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Chk1 regulates the ...
Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A.
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Storgaard Sørensen, Claus (author)
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Syljuåsen, Randi G (author)
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Falck, Jacob (author)
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Schroeder, Tine (author)
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- Rönnstrand, Lars (author)
- Ludwiginstitutet för Cancerforskning
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Khanna, Kum Kum (author)
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Zhou, Bin-Bing (author)
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Bartek, Jiri (author)
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Lukas, Jiri (author)
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(creator_code:org_t)
- 2003
- 2003
- English.
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In: Cancer Cell. - 1535-6108. ; 3:3, s. 247-58
- Related links:
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http://www.ncbi.nlm....
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https://urn.kb.se/re...
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Abstract
Subject headings
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- Chk1 kinase coordinates cell cycle progression and preserves genome integrity. Here, we show that chemical or genetic ablation of human Chk1 triggered supraphysiological accumulation of the S phase-promoting Cdc25A phosphatase, prevented ionizing radiation (IR)-induced degradation of Cdc25A, and caused radioresistant DNA synthesis (RDS). The basal turnover of Cdc25A operating in unperturbed S phase required Chk1-dependent phosphorylation of serines 123, 178, 278, and 292. IR-induced acceleration of Cdc25A proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of Chk1 and Chk2 kinases. Finally, phosphorylation of Chk1 by ATM was required to fully accelerate the IR-induced degradation of Cdc25A. Our results provide evidence that the mammalian S phase checkpoint functions via amplification of physiologically operating, Chk1-dependent mechanisms.
Keyword
- Cell Cycle/*physiology/radiation effects
- Cell Cycle Proteins
- DNA Replication/radiation effects
- DNA-Binding Proteins
- Enzyme Activation
- Hela Cells
- Humans
- Kinetics
- Models; Biological
- Phosphorylation
- Protein Kinases/*metabolism
- Protein-Serine-Threonine Kinases/physiology
- Radiation; Ionizing
- S Phase/radiation effects
- Serine/metabolism
- Signal Transduction
- Tumor Cells; Cultured
- Tumor Suppressor Proteins
- cdc25 Phosphatase/*physiology/radiation effects
Publication and Content Type
- ref (subject category)
- art (subject category)
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