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SOCS3 regulates p21 expression and cell cycle arrest in response to DNA damage

John C Sitko1, Brian Yeh, Moonhong Kim

  • 1Department of Radiation Oncology, UCLA School of Medicine, United States.

Cellular Signalling
|September 17, 2008
PubMed

Insights

Suppressor of Cytokine Signaling (SOCS)-3 is crucial for radiation-induced G1 arrest. SOCS3 deficiency impairs DNA damage response, leading to cell cycle G2/M accumulation and reduced p21 expression.

Area of Science:

  • Cellular and Molecular Biology
  • Genetics and Genomics
  • Cancer Research

Background:

  • Genotoxic agents like ionizing radiation induce cell cycle arrest at G1/S and G2/M checkpoints for DNA repair.
  • DNA damage response involves p53-dependent p21 (Cip1/Waf-1) expression, inhibiting cyclin-dependent kinases and blocking S phase entry.
  • Signaling proteins modulating DNA damage response pathways remain incompletely characterized.

Purpose of the Study:

  • To identify novel regulators of radiation-induced G1 arrest.
  • To investigate the role of Suppressor of Cytokine Signaling (SOCS)-3 in the DNA damage response.
  • To elucidate the mechanism by which SOCS3 influences cell cycle control following DNA damage.

Main Methods:

  • Utilized SOCS3-deficient (knockout) fibroblasts and wild-type (WT) fibroblasts.
  • Irradiated cells and assessed cell cycle distribution (G1, S, G2/M phases).
  • Measured phosphorylation of p53 and H2AX, and quantified p21 and STAT3 expression.
  • Restored G1 arrest in SOCS3 knockout cells via retroviral transduction of WT SOCS3 or dominant-negative STAT3.

Main Results:

  • SOCS3-deficient fibroblasts failed to undergo G1 arrest and accumulated in G2/M phase after radiation.
  • SOCS3 knockout cells exhibited normal p53 and H2AX phosphorylation but failed to upregulate p21 expression.
  • Elevated STAT3 phosphorylation was observed in SOCS3-deficient cells compared to WT cells.
  • Normal G1 arrest was restored in SOCS3 KO cells by reintroducing WT SOCS3 or inhibiting STAT3.

Conclusions:

  • SOCS3 is a critical regulator of radiation-induced G1 arrest.
  • SOCS3 negatively regulates STAT3-dependent radioresistant DNA synthesis.
  • SOCS3 promotes p53-dependent p21 expression, contributing to genome stability.

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