pRB, p107 and the regulation of the E2F transcription factor.
Small DNA tumor viruses, such as adenovirus, encode proteins that deregulate the cell cycle. These proteins are potent transforming agents when tested in standard oncogenic assays. For adenovirus the best characterized viral oncoproteins are the early region 1A (E1A) products. Mutational studies have shown that E1A's oncogenic ability is determined primarily by its ability to bind to certain cellular proteins and interfere with their function. One of these cellular targets for E1A is the product of the retinoblastoma tumor suppressor gene, pRB. pRB is a negative regulator of cell proliferation, and its inactivation has been shown to be an important oncogenic step in the development of many human cancers. In adenovirusmediated transformation, E1A binds to pRB and inactivates it, thus functionally mimicking the loss of pRB often seen in human tumors. There is now compelling evidence to suggest that pRB regulates transcription at specific phases of the cell cycle by physically associating with key transcription factors. The best characterized target of pRB is the transcription factor E2F. The interaction of pRB and E2F leads to the inhibition of E2F-mediated transactivation. Most of the genes that are known to be controlled by E2F have key roles in the regulation of cell proliferation. During cell cycle progression, phosphorylation of pRB appears to change its conformation and E2F is released. In pathogenic settings E2F transactivation is not regulated by pRB binding. In human tumors with mutations in the retinoblastoma gene, functional pRB is absent and hence can no longer inhibit E2F activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Dyson
N
N
Laboratory of Molecular Oncology, Massachusetts General Hospital Cancer Center, Charlestown 02129.
D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002472:Cell Transformation, Viral / Q000502:physiology; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005786:Gene Expression Regulation; D016161:Genes, Retinoblastoma / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D056465:Retinoblastoma-Binding Protein 1; D050720:Retinoblastoma-Like Protein p107; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D009687:Nuclear Proteins; C493844:RBL1 protein, human; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050720:Retinoblastoma-Like Protein p107; D050680:Transcription Factor DP1; D014157:Transcription Factors