Alterations in G1/S cell-cycle control contributing to carcinogenesis.
Mutations involving the retinoblastoma tumor-suppressor gene (RB-1) have been described in a variety of human neoplasms. In addition, many tumors that retain a wild-type RB-1 allele harbor mutations that indirectly impair the function of the RB-1 gene product (pRB). pRB is a nuclear protein that regulates cell-cycle progression and, in at least certain tissues, differentiation. The former has been linked to its ability to form complexes with members of the E2F transcription factor family. E2F DNA-binding sites have been identified in the regulatory regions of a number of genes involved in cell-cycle progression. pRB-E2F complexes actively repress transcription when bound to these sites. All tumor-derived pRB mutants have lost the ability to bind to E2F. Conversely, activation of E2F-responsive genes is sufficient to overcome a pRB-induced cell-cycle block and, in certain cell types, can lead to transformation. Thus, E2F appears to be a physiologically relevant target of pRB action, and deregulation of E2F-responsive genes is a common, and possibly universal, step in human carcinogenesis.
Kaelin
W G
WG
Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. William_Kaelin@dfci.harvard.edu
D000483:Alleles; D002352:Carrier Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D050684:E2F Transcription Factors; D016193:G1 Phase / Q000235:genetics*; D016161:Genes, Retinoblastoma / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase / Q000235:genetics*; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors