Document Detail

SOCS3 regulates p21 expression and cell cycle arrest in response to DNA damage.
MedLine Citation:
PMID:  18793717     Owner:  NLM     Status:  MEDLINE    
Genotoxic agents such as ionizing radiation trigger cell cycle arrest at the G1/S and G2/M checkpoints, allowing cells to repair damaged DNA before entry into mitosis. DNA damage-induced G1 arrest involves p53-dependent expression of p21 (Cip1/Waf-1), which inhibits cyclin-dependent kinases and blocks S phase entry. While much of the core DNA damage response has been well-studied, other signaling proteins that intersect with and modulate this response remain uncharacterized. In this study, we identify Suppressor of Cytokine Signaling (SOCS)-3 as an important regulator of radiation-induced G1 arrest. SOCS3-deficient fibroblasts fail to undergo G1 arrest and accumulate in the G2/M phase of the cell cycle. SOCS3 knockout cells phosphorylate p53 and H2AX normally in response to radiation, but fail to upregulate p21 expression. In addition, STAT3 phosphorylation is elevated in SOCS3-deficient cells compared to WT cells. Normal G1 arrest can be restored in SOCS3 KO cells by retroviral transduction of WT SOCS3 or a dominant-negative mutant of STAT3. Our results suggest a novel function for SOCS3 in the control of genome stability by negatively regulating STAT3-dependent radioresistant DNA synthesis, and promoting p53-dependent p21 expression.
John C Sitko; Brian Yeh; Moonhong Kim; Hong Zhou; Giichi Takaesu; Akihiko Yoshimura; William H McBride; Anahid Jewett; Christina A M Jamieson; Nicholas A Cacalano
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Publication Detail:
Type:  Journal Article     Date:  2008-08-23
Journal Detail:
Title:  Cellular signalling     Volume:  20     ISSN:  1873-3913     ISO Abbreviation:  Cell. Signal.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-10     Completed Date:  2009-02-06     Revised Date:  2013-07-26    
Medline Journal Info:
Nlm Unique ID:  8904683     Medline TA:  Cell Signal     Country:  England    
Other Details:
Languages:  eng     Pagination:  2221-30     Citation Subset:  IM    
Department of Radiation Oncology, UCLA School of Medicine, United States.
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MeSH Terms
Cell Cycle / radiation effects*
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
DNA Damage*
G1 Phase
G2 Phase
Mice, Knockout
Radiation, Ionizing
S Phase
STAT1 Transcription Factor / metabolism
STAT3 Transcription Factor / metabolism
Suppressor of Cytokine Signaling Proteins / metabolism*
Time Factors
Tumor Suppressor Protein p53 / metabolism
Grant Support
R01 CA087887/CA/NCI NIH HHS; R01 CA087887-03/CA/NCI NIH HHS
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p21; 0/STAT1 Transcription Factor; 0/STAT3 Transcription Factor; 0/Socs3 protein, mouse; 0/Stat1 protein, mouse; 0/Stat3 protein, mouse; 0/Suppressor of Cytokine Signaling Proteins; 0/Tumor Suppressor Protein p53

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