Related Experiment Videos
ARF differentially modulates apoptosis induced by E2F1 and Myc
Jamie L Russell1, John T Powers, Robert J Rounbehler
1Department of Carcinogenesis, Science Park-Research Division, University of Texas M. D. Anderson Cancer Center, Smithville, Texas 78957, USA.
Abstract:
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.
Insights
The tumor suppressor ARF is not required for E2F1-induced apoptosis and actually inhibits E2F1's apoptotic function. Inactivating ARF enhances E2F1's ability to promote apoptosis and cell cycle progression.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- The ARF tumor suppressor is involved in p53-dependent apoptosis.
- E2F1 transcription factor promotes proliferation and apoptosis.
- E2F1 regulates the ARF gene, suggesting ARF's role in E2F1-induced apoptosis.
Purpose of the Study:
- To investigate the role of ARF in E2F1-induced apoptosis.
- To determine if ARF is necessary for E2F1 to induce apoptosis.
- To elucidate the relationship between ARF and E2F1 in vivo and in vitro.
Main Methods:
- Experiments were conducted in transgenic epidermis in vivo.
- Studies utilized mouse embryo fibroblast cultures in vitro.
- Assessed apoptosis induction by E2F1 and Myc in the presence and absence of ARF.
Main Results:
- ARF is unnecessary for E2F1-induced apoptosis.
- Inactivation of ARF enhances E2F1's apoptotic function.
- ARF inactivation cooperates with E2F1 to promote S-phase entry.
- E2F1 induces p53 accumulation and phosphorylation in the absence of ARF.
- Myc-induced apoptosis is diminished without ARF.
Conclusions:
- ARF acts as a negative regulator of E2F1 activity.
- ARF is not required for E2F1-mediated apoptosis.
- The absence of ARF potentiates E2F1's pro-apoptotic and proliferative effects.