title: MCT-1 oncogene downregulates p53 and destabilizes genome structure in the response to DNA double-strand damage.
abstract: Tumor suppressor p53 protein mediates checkpoint controls and the apoptotic program that are critical for maintaining genomic integrity and preventing tumorigenesis. Forced-induction of MCT-1 decreased p53 expression before and after genomic insults. While inhibiting protein synthesis, the levels of ubiquinated-p53 and the phospho-MDMA2 were significantly increased in ectopic MCT-1 cells. Abrogation of the proteosome degradation process attenuated p53 destabilization and p21 down-regulation by MCT-1. Concomitantly, MCT-1 overexpression enhanced the phosphorylation status of MAPK (ERK1/ERK2). While MCT-1 gene knockdown or MEK/ERK pathway inhibition dramatically reduced MAPK phosphorylation, the genotoxin-induced p53 and p21 production were noticeably elevated. Upon Etoposide treatment, ectopic MCT-1 cells relaxed S-phase and G2/M checkpoints followed by G1 phase progressing. Moreover, cells inducing with MCT-1 abridged accumulations of G2/M populations in the response to gamma-irradiation. The polyploidy (DNA content>4N) populations were increased in association with p53 loss in MCT-1 oncogenic cells. Alkaline comet assay validated that ectopic MCT-1 cells were less susceptibility to the genotoxicity. Furthermore, the allocation of nuclear MCT-1 induced by the genotoxic stress was moderately coincided with gamma-H2AX appearances. Throughout damage-repairing process, ectopic MCT-1 cells displayed many larger chromosomes and multiple chromosomal fusions compared to the controls that showed increase in chromosomal breaks/gaps and minute chromosomal fragments. Spectral karyotyping analysis precisely identified the acquisition of a single extra copy of chromosome 14 together with a complex genome organizations in ectopic MCT-1 cells, including extra copies of chromosome segments that had been translocated to derivative chromosomes 6 [der(6)] and 9 [der(9)]. In conclusion, MCT-1 deregulates p53-p21 network and impairs the damage checkpoints those are robustly connected to oncogenic chromosomal abnormalities.
authors.affiliation: National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC. hsinling88@nhri.org.tw
authors.forename: Hsin-Ling
authors.initials: HL
authors.lastname: Hsu
authors.forename: Chik On
authors.initials: CO
authors.lastname: Choy
authors.forename: Ravi
authors.initials: R
authors.lastname: Kasiappan
authors.forename: Hung-Ju
authors.initials: HJ
authors.lastname: Shih
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Sawyer
authors.forename: Chung-Li
authors.initials: CL
authors.lastname: Shu
authors.forename: Kang-Lin
authors.initials: KL
authors.lastname: Chu
authors.forename: Yi-Rong
authors.initials: YR
authors.lastname: Chen
authors.forename: Hsin-Fen
authors.initials: HF
authors.lastname: Hsu
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Gartenhaus
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D043171:Chromosomal Instability; D020552:Comet Assay; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D016193:G1 Phase; D016195:G2 Phase; D006657:Histones / Q000378:metabolism; D006801:Humans; D007621:Karyotyping; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D006657:Histones; C115081:MCTS1 protein, human; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D020929:Mitogen-Activated Protein Kinase Kinases