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Differential Cellular Expression of the Human MSH2 Repair Enzyme in Small and Large Intestine¹

Departments of Pediatrics [T. M. W., M. R. K.], and Biochemistry and Molecular Biology [T. M. W., M. R. K.], Herman B. Wells Center for Pediatric Research, and Departments of Neurology and Medical Genetics [J. R. D.] and Pathology and Laboratory Medicine [J. N. E.], Indiana University School of Medicine, and Neurology Service and Pathology and Laboratory Medicine Service, Richard L. Roudebush Veterans' Affairs Medical Center [J. N. E.], Indianapolis, Indiana 46202; and Department of Microbiology and Molecular Genetics, Markey Center for Molecular Genetics, University of Vermont School of Medicine, Burlington, Vermont 05405 [A. E., M. K. L., R. F.]

The human MSH2 (hMSH2) protein is responsible for the initial recognition of mismatched nucleotides during the postreplication mismatch repair process. Loss of hMSH2 function has been demonstrated to lead to the accumulation of replication errors, resulting in a mutator phenotype, which may be responsible for the multiple mutations required for multistage carcinogenesis. Alterations of the hMSH2 gene has been linked to approximately 60% of hereditary nonpolyposis colon cancer cases. Colon tumors in hereditary nonpolyposis colon cancer patients originate within benign preneoplastic adenomas and display replication errors in the form of microsatellite instability. The aim of this study was to investigate the cellular expression of the hMSH2 protein in cells of the large and small intestines. Using antibody specific for hMSH2, we have determined that this protein is highly expressed in cells of the crypts of Lieberkühn that are undergoing rapid renewal in both the ileum and colon. Proliferative perifibroblasts in the colon also showed significant presence of the hMSH2 protein. These results confirm the hypothesis that hMSH2 is expressed in highly proliferative cells of the gut, and mutations in this gene could, therefore, be expected to expedite the progression of adenoma to carcinoma in this tissue.

¹ J. R. D. was supported by a Department of Veteran Affairs Merit Review Grant. This work was supported by NIH Grant RR09884, Council for Tobacco Institute Grant 3739, a Riley Memorial Association Research Award (M. R. K.), and Grants CA56542 and CA67007 (R. F.).

² To whom requests for reprints should be addressed, at Department of Pediatrics, Herman B. Wells Center for Pediatric Research, 702 Barnhill Drive, Room 2664, Indianapolis, IN 46202. Phone: (317) 274-2755; Fax: (317) 274-8679; E-mail: mkelley@indyvax.iupui.edu.

Received 9/ 6/95. Accepted 10/10/95.

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