E2F transcriptional repressor complexes are critical downstream targets of p19(ARF)/p53-induced proliferative arrest.
The p16(INK4a)/pRB/E2F and p19(ARF)/p53 tumor suppressor pathways are disrupted in most human cancers. Both p19(ARF) and p53 are required for the induction of senescence in primary mouse embryonic fibroblasts (MEFs), but little is known about their downstream targets. Disruption of E2F-mediated transcriptional repression in MEFs caused a general increase in the expression of E2F target genes, including p19ARF. We detected no contribution of E2F-mediated transactivation in this setting, indicating that a predominant role of endogenous E2F in asynchronously growing primary MEFs is to repress its target genes. Moreover, relief of transcriptional repression by E2F rendered MEFs resistant to senescence induced by either p19(ARF), p53, or RAS(V12). Thus, E2F transcriptional repressor complexes are critical downstream targets of antiproliferative p19(ARF)/p53 signaling.
Rowland
Benjamin D
BD
Division of Molecular Carcinogenesis, Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Denissov
Serguei G
SG
Douma
Sirith
S
Stunnenberg
Hendrik G
HG
Bernards
René
R
Peeper
Daniel S
DS
D016475:3T3 Cells; D000818:Animals; D018797:Cell Cycle Proteins; D002455:Cell Division; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology; D051379:Mice; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction; D013489:Suppression, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53