Constitutive activation of caspase-3 and Poly ADP ribose polymerase cleavage in fanconi anemia cells.
Fanconi anemia (FA) is a rare syndrome characterized by developmental abnormalities, progressive bone marrow failure, and cancer predisposition. Cells from FA patients exhibit hypersensitivity to DNA cross-linking agents and oxidative stress that may trigger apoptosis. Damage-induced activation of caspases and poly ADP ribose polymerase (PARP) enzymes have been described for some of the FA complementation groups. Here, we show the constitutive activation of caspase-3 and PARP cleavage in the FA cells without exposure to exogenous DNA-damaging factors. These effects can be reversed in the presence of reactive oxygen species scavenger N-acetylcystein. We also show the accumulation of oxidized proteins in FA cells, which is accompanied by the tumor necrosis factor (TNF)-alpha oversecretion and the upregulation of early stress response kinases pERK1/2 and p-P38. Suppression of TNF-alpha secretion by the extracellular signal-regulated kinase inhibitor PD98059 results in reduction of caspase-3 cleavage, suggesting a possible mechanism of caspases-3 activation in FA cells. Thus, the current study is the first evidence demonstrating the damage-independent activation of caspase-3 and PARP in FA cells, which seems to occur through mitogen-activated protein kinase activation and TNF-alpha oversecretion.
Lyakhovich
Alex
A
Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
Surrallés
Jordi
J
D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism*; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D005199:Fanconi Anemia / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3