The role of the transcription factor DP in apoptosis.
DP1 and DP2 function as binding partners for E2F transcription factors. The association of DP with E2F directly enhances both the DNA binding affinity and the transactivation function of the heterodimer. Target genes include those involved in DNA synthesis, cell cycle and apoptosis. E2F/DP activity is carefully regulated since the heterodimer plays a central role in so many vital cellular functions. Indeed, the association of additional proteins, the phosphorylation state, the subcellular localization and the level of expression all contribute to modulating heterodimer activity and are all influenced by DP proteins. Active E2F1/DP1 promotes apoptosis in both a p53-dependent and independent manner. E2F1/DP1 induces the expression of ARF, which in turn blocks MDM2-mediated ubiquination of p53. E2F1/DP1, however, can mediate p53-dependent apoptosis in the absence of ARF through the upregulation of the p53 kinase ATM and by E2F1directly binding to p53, which enhances p53 transcriptional activity. E2F1/DP1 also promotes p53-independent apoptosis by inducing the expression of p73 in addition to upregulating central components of the apoptotic pathway such as casapases, Apaf1 and the pro-apoptotic Bcl2-family members. Lastly, E2F1 inhibits the NFkappaB survival signal. Although the DP proteins may not possess a biological function on their own, they are indispensable for regulating E2F activity and thus play a central role in important cellular functions such as apoptosis.
Hitchens
M R
MR
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Robbins
P D
PD
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D000097782:NF-kappaB-Inducing Kinase
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D017346:Protein Serine-Threonine Kinases; D050680:Transcription Factor DP1; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D000097782:NF-kappaB-Inducing Kinase; C417743:Cdkn2a protein, mouse; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; C493735:TFDP1 protein, human; C094103:TFDP2 protein, human; C493736:Tfdp1 protein, mouse; C490579:Tfdp2 protein, mouse