Genetic instability is a hallmark of cancer. In previous work, we had found that the hypoxic tumor microenvironment is one cause of this genetic instability. Recently, we have found that hypoxia specifically causes decreased expression of the DNA mismatch repair (MMR) factors, MLH1 and PMS2, with MLH1 but not PMS2 down-regulated at the mRNA level. These factors are critical for maintaining genomic integrity by correcting DNA replication errors, and they also play a role in response to DNA damage. Mutations in these and other genes associated with MMR have been linked to hereditary colon cancer.In this renewal application, we propose to explore the mechanism(s) by which the MMR factors MLH1 and PMS2 are down-regulated by hypoxia and potentially by other cell stresses. Transcription regulatory pathways, including histone deacetylation and promoter hypermethylation, will be examined, and critical Mlhl promoter regions will be mapped. The putative roles of p53 and HIF-1, two transcription factors regulated by hypoxia, will be tested, and experiments will be performed to identify other possible trans-acting factors. Using experimental tumor models in mice, we will determine the extent to which hypoxia in vivo can be correlated with reduced MMR gene expression and with increased genetic instability.These studies will provide insight into how the hypoxic tumor microenvironment may contribute to genetic instability and thereby to tumor progression. In addition, the down-regulation of MMR factors detected in response to hypoxia may be a feature of a more general stress response in mammalian cells by which cell mutation rates may be increased under adverse conditions, even if such conditions are not directly genotoxic. Elucidation of this pathway would have important implications for our understanding of the cellular response to a variety of environmental insults and so may bear on pathways of carcinogenesis and aging.
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