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WSB1 overcomes oncogene-induced senescence by targeting ATM for degradation

Jung Jin Kim1, Seung Baek Lee1, Sang-Yeop Yi2

  • 1Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.

Cell Research
|December 14, 2016
PubMed

Insights

WD repeat and SOCS box-containing protein 1 (WSB1) helps cancer cells bypass oncogene-induced senescence (OIS). WSB1 promotes ATM degradation, facilitating abnormal cell proliferation and tumor development.

Area of Science:

  • Cellular Biology
  • Cancer Research
  • Molecular Oncology

Background:

  • Oncogene-induced senescence (OIS) is a critical tumor suppressor mechanism.
  • The pathways by which cancer cells overcome OIS remain incompletely understood.
  • Understanding OIS evasion is crucial for developing cancer therapies.

Purpose of the Study:

  • To investigate the role of WD repeat and SOCS box-containing protein 1 (WSB1) in overcoming OIS.
  • To elucidate the molecular mechanism by which WSB1 facilitates tumor development.
  • To identify upstream regulators of WSB1 in the context of OIS evasion.

Main Methods:

  • Assays to assess OIS bypass and cellular transformation.
  • Ubiquitination and degradation assays for ATM.
  • Kinase assays to identify upstream regulators of WSB1.
  • Analysis of WSB1 expression in human cancer tissues.

Main Results:

  • WSB1 expression promotes bypass of OIS, leading to abnormal proliferation and cellular transformation.
  • WSB1 induces ATM ubiquitination and degradation, facilitating escape from OIS.
  • CDKs phosphorylate and activate WSB1 through promoting its monomerization.
  • WSB1-mediated ATM degradation is an early event in tumorigenesis.

Conclusions:

  • WSB1 is a key E3 ubiquitin ligase involved in overcoming the OIS barrier.
  • WSB1 promotes tumorigenesis by degrading ATM and disrupting senescence.
  • WSB1 represents a potential therapeutic target for early-stage cancers.

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