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Titolo:
The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01
Autore:
Graves, PR; Yu, LJ; Schwarz, JK; Gales, J; Sausville, EA; OConnor, PM; Piwnica-Worms, H;
Indirizzi:
Washington Univ, Sch Med, Howard Hughes Med Inst, Dept Cell Biol & Physiol, St Louis, MO 63110 USA Washington Univ St Louis MO USA 63110 l & Physiol, St Louis, MO 63110 USA NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892 Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA NCI, Dev Therapeut Program, Div Canc Treatment & Diagnosis, NIH, Bethesda,MD 20892 USA NCI Bethesda MD USA 20892 eatment & Diagnosis, NIH, Bethesda,MD 20892 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 8, volume: 275, anno: 2000,
pagine: 5600 - 5605
SICI:
0021-9258(20000225)275:8<5600:TCPKAT>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
CELL-CYCLE REGULATION; TYROSINE KINASE; DNA-DAMAGE; NUCLEAR EXPORT; FISSION YEAST; G(2) ARREST; HUMAN WEE1; PHOSPHORYLATES CDC2; CHECKPOINT PATHWAY; DEPENDENT KINASES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
65
Recensione:
Indirizzi per estratti:
Indirizzo: Piwnica-Worms, H Washington Univ, Sch Med, Howard Hughes Med Inst, Dept Cell Biol & Physiol, Box 8228,660 S Euclid Ave, St Louis, MO 63110 USA Washington Univ Box 8228,660 S Euclid Ave St Louis MO USA 63110
Citazione:
P.R. Graves et al., "The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01", J BIOL CHEM, 275(8), 2000, pp. 5600-5605

Abstract

A checkpoint operating in the G(2) phase of the cell cycle prevents entry into mitosis in the presence of DNA damage, UCN-01, a protein kinase inhibitor currently undergoing clinical trials for cancer treatment, abrogates G(2) checkpoint function and sensitizes p53-defective cancer cells to DNA damaging agents. In most species, the G(2) checkpoint prevents the Cdc25 phosphatase from removing inhibitory phosphate groups from the mitosis-promotingkinase Cdc2. This is accomplished by maintaining Cdc25 in a phosphorylatedform that binds 14-3-3 proteins. The checkpoint kinases, Chk1 and Cds1, are proposed to regulate the interactions between human Cdc25C and 14-3-3 proteins by phosphorylating Cdc25C on serine 216. 14-3-3 proteins, in turn, function to keep Cdc25C out of the nucleus. Here we report that UCN-01 causedloss of both serine 216 phosphorylation and 14-3-3 binding to Cdc25C in DNA-damaged cells. In addition, UCN-01 potently inhibited the ability of Chk1to phosphorylate Cdc25C in vitro. In contrast, Cds1 was refractory to inhibition by UCN-01 in vitro, and Cds1 was still phosphorylated in irradiated cells treated with UCN-01. Thus, neither Cds1 nor kinases upstream of Cds1,such as ataxia telangiectasia-mutated, are targets of UCN-01 action in vivo. Taken together our results identify the Chk1 kinase and the Cdc25C pathway as potential targets of G(2) checkpoint abrogation by UCN-01.

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Documento generato il 26/09/20 alle ore 02:03:52