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Cell Cycle. 2013 Dec 15;12(24):3770-80. doi: 10.4161/cc.26660. Epub 2013 Oct 4.

SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways.

Author information

1
Department of Molecular Biosciences; The Wenner-Gren Institute; Stockholm University; Stockholm, Sweden; Science for Life Laboratory; Division of Translational Medicine and Chemical Biology; Department of Medical Biochemistry and Biophysics; Karolinska Institute; Stockholm, Sweden.
2
Department of Surgery, Otolaryngology; Yale University; New Haven, CT USA; Cancer Center; Yale University, New Haven, CT USA.
3
Science for Life Laboratory; Division of Translational Medicine and Chemical Biology; Department of Medical Biochemistry and Biophysics; Karolinska Institute; Stockholm, Sweden.
4
Department of Molecular Biosciences; The Wenner-Gren Institute; Stockholm University; Stockholm, Sweden.

Abstract

The DNA damage response is coordinated by phosphatidylinositol 3-kinase-related kinases, ATM, ATR, and DNA-PK. SMG-1 is the least studied stress-responsive member of this family. Here, we show that SMG-1 regulates the G 1/S checkpoint through both a p53-dependent, and a p53-independent pathway. We identify Cdc25A as a new SMG-1 substrate, and show that cells depleted of SMG-1 exhibit prolonged Cdc25A stability, failing to inactivate CDK2 in response to radiation. Given an increased tumor growth following depletion of SMG-1, our data demonstrate a novel role for SMG-1 in regulating Cdc25A and suppressing oncogenic CDK2 driven proliferation, confirming SMG-1 as a tumor suppressor.

KEYWORDS:

CDK2; Cdc25A; G1/S checkpoint; SMG-1; cell cycle; p53; tumor suppressor; tumorigenesis

PMID:
24107632
PMCID:
PMC3905069
DOI:
10.4161/cc.26660
[Indexed for MEDLINE]
Free PMC Article

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