title: BMCC1, which is an interacting partner of BCL2, attenuates AKT activity, accompanied by apoptosis.
abstract: BNIP2 and Cdc42GAP homology (BCH) motif-containing molecule at the carboxyl-terminal region 1 (BMCC1) gene is highly expressed in patients with favorable neuroblastoma (NB). It encodes a 340-kDa protein with a conserved BCH scaffold domain that may regulate signaling networks and multiple cellular functions, including apoptosis. In this study, we determined the mechanism by which BMCC1 promotes apoptosis in human NB and non-NB cells, as BMCC1 is normally expressed in various organs, particularly in neuronal and epithelial tissues. We demonstrated in this report that BMCC1 was induced by DNA damage, one of the triggers of intrinsic apoptosis. Accordingly, we investigated whether BMCC1 expression impacts intracellular signals in the regulation of apoptosis via its C-terminal region containing BCH scaffold domain. BMCC1 decreased phosphorylation of survival signals on AKT and its upstream kinase PDK1. BMCC1 upregulation was correlated with the activation of forkhead box-O3a (FOXO3a) (a downstream inducer of apoptosis, which is suppressed by AKT) and induction of BCL2 inhibitor BIM, suggesting that BMCC1 negatively regulates phosphorylation pathway of AKT, resulted in apoptosis. In addition, we found that BNIP2 homology region of BMCC1 interacts with BCL2. Intrinsic apoptosis induced by DNA damage was enhanced by BMCC1 overexpression, and was diminished by knockdown of BMCC1. Taken together, we conclude that BMCC1 promotes apoptosis at multiple steps in AKT-mediated survival signal pathway. These steps include physical interaction with BCL2 and attenuation of AKT-dependent inhibition of FOXO3a functions, such as transcriptional induction of BIM and phosphorylation of ataxia telangiectasia-mutated (ATM) after DNA damage. We propose that downregulation of BMCC1 expression, which is frequently observed in unfavorable NB and epithelial-derived cancers, may facilitate tumor development by abrogating DNA damage repair and apoptosis.
authors.affiliation: 1] Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260-8717, Japan [2] Children's Cancer Research Center, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260-8717, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tatsumi
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260-8717, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Takano
authors.affiliation: 1] Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260-8717, Japan [2] Children's Cancer Research Center, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260-8717, Japan.
authors.forename: M S
authors.initials: MS
authors.lastname: Islam
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260-8717, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yokochi
authors.affiliation: Division Pathology, Chiba Cancer Center, Chuoh-ku, Chiba 260-8717, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Itami
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260-8717, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: 1] Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260-8717, Japan [2] Children's Cancer Research Center, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260-8717, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nakagawara
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010769:Phosphothreonine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C509845:PRUNE2 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D010769:Phosphothreonine; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin