Activated Jak2 with the V617F point mutation promotes G1/S phase transition

The Journal of Biological Chemistry
Christoph WalzMartin Sattler

Abstract

Hematopoietic stem cells in myeloproliferative diseases mostly retain the potential to differentiate but are characterized by hyper-responsiveness to growth factors, as well as partial factor-independent growth. The V617F activating point mutation in Jak2 has recently been associated with myeloproliferative disorders. Using various cell line models, mechanisms that contribute to Jak2V617-mediated signaling were investigated. Treatment of the Jak2V617F mutant-expressing erythroid leukemia cell line HEL with a small molecule Jak2 inhibitor was associated with a dose-dependent G(1) cell cycle arrest. This inhibition correlated with decreased expression of cyclin D2 and increased expression of the cell cycle inhibitor p27(Kip). Inhibition of Jak2V617F with a Jak2-targeted small interfering RNA approach resulted in a similar phenotype. Mechanisms leading to altered p27(Kip) and cyclin D2 likely involve inhibition of STAT5, a major target of Jak2 in hematopoietic cells, because a constitutively active form of STAT5 reduced p27(Kip) and increased cyclin D2 expression. Jak2V617F and constitutively active STAT5 also induced high levels of reactive oxygen species, which are sufficient to promote G(1)/S phase transition. In contrast, trea...Continue Reading

References

Nov 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·A Sala, B Calabretta
Aug 20, 1996·Proceedings of the National Academy of Sciences of the United States of America·M W KieranL I Zon
May 8, 1998·Toxicology and Applied Pharmacology·M SekharamJ Wu
Jun 2, 2000·The Journal of Biological Chemistry·M SattlerJ D Griffin
Apr 6, 2002·Bioorganic & Medicinal Chemistry Letters·James E ThompsonJulie A DeMartino
Apr 11, 2003·Molecular Biology of the Cell·Pipsa SaharinenOlli Silvennoinen
Dec 4, 2004·Genome Biology·Kunihiro YamaokaJohn J O'Shea
Mar 23, 2005·Lancet·E Joanna BaxterUNKNOWN Cancer Genome Project
Apr 29, 2005·The New England Journal of Medicine·Robert KralovicsRadek C Skoda
May 3, 2005·The Journal of Biological Chemistry·Runxiang ZhaoZhizhuang Joe Zhao
Oct 22, 2005·The Journal of Biological Chemistry·Judith StaerkStefan N Constantinescu

❮ Previous
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Citations

Sep 29, 2009·Nature·Mark A DawsonTony Kouzarides
Dec 8, 2006·The New England Journal of Medicine·Peter J Campbell, Anthony R Green
Jul 30, 2010·The Journal of Biological Chemistry·Anurima MajumderPeter P Sayeski
Aug 30, 2008·Molecular Cancer Therapeutics·Jacqueline SayyahPeter P Sayeski
Aug 2, 2008·Blood·Jean-Jacques LatailladeUNKNOWN French INSERM and the European EUMNET Networks on Myelofibrosis
Jul 3, 2009·Blood·Margret S FernandesMartin Sattler
Jan 1, 2011·Revista brasileira de hematologia e hemoterapia·Michelle Maccarini Barcelos, Maria Cláudia Santos-Silva
Sep 25, 2012·Cellular and Molecular Life Sciences : CMLS·Verónica ParrillasMario Mellado
Jun 11, 2010·Genes and Immunity·J K MoralesJ J Ryan
Sep 11, 2014·Journal of Cellular Physiology·Anita Roy, Subrata Banerjee
Oct 25, 2011·Experimental Hematology·Anurima MajumderPeter P Sayeski
Aug 25, 2010·Pharmacology & Therapeutics·Gabriella LeonarduzziGiuseppe Poli
Sep 26, 2009·Clinical Lymphoma & Myeloma·Isabelle Plo, William Vainchenker
May 6, 2009·Biochemical Pharmacology·Anjili MathurEric Bachman
Sep 15, 2006·Mayo Clinic Proceedings·Ricardo H AlvarezJorge E Cortes
Oct 8, 2008·American Journal of Hematology·Wu Hai-JiangDuan Hui-Jun
Jan 11, 2013·Journal of Cellular and Molecular Medicine·Karoline GäblerClaude Haan
Jun 27, 2014·American Journal of Hematology·Xin ZhangSaghi Ghaffari
Jul 14, 2010·Biochemical and Biophysical Research Communications·Xu-Liang ShenFang-Ping Chen
Feb 22, 2012·Expert Opinion on Therapeutic Targets·Mamatha M ReddyMartin Sattler
Dec 10, 2014·Clinical Lymphoma, Myeloma & Leukemia·Florence PasquierWilliam Vainchenker
Jul 25, 2012·Biochimica Et Biophysica Acta·Maria Kleppe, Ross L Levine
Nov 9, 2011·Blood·Emilie-Fleur GautierVéronique Mansat-De Mas
Oct 22, 2016·Experimental Hematology·Ashok Kumar JayaveluThomas G Cotter
May 14, 2017·Blood·Prithviraj Bose, Srdan Verstovsek

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