title: Etoposide induces G2/M arrest and apoptosis in neural progenitor cells via DNA damage and an ATM/p53-related pathway.
abstract: Etoposide (VP-16), an anti-tumor agent, is a topoisomerase II inhibitor that causes DNA damage. In our previous studies, it was shown that VP-16 induces S-phase accumulation and G2/M arrest, eventually resulting in apoptosis, through p53-related pathway in the mouse fetal brain. We injected 4 mg/kg of VP-16 into pregnant mice on day 12 of gestation, and the fetuses were investigated for the cell cycle checkpoint and mechanism of apoptosis. The transition of the neural progenitor cells in the fetuses was delayed as compared to that in the control, and most of the apoptotic cells were BrdU positive. VP-16-induced S-phase accumulation was brought about by the acceleration of G1/S transition rather than by the inhibition of S-phase progression. Phosphorylation of ataxia telangiectasia-mutated kinase (ATM) at Ser1981 and gammaH2AX after VP-16 treatment showed DNA damage. p53 was phosphorylated at Ser15 and 20 and increased after activation of the ATM kinase pathway. Cdc25A degradation might induce the inhibition of S-phase progression. It is supposed that an increase in cyclin A might accelerate G1/S progression. It is also indicated that VP-16-induced G2/M arrest is caused by p21, which inactivates cyclin B-Cdc2 complex and eventually prevents mitotic entry. In p53-deficient fetal brains, G2/M and apoptosis were almost abrogated, although S-phase accumulation still occurred. It is suggested that VP-16 induced p53-independent S-phase accumulation, and p53-dependent G2/M arrest and apoptosis of the neural progenitor cells in fetal mouse brain.
authors.affiliation: Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan. vet0215@yahoo.co.kr
authors.forename: C
authors.initials: C
authors.lastname: Nam
authors.forename: K
authors.initials: K
authors.lastname: Doi
authors.forename: H
authors.initials: H
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D053686:Fetal Stem Cells / Q000187:drug effects / Q000473:pathology*; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D018811:Maternal Exposure; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013687:Telencephalon / Q000187:drug effects / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D005047:Etoposide; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D001973:Bromodeoxyuridine