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J. Biol. Chem., Vol. 280, Issue 20, 19635-19640, May 20, 2005

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The ATM/p53/p21 Pathway Influences Cell Fate Decision between Apoptosis and Senescence in Reoxygenated Hematopoietic Progenitor Cells^*

Xiaoling Zhang, June Li, Daniel P. Sejas, and Qishen Pang¶

From the Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and the Department of Pediatrics University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Hematopoietic cells are often exposed to transient hypoxia as they develop and migrate between blood and tissues. We tested the hypothesis that hypoxia-then-reoxygenation represent a stress for hematopoietic progenitor cells. Here we report that reoxygenation-generated oxidative stress induced senescence, tested as staining for SA--galactosidase (SA--gal), of bone marrow progenitor cells. Reoxygenation induced significant DNA damage and inhibited colony formation in lineage-depleted bone marrow cells enriched for progenitor cells. These reoxygenated cells exhibited a prolonged G₀/G₁ accumulation without significant apoptosis after 24 h of treatments. Reoxygenated bone marrow progenitor cells expressed SA--gal and senescence-associated proteins p53 and p21^WAF1. Reoxygenated Fancc-/- progenitor cells, which underwent significant apoptosis and senescence, tested as staining for SA--gal, also expressed p16^INK4A. Suppression of apoptosis by the pan-caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone dramatically increased senescent Fancc-/- progenitor cells. Senescence induction, tested as staining for SA--gal, in reoxygenated progenitor cells was closely correlated with extent of DNA damage and phosphorylation of ATM at Ser-1981 and p53 at Ser-15. Moreover, inhibition of ATM signaling reduced SA--gal positivity but increased apoptosis of reoxygenated progenitor cells. Thus, these results suggest that the ATM/p53/p21 pathway influences cell fate decision between apoptosis and senescence in reoxygenated hematopoietic progenitor cells.

Received for publication, February 28, 2005 , and in revised form, March 7, 2005.

^* This work was supported by an American Cancer Society (Ohio Division) support grant, a Fanconi Anemia Research Fund grant, and a Trustee grant from the Cincinnati Children's Hospital Medical Center (to Q. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence and reprint requests should be addressed: Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229. Tel.: 513-636-1152; Fax: 513-636-3768; E-mail: qishen.pang{at}cchmc.org.

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