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p53-dependent apoptosis is regulated by a C-terminally alternatively spliced form of murine p53
N Almog1, N Goldfinger, V Rotter
1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
It is now well accepted that the p53 C-terminus plays a central role in controlling the activity of the wild-type molecule. In our previous studies, we observed that a C-terminally altered p53 protein (p53AS), generated by an alternative spliced p53 mRNA, induces an attenuated p53-dependent apoptosis, compared to that induced by the regularly spliced form (p53RS). In the present study we analysed the interrelationships between these two physiological variants of wild-type p53, and found that in cells co-expressing both forms, in contrast to the expected additive effect on the induction of apoptosis, p53AS inhibits apoptosis induced by p53RS. This inhibitory effect is specific for p53-dependent apoptosis and was not evident in a p53-independent apoptotic pathway induced by growth factor deprivation. Furthermore, the expression of p53AS in transiently transfected cells caused both inhibition of apoptosis and inhibition of the p53RS-dependent transactivation of a number of p53 target genes. These results suggest that expression of an alternatively spliced p53 form may serve as an additional level in controlling the complexity of p53 function by the C-terminal domain.
Insights
An alternatively spliced p53 variant (p53AS) inhibits apoptosis induced by the regular p53 form (p53RS). This finding reveals a new regulatory mechanism controlling p53 function and apoptosis.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The p53 C-terminus is crucial for regulating wild-type p53 activity.
- Previously, we found an alternatively spliced p53 variant (p53AS) induces less apoptosis than the regular form (p53RS).
Purpose of the Study:
- To investigate the interaction between p53AS and p53RS.
- To determine the functional consequences of co-expressing these p53 variants.
Main Methods:
- Co-expression of p53AS and p53RS in cells.
- Analysis of apoptosis induction via p53-dependent and independent pathways.
- Assessment of p53 target gene transactivation.
Main Results:
- p53AS inhibits p53RS-induced apoptosis, contrary to an additive effect.
- This inhibition is specific to p53-dependent apoptosis.
- p53AS also suppresses p53RS-mediated transactivation of target genes.
Conclusions:
- Alternatively spliced p53 variants can modulate the function of the canonical p53 protein.
- p53AS acts as a negative regulator of p53-dependent apoptosis and transactivation.
- This suggests a novel layer of complexity in p53 regulation via its C-terminal domain.