{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T02:45:41Z","timestamp":1791081941308,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2009,5,14]],"date-time":"2009-05-14T00:00:00Z","timestamp":1242259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Odyssey Program of the M.D. Anderson Cancer Center"},{"name":"Longevity Foundation"},{"name":"A-T Children's Project in Deerfield Beach, FL"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Ataxia-telangiectasia (A-T) is a genetic disorder caused by a mutation of the Atm gene, which controls DNA repair, cell cycling, and redox homeostasis. Even though oxidative stress has been implicated in the neurological anomalies in A-T, the effects of ATM loss on neural stem cell (NSC) survival has remained elusive. In this study, we investigated the effects of oxidative stress on NSC proliferation in an animal model for A-T neurodegeneration. We found that cultured subventricular zone neurosphere cells from Atm\u2212\/\u2212 mice show impaired proliferation, as well as intrinsic elevation of reactive oxygen species (ROS) levels, compared with those from Atm+\/+ mice. We also show that increasing the levels of ROS by H2O2 treatment significantly reduces Atm+\/+ neurosphere formation and proliferation. In Atm\u2212\/\u2212 neurosphere cells, the Akt and Erk1\/2 pathways are disrupted, together with enhanced activity of the p38 mitogen-activated protein kinase (MAPK). Treatment of these cells with the antioxidant N-acetyl-L-cysteine (NAC) or with a p38 MAPK inhibitor restores normal proliferation and reduced expression of p21cip1 and p27kip1 in the Atm\u2212\/\u2212 NSCs. These observations indicate that ATM plays a crucial role in NSC proliferation, by activating Akt and Erk1\/2 pathways and by suppressing ROS-p38 MAPK signaling. Together, our results suggest that p38 MAPK signaling acts as a negative regulator of NSC proliferation in response to oxidative stress. These findings suggest a potential mechanism for neuronal cell loss as a result of oxidative stress in NSCs in progressive neurodegenerative diseases such as A-T.<\/jats:p>\n               <jats:p>Disclosure of potential conflicts of interest is found at the end of this article.<\/jats:p>","DOI":"10.1002\/stem.125","type":"journal-article","created":{"date-parts":[[2009,5,15]],"date-time":"2009-05-15T01:07:12Z","timestamp":1242349632000},"page":"1987-1998","source":"Crossref","is-referenced-by-count":132,"title":["Loss of ATM Impairs Proliferation of Neural Stem Cells Through Oxidative Stress-Mediated p38 MAPK Signaling"],"prefix":"10.1093","volume":"27","author":[{"given":"Jeesun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul K.Y.","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of 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