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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES005775-13
Application #
6847160
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Reinlib, Leslie J
Project Start
1992-09-30
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
13
Fiscal Year
2005
Total Cost
$327,000
Indirect Cost
Name
Yale University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Sulkowski, Parker L; Sundaram, Ranjini K; Oeck, Sebastian et al. (2018) Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat Genet 50:1086-1092
Kim, Hoon; Lin, Qun; Glazer, Peter M et al. (2018) The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells. Breast Cancer Res 20:16
Sulkowski, Parker L; Scanlon, Susan E; Oeck, Sebastian et al. (2018) PTEN Regulates Nonhomologous End Joining By Epigenetic Induction of NHEJ1/XLF. Mol Cancer Res 16:1241-1254
Lu, Yuhong; Liu, Yanfeng; Oeck, Sebastian et al. (2018) Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1. Mol Cancer Res 16:1458-1469
Scanlon, Susan E; Hegan, Denise C; Sulkowski, Parker L et al. (2018) Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient human renal cell carcinoma. Oncotarget 9:4647-4660
Scanlon, Susan E; Scanlon, Christine D; Hegan, Denise C et al. (2017) Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells. Carcinogenesis 38:627-637
Gupta, Anisha; Quijano, Elias; Liu, Yanfeng et al. (2017) Anti-tumor Activity of miniPEG-?-Modified PNAs to Inhibit MicroRNA-210 for Cancer Therapy. Mol Ther Nucleic Acids 9:111-119
Sulkowski, Parker L; Corso, Christopher D; Robinson, Nathaniel D et al. (2017) 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med 9:
Yu, Chang; Zelterman, Daniel (2017) A parametric model to estimate the proportion from true null using a distribution for p-values. Comput Stat Data Anal 114:105-118
Czochor, Jennifer R; Sulkowski, Parker; Glazer, Peter M (2016) miR-155 Overexpression Promotes Genomic Instability by Reducing High-fidelity Polymerase Delta Expression and Activating Error-Prone DSB Repair. Mol Cancer Res 14:363-73

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