SOCS3 regulates p21 expression and cell cycle arrest in response to DNA damage.
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.
Sitko
John C
JC
Department of Radiation Oncology, UCLA School of Medicine, United States.
Yeh
Brian
B
Kim
Moonhong
M
Zhou
Hong
H
Takaesu
Giichi
G
Yoshimura
Akihiko
A
McBride
William H
WH
Jewett
Anahid
A
Jamieson
Christina A M
CA
Cacalano
Nicholas A
NA
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle / Q000528:radiation effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D016193:G1 Phase; D016195:G2 Phase; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D010766:Phosphorylation; D011839:Radiation, Ionizing; D016196:S Phase; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016159:Tumor Suppressor Protein p53
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