<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Analysis of coding microsatellite mutations in MSI colorectal carcinomas and characterization of their effects on the cellular glycosylation machinery"^^ . "Microsatellite instability (MSI), i.e. length variations of repetitive DNA sequences (microsatellites) occurs in colorectal cancer (CRC) due to defects in the DNA mismatch repair (MMR) system and is a hallmark of tumors associated with hereditary non-polyposis colorectal cancer (HNPCC, 1 – 5% of total CRC) as well as sporadic CRC (15% of total CRC). Instability in coding region microsatellites (cMNR) of expressed genes lead to frameshift mutations and a subsequent loss of protein function or the translation of a truncated protein. Despite the obvious significance of altered glycoprotein synthesis, transport and glycosylation patterns in colorectal cancer, aberrant glycosylation and glycosylation pathways have not been investigated in MSI colorectal tumors. Using a bioinformatics-based approach 28 cMNR harboring candidate genes were identified that encode proteins of the cellular glycosylation machinery. Coding MNR mutation analysis in MSI CRC cell lines revealed a high mutation frequency in two genes: the glycoprotein transporter gene LMAN1/ERGIC53 (52%; 12/23) and the xylosyltransferase gene XYLT2 (35%; 8/23) that catalyzes the first step in proteoglycan synthesis. Apart from their occurrence in cultured cell lines these genetic alterations were also found at similar frequency in MSI colorectal adenomas (LMAN1: 40%, 8/20; XYLT2: 21%, 4/19) as well as carcinomas (LMAN1: 46%, 78/170; XYLT2: 26%, 27/105). Biallelic mutations, abrogating normal protein function, were detected in MSI CRC cell lines (LMAN1, XYLT2) and in primary colorectal tumors (LMAN1). Biallelic mutant LMAN1 was transcribed but not translated into a stable protein in MSI CRC cell lines or LMAN1-mutated areas in tumors. MSI CRC cell lines with biallelic LMAN1 mutations behaved different to LMAN1-proficient CRC cell lines. LMAN1-deficient cell lines exhibited severely reduced transport and secretion of the LMAN1 cargo protein alpha-1-antitrypsin (A1AT), an inhibitor of angiogenesis and tumor growth but impaired secretion could be restored upon LMAN1 re-expression. A strong correlation between lower local levels of A1AT and enhanced tumor growth has been described. Furthermore, re-expression of LMAN1 in LMAN1-deficient LoVo cells led to a cell surface glycoprotein pattern different from the pattern observed on LoVo cells lacking LMAN1. Increased binding of PHA-L lectins to the cell surface suggested a glycosylation pattern known to be involved in the progression of cancer from a tumorigenic to a metastatic phenotype. A radioactive incorporation assay with 3H-xylose also revealed changes in proteoglycan synthesis of a XYLT2-deficient MSI CRC cell line transiently transfected with a XYLT2-construct. Overall, two members of the cellular glycosylation machinery, a glycoprotein transporter and a glycosyltransferase, appear to be involved in MSI tumorigenesis. Genetic alterations in LMAN1 and XYLT2 mark early events already detectable in preneoplastic lesions. Furthermore, loss of LMAN1 and XYLT2 protein function changed the secretion of proteins and the cell surface glycosylation pattern. Both genes might influence MSI tumor progression by changing cell-cell communication and interactions. "^^ . "2010" . . . . . . . . "Nina"^^ . "Röckel"^^ . "Nina Röckel"^^ . . . . . . "Analysis of coding microsatellite mutations in MSI colorectal carcinomas and characterization of their effects on the cellular glycosylation machinery (PDF)"^^ . . . "Dissertation_Nina_Roeckel.pdf"^^ . . . "Analysis of coding microsatellite mutations in MSI colorectal carcinomas and characterization of their effects on the cellular glycosylation machinery (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Analysis of coding microsatellite mutations in MSI colorectal carcinomas and characterization of their effects on the cellular glycosylation machinery (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Analysis of coding microsatellite mutations in MSI colorectal carcinomas and characterization of their effects on the cellular glycosylation machinery (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Analysis of coding microsatellite mutations in MSI colorectal carcinomas and characterization of their effects on the cellular glycosylation machinery (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Analysis of coding microsatellite mutations in MSI colorectal carcinomas and characterization of their effects on the cellular glycosylation machinery (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #11104 \n\nAnalysis of coding microsatellite mutations in MSI colorectal carcinomas and characterization of their effects on the cellular glycosylation machinery\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .