Mutation in any of five human DNA mismatch repair (MMR) gene homologs, MSH2, MSH6, MLH1, PSM2 and PMS1, contributes to both hereditary and spontaneous cancers. As a primary example., hereditary non-polyposis colorectal cancer (HNPCC) is frequently associated with germline mutations in the MMR genes and accounts for approximately 5% of the total colorectal cancer burden.. Such results have provided support for the notion that a mutator phenotype is common underlying feature of tumor cells. Interestingly, amongst HNPCC kindreds MLH1 and MHS2 families are common whereas PSMS2 and PMS1 families are rare. Mice defective in Msh2, M1h1, Msh6 and Pms2 all develop tumors, although the respective tumor spectra differ. Most notably, whereas Mlh1-deficient mice developed lymphomas and tumors characteristic of HNPCC, e.g. intestinal tumors and sebaceous gland tumors, Pms2- deficient mice developed primarily lymphomas and sarcomas were not susceptible to intestinal tumors. Interestingly, amongst HNPCC kindreds MLH1 and MSH2 families are common, whereas PSM2 and PSM1 families are rare. Mice defective in Msh2, Mlh1, Msh6 and Pms 2 will develop tumors, although the respective tumor spectra differ. Most notably, whereas Mlh1-deficient mice developed lymphomas and tumors characteristic of HNPCC, e.g. intestinal tumors and sebaceous gland tumors, Pms2-deficient mice developed primarily lymphomas and sarcomas but were not susceptible to intestinal tumors. This tumor spectra difference and the lack of PMS2 kindreds are especially perplexing for at least two reasons: 1) Mlh1p and Pms2p act as a heterodimer while fulfilling the major """"""""MutL"""""""" role during MMR in both yeast and mammalian cells, and 2) Multiple tissues of mice lacking either functional Mlhlp or Pms2p both show strong mutator phenotypes. Such results raise several important issues such as whether an increase in mutation is sufficient for the development of HNPCC-like tumors, whether other MMR-related functions, besides mutation avoidance are differentially affected by Mlhl versus. Pms2 deficiency, and whether the """"""""backup"""""""" pathways exist for MMR functions. We will address such issues by studying further mice defective in each of the MutL homologs, Mlhl, Pms1 and Pms2. We will examine intestinal tumor susceptibility associated with Mlh1 or Pms2 null mutation in C57BL/6 and 129/Sv backgrounds. We will study mice with mutations in two MutL homologs by monitoring tumor formation and mutation. We will determine the effect of Mlh1-versus Pms2-deficiency on cellular responses to DNA damaging agents, We will test for cooperative or synergistic , effects of inactivation mutations in Mlhl1 (or Pms2) and IL-10 as a means to address relationships interactions between MMR deficiency and inflammatory bowel disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM032741-21
Application #
6625033
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Anderson, Richard A
Project Start
1983-12-01
Project End
2004-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
21
Fiscal Year
2003
Total Cost
$324,816
Indirect Cost
Name
Oregon Health and Science University
Department
Genetics
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Johnson, Jennifer R; Erdeniz, Naz; Nguyen, Megan et al. (2010) Conservation of functional asymmetry in the mammalian MutL? ATPase. DNA Repair (Amst) 9:1209-13
Miller, Ashleigh J; Dudley, Sandra D; Tsao, Jen-Lan et al. (2008) Tractable Cre-lox system for stochastic alteration of genes in mice. Nat Methods 5:227-9
Deschenes, Suzanne M; Tomer, Guy; Nguyen, Megan et al. (2007) The E705K mutation in hPMS2 exerts recessive, not dominant, effects on mismatch repair. Cancer Lett 249:148-56
Guillon, Helene; Baudat, Frederic; Grey, Corinne et al. (2005) Crossover and noncrossover pathways in mouse meiosis. Mol Cell 20:563-73
Chen, Peng-Chieh; Dudley, Sandra; Hagen, Wayne et al. (2005) Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Cancer Res 65:8662-70
Sansom, Owen J; Bishop, Stefan M; Court, Helen et al. (2003) Apoptosis and mutation in the murine small intestine: loss of Mlh1- and Pms2-dependent apoptosis leads to increased mutation in vivo. DNA Repair (Amst) 2:1029-39
Gutmann, D H; Winkeler, E; Kabbarah, O et al. (2003) Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice. Oncogene 22:4581-5
Tomer, Guy; Buermeyer, Andrew B; Nguyen, Megan M et al. (2002) Contribution of human mlh1 and pms2 ATPase activities to DNA mismatch repair. J Biol Chem 277:21801-9
Tsao, Jen-Lan; Dudley, Sandra; Kwok, Brian et al. (2002) Diet, cancer and aging in DNA mismatch repair deficient mice. Carcinogenesis 23:1807-10
Buermeyer, A B; Wilson-Van Patten, C; Baker, S M et al. (1999) The human MLH1 cDNA complements DNA mismatch repair defects in Mlh1-deficient mouse embryonic fibroblasts. Cancer Res 59:538-41

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