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Phosphorylation and stabilization of TAp63gamma by IkappaB kinase-beta
Mary MacPartlin1, Shelya X Zeng, Hua Lu
1Center for Hematologic Malignancies, Oregon Health & Science University Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.
Abstract:
Post-translational modification of the p53 family members is key to their regulation. Here we report the phosphorylation of TAp63gamma, but not DeltaNp63gamma, by IkappaB kinase beta (IKKbeta). Activation of IKKbeta by gamma radiation or tumor necrosis factor-alpha led to increased TAp63gamma protein levels in cells. IKKbeta, but not its kinase-defective mutant IKKbeta-K44A, led to this observed stabilization of TAp63gamma. This stabilization of TAp63gamma in response to gamma radiation was significantly decreased in the absence of IKKbeta. Phosphorylation of TAp63gamma blocks ubiquitylation and possible degradation of this protein. We postulate that phosphorylation of TAp63gamma by IKKbeta stabilizes the TAp63gamma protein by blocking ubiquitylation-dependent degradation of this protein.
Insights
IkappaB kinase beta (IKKbeta) phosphorylates and stabilizes TAp63gamma, a key p53 family member. This phosphorylation prevents protein degradation, impacting cellular regulation after DNA damage.
Area of Science:
- Molecular Biology
- Cellular Regulation
- Protein Biochemistry
Background:
- Post-translational modifications critically regulate p53 family proteins.
- Understanding TAp63gamma regulation is essential for comprehending cellular responses to stress.
Purpose of the Study:
- To investigate the role of IkappaB kinase beta (IKKbeta) in TAp63gamma post-translational modification.
- To elucidate the mechanism by which IKKbeta affects TAp63gamma protein stability.
Main Methods:
- Investigated the phosphorylation of TAp63gamma and DeltaNp63gamma by IKKbeta in vitro and in cell-based assays.
- Utilized gamma radiation and tumor necrosis factor-alpha to activate IKKbeta.
- Employed a kinase-defective IKKbeta mutant (IKKbeta-K44A) to confirm IKKbeta's kinase activity dependence.
- Assessed TAp63gamma protein levels and ubiquitylation status under various conditions, including IKKbeta knockdown.
Main Results:
- IKKbeta specifically phosphorylates TAp63gamma, but not DeltaNp63gamma.
- Activation of IKKbeta by gamma radiation or TNF-alpha increases TAp63gamma protein levels.
- IKKbeta-mediated stabilization of TAp63gamma is dependent on its kinase activity and presence.
- Phosphorylation by IKKbeta inhibits TAp63gamma ubiquitylation and subsequent degradation.
Conclusions:
- IKKbeta plays a crucial role in stabilizing TAp63gamma protein levels through phosphorylation.
- This stabilization mechanism protects TAp63gamma from ubiquitylation-dependent degradation, particularly in response to DNA damage.
- The findings reveal a novel regulatory pathway for the p53 family member TAp63gamma.
