title: Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster.
abstract: Fas-mediated apoptosis is an important regulator of cell survival, and abnormalities in this system have been shown to result in a number of human pathological conditions. A secreted member of the tumor necrosis factor receptor superfamily, DcR3, was recently reported to be amplified in human lung and colon cancers as a negative regulator of Fas-mediated apoptosis. We identified this gene, which we call M68. M68 genomic DNA, mRNA, and protein levels were examined in a series of human gastrointestinal tract tumors. Using M68 immunohistochemistry and a scoring system similar to that used for HER-2/neu, we found that M68 protein was overexpressed in 30 of 68 (44%) human adenocarcinomas of the esophagus, stomach, colon, and rectum. Tumors examined by Northern blot revealed M68 mRNA highly elevated in a similar fraction of primary tumors from the same gastrointestinal tract regions, as well as in the colon adenocarcinoma cell lines SW480 and SW1116. Further, we found M68 protein to be overexpressed in a substantial number of tumors in which gene amplification could not be detected by fluorescence in situ hybridization or quantitative genomic PCR, suggesting that overexpression of M68 may precede amplification in tumors. Finally, we find that M68 lies within a four-gene cluster that includes a novel helicase-like gene (NHL) related to RAD3/ERCC2, a plasma membrane Ras-related GTPase and a member of the stathmin family, amplification or overexpression of which may also contribute to cell growth and tumor progression.
authors.affiliation: Department of Human Genetics, Merck Research Laboratories, West Point, PA 19486-0004, USA. chang_bai@merck.com
authors.forename: C
authors.initials: C
authors.lastname: Bai
authors.forename: B
authors.initials: B
authors.lastname: Connolly
authors.forename: M L
authors.initials: ML
authors.lastname: Metzker
authors.forename: C A
authors.initials: CA
authors.lastname: Hilliard
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: V
authors.initials: V
authors.lastname: Sandig
authors.forename: A
authors.initials: A
authors.lastname: Soderman
authors.forename: S M
authors.initials: SM
authors.lastname: Galloway
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: C P
authors.initials: CP
authors.lastname: Austin
authors.forename: C T
authors.initials: CT
authors.lastname: Caskey
mesh_terms: D020727:ADP-Ribosylation Factors; D000595:Amino Acid Sequence; D017209:Apoptosis; D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics*; D020224:Expressed Sequence Tags; D020558:GTP Phosphohydrolases / Q000235:genetics; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D005796:Genes; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009414:Nerve Growth Factors / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D050777:Stathmin; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology
chemical_list: D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; C112285:STMN3 protein, human; D050777:Stathmin; C505911:TNFRSF6B protein, human; D019014:fas Receptor; C097313:ADP-ribosylation factor related proteins; D020558:GTP Phosphohydrolases; D004265:DNA Helicases; D020727:ADP-Ribosylation Factors