Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1823, Issue 4, Pages 889-899Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2012.01.017
Keywords
hMSH3; Down-regulation; Hypoxia; HIF-1; p53; Colorectal cancer
Categories
Funding
- Japan Society for the Promotion of Science [21591736, 22591495]
- Toho University School of Medicine [22-8, 23-10]
- NIH [R01 CA72851]
- Sammons Cancer Center, Baylor University Medical Center
- Grants-in-Aid for Scientific Research [22501012, 22591495, 21591736] Funding Source: KAKEN
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Down-regulation of hMSH3 is associated with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability in colorectal cancer (CRC). However, the mechanism that down-regulates hMSH3 in CRC is not known. In this study, a significant association between over-expression of glucose transporter 1, a marker for hypoxia, and down-regulation of hMSH3 in CRC tissues was observed. Therefore, we examined the effect of hypoxia on the expression of hMSH3 in human cell lines. When cells with wild type p53 (wt-p53) were exposed to hypoxia, rapid down-regulation of both hMSH2 and hMSH3 occurred. In contrast, when null or mutated p53 (null/mut-p53) cells were exposed to hypoxia, only hMSH3 was down-regulated, and at slower rate than wt-p53 cells. Using a reporter assay, we found that disruption of the two putative hypoxia response elements (HREs) located within the promoter region of the hMSH3 abrogated the suppressive effect of hypoxia on reporter activity regardless of p53 status. In an EMSA, two different forms of HIF-1 alpha complexes that specifically bind to these HREs were detected. A larger complex containing HIF-1 alpha predominantly bound to the HREs in hypoxic null/mut-p53 cells whereas a smaller complex predominated in wt-p53 cells. Finally, HIF-1 alpha knockdown by siRNA significantly inhibited down-regulation of hMSH3 by hypoxia in both wt-p53 and mut-p53 cells. Taken together, our results suggest that the binding of HIF-1 alpha complexes to HRE sites is necessary for down-regulation of hMSH3 in both wt-p53 and mut-p53 cells. (c) 2012 Elsevier B.V. All rights reserved.
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