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REGγ deficiency promotes premature aging via the casein kinase 1 pathway

Lei Li1, Dengpan Zhao, Haibin Wei

  • 1Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.

Proceedings of the National Academy of Sciences of the United States of America
|June 15, 2013
PubMed

Insights

The proteasome activator REGγ is crucial for preventing premature aging by regulating casein kinase 1δ (CK1δ), Mdm2, and tumor protein 53 (p53) levels. This discovery offers new insights into aging and potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Aging Research
  • Proteostasis

Background:

  • The proteasome activator REGγ (11S regulatory particles, 28-kDa proteasome activator) is implicated in regulating tumor protein 53 (p53).
  • The precise molecular mechanisms and in vivo significance of the REGγ-p53 interaction are not fully understood.

Purpose of the Study:

  • To elucidate the molecular interplay between REGγ and p53 in vivo.
  • To investigate the role of REGγ in aging and identify key regulatory pathways involved.

Main Methods:

  • Generation and analysis of REGγ-deficient mice.
  • Antibody array analysis to identify REGγ targets.
  • Gene silencing and activity inhibition of CK1δ.
  • Assessment of Mdm2 and p53 protein levels and transcription.
  • Cellular senescence assays in mouse embryonic fibroblasts (MEFs).

Main Results:

  • REGγ-deficient mice exhibit premature aging phenotypes linked to elevated CK1δ and p53.
  • CK1δ is identified as a direct target of REGγ; its inhibition stabilizes Mdm2.
  • REGγ deficiency leads to reduced Mdm2 protein despite enhanced transcription, correlating with increased p53.
  • Restoration of Mdm2 in REGγ-deficient MEFs rescues cellular senescence.
  • p53 haplodeficiency attenuates premature aging in REGγ-deficient mice.

Conclusions:

  • A novel regulatory pathway (REGγ-CK1δ-Mdm2-p53) governing cellular aging is established.
  • This pathway highlights the critical role of CK1δ-Mdm2-p53 in the aging process.
  • Modulating REGγ-proteasome activity may offer a therapeutic strategy for aging-associated disorders.
Keywords:
PA28γcasein kinase 1

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