb/E2F pathway: expanding roles and emerging paradigms

摘要: The retinoblastoma gene was identified over a decade ago as the first tumor suppressor. Although initially cloned result of its frequent mutation in rare pediatric eye tumor, (Friend et al. 1986; Fung 1987; Lee 1987), it is now thought to play fundamental role cellular regulation and target tumorigenic mutations many cell types. encodes 928–amino acid phosphoprotein, Rb, which arrests cells G1 phase (Weinberg 1995). Rb phosphorylated dephosphorylated during cycle; hyperphosphorylated (inactive) form predominates proliferating cells, whereas hypophosphorylated (active) generally more abundant quiescent or differentiating (Chen 1989). As demonstration suppressor activity, reintroduced into Rb-deficient blocked several features malignant phenotype (Huang 1988). Mutations affecting are frequently encountered, not only but also other cancers such osteosarcoma, small lung cancer, prostate breast cancer Harbour 1988; T’Ang Bookstein 1990). Indeed, children with hereditary have 30-fold increased risk developing second, nonocular malignancy, especially bone soft tissue sarcomas adolescence cutaneous melanomas adulthood (Eng 1993; Moll 1997). These second neoplasms occur almost exclusively patients who germ-line gene. further indication suppression, can be functionally inactivated by constitutive hyperphosphorylation tumors that do (Sherr 1996). In addition, DNA viruses express oncoproteins, adenovirus E1A, SV40 large antigen, human papillomavirus (HPV) E7, bind inactivate Rb; these proteins required for transform (DeCaprio Whyte Dyson function depends, at least part, on interactions E2F family DNA-binding transcription factors (E2F) (Chellappan 1991; 1998; Nevins 1998). sites found promoters genes important cycle progression, appears repress through interaction (Blake Azizkhan 1989; Thalmeier Dalton 1992; Ohtani Recent findings Rb/E2F field clarifying how this pathway regulates transition from S molecular level. Other emerging results show parts may even roles beyond control. article, we review current understanding mechanism action regulation, apoptosis, development. We refer readers recent reviews Bartek (1997), (1998), Lipinski Jacks (1999), Sherr Roberts (1999) additional in-depth analysis historical perspectives.