NPM phosphorylation stimulates Cdk1, overrides G2/M checkpoint and increases leukemic blasts in mice.

Carcinogenesis
Wei DuQishen Pang

Abstract

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 G(2)/M cell cycle arrest, phosphorylation of Cdk1 at Tyr15 (Cdc2(Tyr15)) and increased cytoplasmic accumulation of Cdc25C. Strikingly, stress-induced Cdk1(Tyr15) 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 G(2)/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 p...Continue Reading

References

Apr 21, 1995·The Journal of Biological Chemistry·S D PattersonG I Latter
Dec 15, 1995·European Journal of Biochemistry·N van BelzenF T Bosman
Jan 1, 1996·The Journal of Pathology·Y NozawaF T Bosman
Dec 31, 1997·Journal of the Society for Gynecologic Investigation·L B ShieldsD D Taylor
Feb 19, 2000·Current Opinion in Genetics & Development·C J Sherr, J D Weber
Jun 19, 2001·Biochimica Et Biophysica Acta·V A Smits, R H Medema
Jan 4, 2003·The Journal of Biological Chemistry·Attila SzebeniMark O J Olson
May 27, 2003·Nature Cell Biology·Dmitry V BulavinAlbert J Fornace
Jul 29, 2003·The Journal of Biological Chemistry·Qishen PangGrover C Bagby
Sep 25, 2003·Proceedings of the National Academy of Sciences of the United States of America·Emmanuelle PasseguéIrving L Weissman
Jan 20, 2004·Molecular and Cellular Biology·David BertwistleCharles J Sherr
Apr 15, 2004·Molecular and Cellular Biology·Dony A MaiguelFrance Carrier
Jun 11, 2004·The Journal of Biological Chemistry·Hong ZhangSteven Pelech
Aug 18, 2004·The Journal of Biological Chemistry·June LiQishen Pang
Oct 16, 2004·Molecular and Cellular Biology·Suzanne N BradyJason D Weber
Jan 22, 2005·The New England Journal of Medicine·Brunangelo FaliniUNKNOWN GIMEMA Acute Leukemia Working Party
Jul 12, 2005·Nature·Silvia GrisendiPier Paolo Pandolfi
Oct 4, 2005·Molecular and Cellular Biology·Emanuela ColomboPier Giuseppe Pelicci
Mar 17, 2006·Molecular Biology of the Cell·Emilie LouvetDanièle Hernandez-Verdun
Jun 24, 2006·Nature Reviews. Cancer·Silvia GrisendiPier Paolo Pandolfi
Aug 17, 2006·Journal of Cell Science·Sandeep S Negi, Mark O J Olson

❮ Previous
Next ❯

Citations

Aug 17, 2010·Ageing Research Reviews·Li-Hsin ChenShih-Hwa Chiou
Feb 18, 2014·Molecular & Cellular Proteomics : MCP·Rosalynn C MoldenBenjamin A Garcia
Sep 7, 2019·Journal of Experimental & Clinical Cancer Research : CR·Annapurna PranatharthiSweta Srivastava
Nov 5, 2015·Oncotarget·Rachel Hiu Ha ChingTerence Kin Wah Lee
May 8, 2021·Journal of Cellular Physiology·Fateme Karimi DermaniRazieh Amini

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.