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Ras-induced reactive oxygen species promote growth factor-independent proliferation in human CD34+ hematopoietic progenitor cells

Hole, Paul Spencer, Pearn, Lorna, Tonks, Amanda Jayne, James, Philip Eurig, Burnett, Alan Kenneth, Darley, Richard Lawrence and Tonks, Alex 2010. Ras-induced reactive oxygen species promote growth factor-independent proliferation in human CD34+ hematopoietic progenitor cells. Blood 115 (6) , pp. 1238-1246. 10.1182/blood-2009-06-222869

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Abstract

Excessive production of reactive oxygen species (ROS) is a feature of human malignancy and is often triggered by activation of oncogenes such as activated Ras. ROS act as second messengers and can influence a variety of cellular process including growth factor responses and cell survival. We have examined the contribution of ROS production to the effects of N-RasG12D and H-RasG12V on normal human CD34+ progenitor cells. Activated Ras strongly up-regulated the production of both superoxide and hydrogen peroxide through the stimulation of NADPH oxidase (NOX) activity, without affecting the expression of endogenous antioxidants or the production of mitochondrially derived ROS. Activated Ras also promoted both the survival and the growth factor–independent proliferation of CD34+ cells. Using oxidase inhibitors and antioxidants, we found that excessive ROS production by these cells did not contribute to their enhanced survival; rather, ROS promoted their growth factor–independent proliferation. Although Ras-induced ROS production specifically activated the p38MAPK oxidative stress response, this failed to induce expression of the cell-cycle inhibitor, p16INK4A; instead, ROS promoted the expression of D cyclins. These data are the first to show that excessive ROS production in the context of oncogene activation can promote proliferative responses in normal human hematopoietic progenitor cells.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QR Microbiology
R Medicine > RC Internal medicine
Publisher: American Society of Hematology
ISSN: 0006-4971
Last Modified: 08 Aug 2019 20:37
URI: http://orca.cf.ac.uk/id/eprint/28335

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