Journal Article

NPM phosphorylation stimulates Cdk1, overrides G<sub>2</sub>/M checkpoint and increases leukemic blasts in mice

Wei Du, Yun Zhou, Suzette Pike and Qishen Pang

in Carcinogenesis

Volume 31, issue 2, pages 302-310
Published in print February 2010 | ISSN: 0143-3334
Published online November 2009 | e-ISSN: 1460-2180 | DOI:
NPM phosphorylation stimulates Cdk1, overrides G2/M checkpoint and increases leukemic blasts in mice

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An elevated level of nucleophosmin (NPM) is often found in actively proliferative cells including human tumors. To identify the regulatory role for NPM phosphorylation in proliferation and cell cycle control, a series of mutants targeting the consensus cyclin-dependent kinase (CDK) phosphorylation sites was created to mimic or abrogate either single-site or multi-site phosphorylation. Simultaneous inactivation of two CDK phosphorylation sites at Ser10 and Ser70 (NPM-AA) induced G2/M cell cycle arrest, phosphorylation of Cdk1 at Tyr15 (Cdc2Tyr15) and increased cytoplasmic accumulation of Cdc25C. Strikingly, stress-induced Cdk1Tyr15 and Cdc25C sequestration was suppressed by expression of a phosphomimetic NPM mutant created on the same CDK sites (S10E/S70E, NPM-EE). Further analysis revealed that phosphorylation of NPM at both Ser10 and Ser70 was required for proper interaction between Cdk1 and Cdc25C. Moreover, NPM-EE directly bound to Cdc25C and prevented phosphorylation of Cdc25C at Ser216 during mitosis. Finally, NPM-EE overrided stress-induced G2/M arrest and increased leukemia blasts in a NOD/SCID xenograft model. Thus, these findings reveal a novel function of NPM on regulation of cell cycle progression, in which phosphorylation of NPM controls cell cycle progression at G2/M transition through modulation of Cdk1 and Cdc25C activities.

Journal Article.  5626 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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