TY - JOUR
T1 - E2F transcriptional repressor complexes are critical downstream targets of p19ARF/p53-induced proliferative arrest
AU - Rowland, Benjamin D.
AU - Denissov, Serguei G.
AU - Douma, Sirith
AU - Stunnenberg, Hendrik G.
AU - Bernards, René
AU - Peeper, Daniel S.
N1 - Funding Information:
We thank C. Sherr for generously providing a p19 ARF retroviral vector, K. Helin, W. Krek, and X. Lu for (mutant) E2F-1 vectors, T. Brummelkamp for p19 ARF - and p53-RFP retroviral vectors, J. Jonkers for p53 −/− MEFs, and J.-H. Dannenberg and H. te Riele for wild-type and triple knockout MEFs. We thank our colleagues for helpful discussions and A. Berns for critically reading the manuscript. This work was supported by grants from the Netherlands Organization for Scientific Research and the Dutch Cancer Society.
PY - 2002/7
Y1 - 2002/7
N2 - The p16INK4a/pRB/E2F and p19ARF/p53 tumor suppressor pathways are disrupted in most human cancers. Both p19ARF 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 p19ARF, p53, or RASV12. Thus, E2F transcriptional repressor complexes are critical downstream targets of antiproliferative p19ARF/p53 signaling.
AB - The p16INK4a/pRB/E2F and p19ARF/p53 tumor suppressor pathways are disrupted in most human cancers. Both p19ARF 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 p19ARF, p53, or RASV12. Thus, E2F transcriptional repressor complexes are critical downstream targets of antiproliferative p19ARF/p53 signaling.
UR - http://www.scopus.com/inward/record.url?scp=0036653392&partnerID=8YFLogxK
U2 - 10.1016/S1535-6108(02)00085-5
DO - 10.1016/S1535-6108(02)00085-5
M3 - Article
C2 - 12150825
AN - SCOPUS:0036653392
SN - 1535-6108
VL - 2
SP - 55
EP - 65
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -