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Molecular and Cellular Biology, March 2002, p. 1360-1368, Vol. 22, No. 5
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.5.1360-1368.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

ARF Differentially Modulates Apoptosis Induced by E2F1 and Myc

Jamie L. Russell, John T. Powers, Robert J. Rounbehler, Pamela M. Rogers, Claudio J. Conti, and David G. Johnson*

Department of Carcinogenesis, Science Park-Research Division, University of Texas M. D. Anderson Cancer Center, Smithville, Texas 78957

Received 28 August 2001/ Returned for modification 4 December 2001/ Accepted 5 December 2001

The ARF tumor suppressor participates in a p53-dependent apoptotic pathway that is stimulated in response to some oncogenic stimuli. The E2F1 transcription factor is a critical downstream target of the Rb tumor suppressor and, when active, can promote proliferation as well as apoptosis. The finding that E2F1 transcriptionally regulates the ARF gene has led to the suggestion that ARF contributes to E2F1-induced apoptosis. Counter to this hypothesis, this study demonstrates not only that ARF is unnecessary for E2F1 to induce apoptosis but also that inactivation of ARF actually enhances the ability of E2F1 to promote apoptosis. Inactivation of ARF also cooperates with E2F1 activity to promote entry into the S phase of the cell cycle. This relationship between ARF and E2F1 is demonstrated in transgenic epidermis in vivo and in mouse embryo fibroblast cultures in vitro. In contrast, the ability of Myc to induce apoptosis is diminished in the absence of ARF. E2F1 induces the accumulation of p53 in the absence of ARF, and this is associated with the phosphorylation of p53 on several residues. These findings demonstrate that ARF is a negative regulator of E2F1 activity and is not required for E2F1-induced apoptosis.

* Corresponding author. Mailing address: U.T. M.D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Smithville, TX 78957. Phone: (512) 237-9511. Fax: (512) 237-9566. E-mail: djohnson{at}sprd1.mdacc.tmc.edu.

Molecular and Cellular Biology, March 2002, p. 1360-1368, Vol. 22, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.5.1360-1368.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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