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P16INK4A drives RB1 degradation by UTP14A-catalyzed K810 ubiquitination

Wenjie Weng1, Baozhen Zhang1, Dajun Deng1

  • 1Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing) Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China.

Iscience
|October 1, 2024
PubMed

Insights

The study reveals that P16INK4A promotes RB1 degradation via UTP14A, forming a negative feedback loop. This P16INK4A-UTP14A-RB1 axis impacts cell cycle regulation and proteome ubiquitination, offering potential anticancer drug targets.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • P16INK4A and RB1 expression are inversely correlated in cancer.
  • P16INK4A inhibits CDK4-mediated RB1 phosphorylation.
  • The coordinated regulation of cell cycle by P16INK4A and RB1 requires further investigation.

Purpose of the Study:

  • To elucidate the regulatory relationship between P16INK4A and RB1.
  • To investigate the role of P16INK4A in RB1 ubiquitination and degradation.
  • To explore the function of P16INK4A in regulating proteome-scale ubiquitination and cell proliferation.

Main Methods:

  • Western blotting to assess protein levels and ubiquitination.
  • Immunoprecipitation to study protein interactions.
  • Cell cycle analysis to evaluate proliferation.

Main Results:

  • P16INK4A upregulates the E3 ligase UTP14A, promoting RB1 ubiquitination at K810 and subsequent degradation.
  • Loss of P16INK4A disrupts UTP14A-mediated RB1 degradation, leading to RB1 accumulation.
  • P16INK4A loss inhibits RB1 ubiquitination independently of cell cycle progression.
  • P16INK4A regulates proteome-scale ubiquitination in a cell cycle-dependent manner, inhibiting proliferation.

Conclusions:

  • A negative feedback loop exists between P16INK4A and RB1 expression.
  • Disruption of this loop can partially rescue biological outcomes of P16INK4A loss.
  • P16INK4A has a novel role in regulating proteome-scale ubiquitination and inhibiting cell proliferation, presenting a potential therapeutic target for cancer.
Keywords:
Cellular physiologyFunctional aspects of cell biologyMolecular interactionMolecular physiology

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