E2F transcriptional repressor complexes are critical downstream targets of p19(ARF)/p53-induced proliferative arrest

Benjamin D Rowland; Serguei G Denissov; Sirith Douma; Hendrik G Stunnenberg; René Bernards; Daniel S Peeper

doi:10.1016/s1535-6108(02)00085-5

E2F transcriptional repressor complexes are critical downstream targets of p19(ARF)/p53-induced proliferative arrest

Cancer Cell. 2002 Jul;2(1):55-65. doi: 10.1016/s1535-6108(02)00085-5.

Authors

Benjamin D Rowland¹, Serguei G Denissov, Sirith Douma, Hendrik G Stunnenberg, René Bernards, Daniel S Peeper

Affiliation

¹ Division of Molecular Carcinogenesis, Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

PMID: 12150825
DOI: 10.1016/s1535-6108(02)00085-5

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3 Cells
Animals
Cell Cycle Proteins*
Cell Division
Cellular Senescence / genetics
Cellular Senescence / physiology
Cyclin-Dependent Kinase Inhibitor p16 / genetics
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
DNA-Binding Proteins*
E2F Transcription Factors
Fibroblasts / cytology
Fibroblasts / metabolism
Gene Expression Regulation, Neoplastic
Genes, ras / physiology
Mice
Models, Genetic
Promoter Regions, Genetic
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
Sequence Deletion
Signal Transduction
Suppression, Genetic
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Suppressor Protein p14ARF / genetics
Tumor Suppressor Protein p14ARF / metabolism*
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*

Substances

Cdkn2a protein, mouse
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p16
DNA-Binding Proteins
E2F Transcription Factors
Proto-Oncogene Proteins
Transcription Factors
Tumor Suppressor Protein p14ARF
Tumor Suppressor Protein p53