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HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression.

Publication ,  Journal Article
Koshiji, M; To, KK-W; Hammer, S; Kumamoto, K; Harris, AL; Modrich, P; Huang, LE
Published in: Mol Cell
March 18, 2005

Hypoxia promotes genetic instability by undefined mechanisms. The transcription factor HIF-1alpha is crucial for the cellular response to hypoxia and is frequently overexpressed in human cancers, resulting in the activation of genes essential for cell survival. Here, we demonstrate that HIF-1alpha is responsible for genetic instability at the nucleotide level by inhibiting MSH2 and MSH6, thereby decreasing levels of the MSH2-MSH6 complex, MutSalpha, which recognizes base mismatches. HIF-1alpha displaces the transcriptional activator Myc from Sp1 binding to repress MutSalpha expression in a p53-dependent manner; Sp1 serves as a molecular switch by recruiting HIF-1alpha to the gene promoter under hypoxia. Furthermore, in human sporadic colon cancers, HIF-1alpha overexpression is statistically associated with the loss of MSH2 expression, especially when p53 is immunochemically undetectable. These findings indicate that the regulation of DNA repair is an integral part of the hypoxic response, providing molecular insights into the mechanisms underlying hypoxia-induced genetic instability.

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Published In

Mol Cell

DOI

ISSN

1097-2765

Publication Date

March 18, 2005

Volume

17

Issue

6

Start / End Page

793 / 803

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Transcription, Genetic
  • Transcription Factors
  • Sp1 Transcription Factor
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins
  • Protein Binding
  • Promoter Regions, Genetic
  • MutS Homolog 2 Protein
 

Citation

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Koshiji, M., To, K.-W., Hammer, S., Kumamoto, K., Harris, A. L., Modrich, P., & Huang, L. E. (2005). HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Mol Cell, 17(6), 793–803. https://doi.org/10.1016/j.molcel.2005.02.015
Koshiji, Minori, Kenneth K-W To, Stefanie Hammer, Kensuke Kumamoto, Adrian L. Harris, Paul Modrich, and L Eric Huang. “HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression.Mol Cell 17, no. 6 (March 18, 2005): 793–803. https://doi.org/10.1016/j.molcel.2005.02.015.
Koshiji M, To KK-W, Hammer S, Kumamoto K, Harris AL, Modrich P, et al. HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Mol Cell. 2005 Mar 18;17(6):793–803.
Koshiji, Minori, et al. “HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression.Mol Cell, vol. 17, no. 6, Mar. 2005, pp. 793–803. Pubmed, doi:10.1016/j.molcel.2005.02.015.
Koshiji M, To KK-W, Hammer S, Kumamoto K, Harris AL, Modrich P, Huang LE. HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Mol Cell. 2005 Mar 18;17(6):793–803.
Journal cover image

Published In

Mol Cell

DOI

ISSN

1097-2765

Publication Date

March 18, 2005

Volume

17

Issue

6

Start / End Page

793 / 803

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Transcription, Genetic
  • Transcription Factors
  • Sp1 Transcription Factor
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins
  • Protein Binding
  • Promoter Regions, Genetic
  • MutS Homolog 2 Protein