title: The human homolog of yeast SEP1 is a novel candidate tumor suppressor gene in osteogenic sarcoma.
abstract: The hSEP1 gene is the human homolog of yeast SEP1. Yeast SEP1 is a multifunctional gene that regulates a variety of nuclear and cytoplasmic functions including homologous recombination, meiosis, telomere maintenance, RNA metabolism and microtubule assembly. The function of hSEP1 is not known. We show loss or reduced expression of hSEP1 messenger RNA (mRNA) in three of four primary osteogenic sarcoma (OGS)-derived cell lines and in eight of nine OGS biopsy specimen. In addition, we find a heterozygous missense mutation (Valine(1484)>Alanine) at a conserved amino acid in the primary OGS-derived cell line U2OS. Importantly, we identified a homozygous missense mutation involving a CG-dinucleotide leading to a change in a conserved amino acid, aspartic acid(1137) >asparagine, in the primary OGS-derived cell line, TE85. hSEP1 mRNA expression was nearly undetectable in TE85 and low in U2OS cell lines. None of these mutations were identified in 20 normal samples consisting of bone, cartilage and fibroblast. The hSEP1 gene is located in chromosome 3 at 3q25-26.1 between markers D3S1309 and D3S1569. An adjacent locus defined by the polymorphic markers D3S1212 and D3S1245 has previously been reported to undergo loss of heterozygosity (LOH) at a >70% frequency in OGS and claimed to harbor an important tumor suppressor gene in osteosarcoma. The homozygous mutation in the hSEP1 mRNA in TE85 cell line suggest that this gene itself is subject to LOH. Taken together, these results suggest that hSEP1 acts as a tumor suppressor gene in OGS.
authors.affiliation: Department of Orthopedic Research, Mayo Clinic and Foundation, 200 First Street SW, Medical Sciences Building 3-15, Rochester, MN 55905, USA.
authors.forename: Kunbo
authors.initials: K
authors.lastname: Zhang
authors.forename: Norbert
authors.initials: N
authors.lastname: Dion
authors.forename: Bruno
authors.initials: B
authors.lastname: Fuchs
authors.forename: Tim
authors.initials: T
authors.lastname: Damron
authors.forename: Steven
authors.initials: S
authors.lastname: Gitelis
authors.forename: Ronald
authors.initials: R
authors.lastname: Irwin
authors.forename: Mary
authors.initials: M
authors.lastname: O'Connor
authors.forename: Herbert
authors.initials: H
authors.lastname: Schwartz
authors.forename: Sean P
authors.initials: SP
authors.lastname: Scully
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rock
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bolander
authors.forename: Gobinda
authors.initials: G
authors.lastname: Sarkar
mesh_terms: D001483:Base Sequence; D001706:Biopsy; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D005095:Exoribonucleases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D009154:Mutation; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D018076:DNA, Complementary; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D005095:Exoribonucleases; C068398:XRN1 protein, S cerevisiae