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Tumor suppressor protein p53-mediated repression of human mitotic centromere-associated kinesin gene expression is exerted via down-regulation of Sp1 level

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Author(s)
Do Youn JunJi Young LeeHae Sun ParkYun Han LeeYoung Ho Kim
Keimyung Author(s)
Lee, Yun Han
Department
Dept. of Molecular Medicine (분자의학)
Journal Title
PloS One
Issued Date
2017
Volume
12
Issue
12
Abstract
The repressive role of p53 on the human mitotic centromere-associated kinesin (MCAK) core promoter from ‒266 to +54, relative to the transcription start site, has been determined. The MCAK mRNA and protein levels were 2.1- and 3.0-fold higher, respectively, in HCT116 (p53‒/‒) than in HCT116 (p53+/+) cells. Enforced down-regulation of p53 levels either in HCT116 (p53+/+) cells by p53 RNAi treatment or in MCF-7 cells using shRNA for p53 (shp53) resulted in a remarkable increase in the MCAK protein level. Site-directed mutagenesis and ChIP analyses showed that p53-mediated repression of the MCAK core promoter activity was not directly exerted by p53-binding to putative p53-response elements (p53-RE1 at -173/-166 and p53-RE2 at -245/-238), but indirectly by attenuating Sp1 binding to GC-motifs (GC1 at -93/-84 and GC2 at -119/-110). Treatment of HEK-293 cells bearing the MCAK core promoter-reporter (pGL2-320-Luc) with mithramycin A, which down-regulates Sp1 gene expression, reduced the promoter activity as well as endogenous MCAK levels. Exposure of HCT116 (p53+/+) cells to nutlin-3a, a validated activator of p53, caused a simultaneous reduction in Sp1 and MCAK protein levels, but not in HCT116 (p53-/-) cells. In contrast to wild-type (wt)-p53, tumor-derived p53 mutants (p53V143A, p53R248W, and p53R273H) failed to repress the Sp1-dependent activation of the MCAK promoter and to down-regulate endogenous levels of Sp1 and MCAK proteins. Collectively, these findings demonstrate that p53 can repress MCAK promoter activity indirectly via down-regulation of Sp1 expression level, and suggest that MCAK elevation in human tumor cells might be due to p53 mutation.
Keimyung Author(s)(Kor)
이윤한
Publisher
School of Medicine (의과대학)
Citation
Do Youn Jun et al. (2017). Tumor suppressor protein p53-mediated repression of human mitotic centromere-associated kinesin gene expression is exerted via down-regulation of Sp1 level. PloS One, 12(12), e0189698–e0189698. doi: 10.1371/journal.pone.0189698
Type
Article
ISSN
1932-6203
DOI
10.1371/journal.pone.0189698
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/41562
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Molecular Medicine (분자의학)
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