Abstract
DNA damage checkpoints are essential for maintenance of genome integrity. We report here that inducible overexpression of the transcription factor Sharp-1 results in an S and G2/M cell cycle arrest, concomitant with the upregulation of Brca1 and GADD45alpha expression. In addition, we show that endogenous Sharp-1 mRNA is increased by DNA-damaging agents. Consistently, Sharp-1 overexpressing cells exhibit reduced apoptosis in response to chemotherapeutic drugs along with lower p53 expression and activity. Our studies identify a novel function for Sharp-1 in cell cycle arrest and DNA damage-induced apoptosis. Inappropriate Sharp-1 expression may therefore be associated with tumorigenesis.
2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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BRCA1 Protein / genetics
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Blotting, Western
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Caspase 3 / metabolism
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Cell Cycle / drug effects
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Cell Cycle / genetics*
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Cell Cycle Proteins / genetics
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Cisplatin / pharmacology
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DNA Damage / drug effects
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DNA Damage / genetics*
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Etoposide / pharmacology
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Fluorouracil / pharmacology
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Mice
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NIH 3T3 Cells
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Nuclear Proteins / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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BRCA1 Protein
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Bhlhb3 protein, mouse
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Cell Cycle Proteins
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Gadd45a protein, mouse
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Nuclear Proteins
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Transcription Factors
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Tumor Suppressor Protein p53
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Etoposide
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Caspase 3
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Cisplatin
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Fluorouracil