PEA15 regulates the DNA damage-induced cell cycle checkpoint and oncogene-directed transformation.
Regulation of the DNA damage response and cell cycle progression is critical for maintaining genome integrity. Here, we report that in response to DNA damage, COPS5 deubiquitinates and stabilizes PEA15 in an ATM kinase-dependent manner. PEA15 expression oscillates throughout the cell cycle, and the loss of PEA15 accelerates cell cycle ... progression by activating CDK6 expression via the c-JUN transcription factor. Cells lacking PEA15 exhibit a DNA damage-induced G2/M checkpoint defect due to increased CDC25C activity and, consequentially, higher cyclin-dependent kinase 1 (CDK1)/cyclin B activity, and accordingly they have an increased rate of spontaneous mutagenesis. We find that oncogenic RAS inhibits PEA15 expression and that ectopic PEA15 expression blocks RAS-mediated transformation, which can be partially rescued by ectopic expression of CDK6. Finally, we show that PEA15 expression is downregulated in colon, breast, and lung cancer samples. Collectively, our results demonstrate that tumor suppressor PEA15 is a regulator of genome integrity and is an integral component of the DNA damage response pathway that regulates cell cycle progression, the DNA-damage-induced G2/M checkpoint, and cellular transformation.
Mesh Terms:
Amino Acid Sequence, Animals, Ataxia Telangiectasia Mutated Proteins, COP9 Signalosome Complex, Cell Cycle Checkpoints, Cell Line, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase 6, DNA Damage, DNA Methylation, Epigenesis, Genetic, G2 Phase Cell Cycle Checkpoints, Gene Silencing, Humans, Intracellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Oncogenes, Peptide Hydrolases, Phosphoproteins, Proteasome Endopeptidase Complex, Protein Binding, Protein Processing, Post-Translational, Protein Stability, Proteolysis, Two-Hybrid System Techniques, Ubiquitination, cdc25 Phosphatases, ras Proteins
Amino Acid Sequence, Animals, Ataxia Telangiectasia Mutated Proteins, COP9 Signalosome Complex, Cell Cycle Checkpoints, Cell Line, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase 6, DNA Damage, DNA Methylation, Epigenesis, Genetic, G2 Phase Cell Cycle Checkpoints, Gene Silencing, Humans, Intracellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Oncogenes, Peptide Hydrolases, Phosphoproteins, Proteasome Endopeptidase Complex, Protein Binding, Protein Processing, Post-Translational, Protein Stability, Proteolysis, Two-Hybrid System Techniques, Ubiquitination, cdc25 Phosphatases, ras Proteins
Mol. Cell. Biol.
Date: Jun. 01, 2014
PubMed ID: 24710276
View in: Pubmed Google Scholar
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