title: ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53.
abstract: In response to DNA damage, ataxia-telangiectasia mutant and ataxia-telangiectasia and Rad-3 activate p53, resulting in either cell cycle arrest or apoptosis. We report here that DNA damage stimuli, including etoposide (ETOP), adriamycin (ADR), ionizing irradiation (IR), and ultraviolet irradiation (UV) activate ERK1/2 (ERK) mitogen-activated protein kinase in primary (MEF and IMR90), immortalized (NIH3T3) and transformed (MCF-7) cells. ERK activation in response to ETOP was abolished in ATM-/- fibroblasts (GM05823) and was independent of p53. The MEK1 inhibitor PD98059 prevented ERK activation but not p53 stabilization. Maximal ERK activation in response to DNA damage was not attenuated in MEF(p53-/-). However, ERK activation contributes to either cell cycle arrest or apoptosis in response to low or high intensity DNA insults, respectively. Inhibition of ERK activation by PD98059 or U0126 attenuated p21(CIP1) induction, resulting in partial release of the G(2)/M cell cycle arrest induced by ETOP. Furthermore, PD98059 or U0126 also strongly attenuated apoptosis induced by high dose ETOP, ADR, or UV. Conversely, enforced activation of ERK by overexpression of MEK-1/Q56P sensitized cells to DNA damage-induced apoptosis. Taken together, these results indicate that DNA damage activates parallel ERK and p53 pathways in an ATM-dependent manner. These pathways might function cooperatively in cell cycle arrest and apoptosis.
authors.affiliation: Department of Medicine and Father Sean O'Sullivan Research Institute, St. Joseph's Hospital and McMaster University, 708-25 Charlton Avenue, Hamilton L8N 1Y2, Canada. damut@mcmaster.ca
authors.forename: Damu
authors.initials: D
authors.lastname: Tang
authors.forename: Dongcheng
authors.initials: D
authors.lastname: Wu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Jill M
authors.initials: JM
authors.lastname: Lahti
authors.forename: Lieqi
authors.initials: L
authors.lastname: Liu
authors.forename: Brie
authors.initials: B
authors.lastname: Mazza
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Kidd
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Ingram
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D005047:Etoposide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases