Other

Dana-farber-cancer Institute Inc.

Oregon Health & Science University

Roni J Bollag

Richard D Kolodner

Robert M Liskay

Sean M Baker

C Eric Bronner

Howard J Rasmussen

Carlos M Isales

Genomic sequences of human mismatch repair genes and gene products are described, as are methods of detecting mutations and/or polymorphisms in those genes. Also described are methods of diagnosing cancer susceptibility in a subject, and methods of identifying and classifying mismatch-repair-defective tumors. In particular, sequences and methods relating to human mutL homologs, hMLH1 and hPMS1 genes and gene products are provided.

Compositions and methods relating to DNA mismatch repair genes

The examples demonstrate that GIP receptor mRNA and protein are present in normal bone and osteoblastic-like cell lines, and that high-affinity receptors for GIP can be demonstrated by I GIP binding studies. When applied to osteoblast-like cells (SaOS2), GIP stimulated an increase in cellular cAMP content and in intracellular calcium, with both responses being dose dependent. Moreover, administration of GIP results in elevated expression of collagen type I mRNA as well as an increase in alkaline phosphatase activity. Both of these effects reflect anabolic actions of presumptive osteoblasts. These results provide the first evidence that GIP receptors are present in bone and osteoblastic like cells and that GIP modulates the function of these cells. GIP has anabolic actions on remodeling bone, increasing vertebral bone density in a rat model of osteoporosis. GIP at 10 nM inhibits PTH-induced bone resorption in a fetal long bone assay and stimulates the synthesis of type 1 collagen mRNA. Transgenic mice overexpressing GIP have increased bone density compared to same age controls. GIP or analoges thereof can therefore be used as a therapeutic to inhibit bone resorption and to maintain or increase bone density. GIP antagonists, compounds which block binding to the GIP receptor, can be used to decrease bone density.

Glucose-dependent insulinotropic peptide for use as an osteotropic hormone

Genomic sequences of human mismatch repair genes are described, as are methods of detecting mutations and/or polymorphisms in those genes. Also described are methods of diagnosing cancer susceptibility in a subject, and methods of identifying and classifying mismatch-repair-defective tumors. In particular, sequences and methods relating to human mutL homologs, hMLH1 and hPMS1 genes are provided.

Composition and methods relating to DNA mismatch repair genes

We have discovered two human genes, hMLH1 and hPMS1, each of which apparently encodes for a protein involved in DNA mismatch repair. The hMLH1 gene encodes for a protein which is homologous to the bacterial DNA mismatch repair protein MutL, and is located on human chromosome 3p21.3-23. We believe that mutations in the hMLH1 gene cause hereditary non-polyposis colon cancer (HNPCC) in some individuals based upon the similarity of the hMLH1 gene product to the yeast DNA mismatch repair protein MLH1, the coincident location of the hMLH1 gene and the HNPCC locus on chromosome 3, and hMLH1 missense mutations in affected individuals from a chromosome 3-linked HNPCC family. The human hPMS1 gene is homologous to the yeast DNA mismatch repair gene PMS1, and is located on human chromosome 7q. We believe that the hPMS1 gene is a strong candidate for HNPCC testing because the yeast proteins MLH1 and PMS1 have been shown to be involved in the same DNA repair pathway and because hMLH1 and hMSH2 have both been implicated in HNPCC families. The most immediate use for hMLH1 and hPMS1 will be in screening tests on individuals who are members of families which exhibit high frequencies of early onset cancer. We have also isolated and sequenced mouse MLH1 and PMS1 genes. We have produced chimeric mice with a mutant form of the PMS1 gene that will enable us to derive mice that are heterozygous or homozygous for mutation in mPMS1. These mice will be useful for cancer research. We have also produced and isolated antibodies directed to hPMS1 which are useful in assays to detect the presence of protein in tumor samples.

Growing community of inventors

Martinez, GA, United States of America

Roni J Bollag