title: Novel 1p tumour suppressor Dnmt1-associated protein 1 regulates MYCN/ataxia telangiectasia mutated/p53 pathway.
abstract: Neuroblastoma (NB) is a paediatric solid tumour which originates from sympathetic nervous tissues. Deletions in chromosome 1p are frequently found in unfavourable NBs and are correlated with v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) amplification; however, it remains to be elucidated how the 1p loss contributes to MYCN-related oncogenic processes in NB. In this study, we identified the role of Dnmt1-associated protein 1 (DMAP1), coded on chromosome 1p34, in the processes. We studied the expression and function of DMAP1 in NB and found that low-level expression of DMAP1 related to poor prognosis, unfavourable histology and 1p Loss of heterozygosity (LOH) of primary NB samples. Intriguingly, DMAP1 induced ataxia telangiectasia mutated (ATM) phosphorylation and focus formation in the presence of a DNA damage reagent, doxorubicin. By DMAP1 expression in NB and fibroblasts, p53 was activated in an ATM-dependent manner and p53-downstream pro-apoptotic Bcl-2 family molecules were induced at the mRNA level, resulting in p53-induced apoptotic death. BAX and p21(Cip1/Waf1) promoter activity dependent on p53 was clearly up-regulated by DMAP1. Further, MYCN transduction in MYCN single-copy NB cells accelerated doxorubicin (Doxo)-induced apoptotic cell death; MYCN is implicated in DMAP1 protein stabilisation and ATM phosphorylation in these situations. DMAP1 knockdown attenuated MYCN-dependent ATM phosphorylation and NB cell apoptosis. Together, DMAP1 appears to be a new candidate for a 1p tumour suppressor and its reduction contributes to NB tumourigenesis via inhibition of MYCN-related ATM/p53 pathway activation.
authors.affiliation: Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Japan.
authors.forename: Yohko
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Takenobu
authors.affiliation: Laboratory of Cancer Genomics, Chiba Cancer Center Research Institute, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Ohira
authors.affiliation: Department of Pathology, National Center for Child Health and Development, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakazawa
authors.affiliation: Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Akita
authors.affiliation: Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Shimozato
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
authors.affiliation: Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Japan. Electronic address: tkamijo@chiba-cc.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Kamijo
mesh_terms: D017209:Apoptosis; D001260:Ataxia Telangiectasia / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002675:Child, Preschool; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C411744:DMAP1 protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; DMAP1; MYCN; Neuroblastoma; p53