title: The ATM/p53/p21 pathway influences cell fate decision between apoptosis and senescence in reoxygenated hematopoietic progenitor cells.
abstract: 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-beta-galactosidase (SA-beta-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 G(0)/G(1) accumulation without significant apoptosis after 24 h of treatments. Reoxygenated bone marrow progenitor cells expressed SA-beta-gal and senescence-associated proteins p53 and p21(WAF1). Reoxygenated Fancc-/- progenitor cells, which underwent significant apoptosis and senescence, tested as staining for SA-beta-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-beta-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-beta-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.
authors.affiliation: Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Ohio 45229, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.forename: June
authors.initials: J
authors.lastname: Li
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sejas
authors.forename: Qishen
authors.initials: Q
authors.lastname: Pang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence / Q000502:physiology; D003114:Colony-Forming Units Assay; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005199:Fanconi Anemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D001616:beta-Galactosidase