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p53-independent apoptosis induced by muscle differentiation stimuli in polyomavirus large T-expressing myoblasts
V Gottifredi1, A Peschiaroli, G M Fimia
1Isituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biotecnologie Cellulari ed Ematologia, Sezione di Genetica Molecolare, Università di Roma La Sapienza, Viale Regina Elena 324, Italy.
Abstract:
Abnormal proliferation signals, driven by cellular or viral oncogenes, can result in the induction of apoptosis under sub-optimal cell growth conditions. The tumor suppressor p53 plays a central role in mediating oncogene-induced apoptosis, therefore transformed cells lacking p53 are generally resistant to apoptosis-promoting treatments. In a previous work we have reported that the expression of polyomavirus large T antigen causes apoptosis in differentiating myoblasts and that this phenomenon is dependent on the onset of muscle differentiation in the absence of a correct cell cycle arrest. Here we report that polyomavirus large T increases the levels and activity of p53, but these alterations are not involved in the apoptotic mechanism. Apoptosis in polyomavirus large T-expressing myoblasts is not prevented by the expression of a p53 dominant-negative mutant nor it is increased by p53 over-expression. Moreover, forced differentiation induced through the over-expression of the muscle regulatory factor MyoD, leads to apoptosis without altering p53 function and, more significantly, even in a p53-null background. Our results indicate that apoptosis induced by the activation of muscle differentiation pathways in oncogene-expressing cells can occur in a p53-independent manner.
Insights
Oncogene-expressing cells undergoing muscle differentiation can experience programmed cell death (apoptosis) independently of the tumor suppressor p53. This finding challenges the traditional view of p53
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Abnormal proliferation signals from oncogenes can trigger apoptosis, a process typically mediated by the tumor suppressor p53.
- Cells lacking functional p53 are often resistant to apoptosis-inducing treatments, posing challenges in cancer therapy.
- Previous research indicated polyomavirus large T antigen induces apoptosis in differentiating myoblasts, linked to muscle differentiation and cell cycle dysregulation.
Purpose of the Study:
- To investigate the role of p53 in polyomavirus large T antigen-induced apoptosis in differentiating myoblasts.
- To determine if p53 alterations are involved in the apoptotic mechanism triggered by polyomavirus large T.
- To explore the p53-dependency of apoptosis during oncogene-induced muscle differentiation.
Main Methods:
- Analysis of p53 levels and activity in myoblasts expressing polyomavirus large T antigen.
- Assessment of apoptosis induction using p53 dominant-negative mutants and p53-null cell backgrounds.
- Forced muscle differentiation via MyoD overexpression to induce apoptosis and evaluate p53's role.
Main Results:
- Polyomavirus large T antigen increases p53 levels and activity, but these changes do not mediate the observed apoptosis.
- Apoptosis in polyomavirus large T-expressing myoblasts is not inhibited by p53 dominant-negative mutants or enhanced by p53 overexpression.
- Forced muscle differentiation through MyoD overexpression induces apoptosis independently of p53 status, even in p53-null cells.
Conclusions:
- Apoptosis triggered by muscle differentiation pathways in oncogene-expressing cells can occur independently of p53.
- This study reveals a novel p53-independent mechanism for oncogene-induced apoptosis during differentiation.
- Findings suggest potential therapeutic strategies targeting p53-independent pathways in certain cancers.