CHIP promotes autophagy-mediated degradation of aggregating mutant p53 in hypoxic conditions

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Tumor suppressor protein p53 is known to aggregate in the hypoxic core of solid tumors.
• C terminus of Hsc70-interacting protein (CHIP) possesses both chaperone and E3 ligase activities, influencing wild-type and mutant p53 levels.

Purpose of the Study:

• To investigate the selective degradation of aggregating mutant p53 by CHIP.
• To elucidate the mechanisms and domains of CHIP involved in p53 degradation.
• To explore the therapeutic implications of CHIP-mediated p53 degradation in hypoxic tumors.

Main Methods:

• CHIP silencing experiments under normoxic and hypoxic conditions.
• Analysis of CHIP domain interactions (U-box and TPR) with aggregating and non-aggregating p53 mutants.
• Investigation of the p53 degradation pathway, including ubiquitination and autophagy.
• Quantification of aggregating p53 levels under various conditions (normoxia, hypoxia, serum starvation).

Main Results:

• CHIP selectively degrades aggregating mutant p53 under both normal and hypoxic conditions.
• CHIP silencing increases aggregating mutant p53 levels, while non-aggregating mutants are unaffected.
• The U-box domain of CHIP binds aggregating p53, while the TPR domain binds non-aggregating p53.
• Mutant p53 degradation by CHIP occurs via K63-linked polyubiquitination and autophagy.
• Aggregating mutant p53 levels are reduced threefold by CHIP under hypoxia and fivefold under serum starvation.
• p53 stabilizes CHIP at the post-translational level, indicating a synergistic interaction.

Conclusions:

• CHIP plays a crucial role in the selective degradation of aggregating mutant p53, particularly in hypoxic tumor environments.
• The distinct domain interactions of CHIP with different p53 forms highlight a specific regulatory mechanism.
• CHIP-mediated autophagy offers a promising therapeutic strategy for targeting oncogenic mutant p53 in solid tumors.