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KLHL4, a novel p53 target gene, inhibits cell proliferation by activating p21WAF/CDKN1A

Seo-Hyun Choi1, Su-Yeon Cho1, Jiyang Song1

  • 1Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMoon-Ku, Seoul, 03722, Republic of Korea.

Biochemical and Biophysical Research Communications
|August 6, 2020
PubMed

Insights

The study reveals that KLHL4, a protein linked to X-linked cleft palate, is upregulated by p53. This upregulation inhibits cell proliferation by activating the p21 gene, suggesting a new role for KLHL4 in cell cycle regulation.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • KLHL4 is a member of the KLHL protein family, known to bind Cul3 E3 ligase and mediate protein ubiquitination.
  • The KLHL4 gene is located on the X chromosome and is associated with X-linked cleft palate (CPX).
  • The precise biological functions of KLHL4 remain largely uncharacterized.

Purpose of the Study:

  • To investigate the biological functions of KLHL4.
  • To determine if KLHL4 is a target gene of p53.
  • To elucidate the role of KLHL4 in cell proliferation and cell cycle regulation.

Main Methods:

  • Microarray analysis of HEK293A cells expressing ectopic p53.
  • Western blot analysis to assess KLHL4 protein expression.
  • Co-immunoprecipitation to study protein interactions.
  • Analysis of p21(WAF/CDKN1A) transcription activation.
  • Assessment of MEF cell proliferation in Klhl4 knockout models.

Main Results:

  • KLHL4 mRNA expression increased 3-fold in HEK293A cells with ectopic p53.
  • Both KLHL4 mRNA and protein levels were elevated by p53 or DNA damage, indicating KLHL4 is a p53 target gene.
  • KLHL4 activates p21(WAF/CDKN1A) transcription by enhancing p53 binding to the p21 promoter.
  • KLHL4 interacts with Cul3, suggesting a role in ubiquitin-mediated degradation.
  • Klhl4 knockout MEF cells exhibited faster proliferation compared to wild-type cells.

Conclusions:

  • KLHL4 is a p53 target gene that inhibits cell proliferation.
  • KLHL4 promotes p21(WAF/CDKN1A) transcription, a key cell-cycle inhibitor.
  • These findings suggest KLHL4 plays a role in regulating cell proliferation through the p53-p21 pathway.
Keywords:
Cell proliferationCullinDNA damageKLHL4Ubiquitinationp21p53

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