title: Cdk5 activator-binding protein C53 regulates apoptosis induced by genotoxic stress via modulating the G2/M DNA damage checkpoint.
abstract: In response to DNA damage, the cellular decision of life versus death involves an intricate network of multiple factors that play critical roles in regulation of DNA repair, cell cycle, and cell death. DNA damage checkpoint proteins are crucial for maintaining DNA integrity and normal cellular functions, but they may also reduce the effectiveness of cancer treatment. Here we report the involvement of Cdk5 activator p35-binding protein C53 in regulation of apoptosis induced by genotoxic stress through modulating Cdk1-cyclin B1 function. C53 was originally identified as a Cdk5 activator p35-binding protein and a caspase substrate. Importantly, our results demonstrated that C53 deficiency conferred partial resistance to genotoxic agents such as etoposide and x-ray irradiation, whereas ectopic expression of C53 rendered cells susceptible to multiple genotoxins that usually trigger G(2)/M arrest. Furthermore, we found that Cdk1 activity was required for etoposide-induced apoptosis of HeLa cells. Overexpression of C53 promoted Cdk1 activity and nuclear accumulation of cyclin B1, whereas C53 deficiency led to more cytoplasmic retention of cyclin B1, suggesting that C53 acts as a pivotal player in modulating the G(2)/M DNA damage checkpoint. Finally, C53 and cyclin B1 co-localize and associate in vivo, indicating a direct role of C53 in regulating the Cdk1-cyclin B1 complex. Taken together, our results strongly indicate that in response to genotoxic stress, C53 serves as an important regulatory component of the G(2)/M DNA damage checkpoint. By overriding the G(2)/M checkpoint-mediated inhibition of Cdk1-cyclin B1 function, ectopic expression of C53 may represent a novel approach for chemo- and radio-sensitization of cancer cells.
authors.affiliation: Children's Memorial Research Center, The Robert H. Lurie Comprehensive Cancer Center, The Feinberg School of Medicine and IGP Graduate Program, Northwestern University, Chicago, Illinois 60614, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Jiang
authors.forename: Shouqing
authors.initials: S
authors.lastname: Luo
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D019926:Cyclin B / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D056744:Cyclin B1; D004249:DNA Damage / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D009153:Mutagens; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C534699:CCNB1 protein, human; C405928:CDK5RAP3 protein, human; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009153:Mutagens; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D005047:Etoposide; D016203:CDC2 Protein Kinase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases