國家衛生研究院 NHRI:Item 3990099045/2180
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    题名: MCT-1 oncogene downregulates p53 and destabilizes genome structure in the response to DNA double-strand damage
    作者: Hsu, HL;Choy, CO;Kasiappan, R;Shih, HJ;Sawyer, JR;Shu, CL;Chu, KL;Chen, YR;Hsu, HF;Gartenhaus, RB
    贡献者: Division of Molecular and Genomic Medicine
    摘要: 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 phos-phorylation, 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. Through-out 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 pS3-p21 network and impairs the damage checkpoints those are robustly connected to oncogenic chromosomal abnormalities. (C) 2007 Elsevier B.V. All rights reserved.
    关键词: Genetics & Heredity;Toxicology
    日期: 2007-09-01
    關聯: DNA Repair. 2007 Sep;6(9):1319-1332.
    Link to: http://dx.doi.org/10.1016/j.dnarep.2007.02.028
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1568-7864&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000249332200010
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=34547842074
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