4.5 Article

ARF differentially modulates apoptosis induced by E2F1 an Myc

Journal

MOLECULAR AND CELLULAR BIOLOGY
Volume 22, Issue 5, Pages 1360-1368

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.22.5.1360-1368.2002

Keywords

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Funding

  1. NCI NIH HHS [CA79648, P30 CA016672, CA16672, R01 CA079648, CA42157, R01 CA042157] Funding Source: Medline
  2. NIEHS NIH HHS [ES007784, P30 ES007784] Funding Source: Medline
  3. NATIONAL CANCER INSTITUTE [R01CA079648, P30CA016672, R01CA042157] Funding Source: NIH RePORTER
  4. NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [P30ES007784] Funding Source: NIH RePORTER

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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 E2FI to induce apoptosis but also that inactivation of ARF actually enhances the ability of E2FI to promote apoptosis. Inactivation of ARF also cooperates with E2FI activity to promote entry into the S phase of the cell cycle. This relationship between ARF and E2FI 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.

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