NORMAL GENOMIC

• Baek SK, Woo JS, Kwon SY, Lee SH, Chae YS, Jung KY
• Prognostic significance of the MUC1 and MUC4 expressions in thyroidpapillary carcinoma.
• Laryngoscope. 2007; 117: 911-6
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• OBJECTIVES: The aim of the present study was to examine the expressions ofmucin genes MUC1 and MUC4 and to evaluate the difference of theirexpressions in normal thyroid tissue, follicular adenoma, and papillarycarcinoma. Furthermore, we aimed to estimate their prognostic significancein papillary carcinoma. METHODS: We performed semiquantitativereverse-transcription polymerase chain reaction for determining the MUC1and MUC4 mRNA expressions, and immunohistochemical staining was performedto determine the MUC1 and MUC4 protein expressions in 22 normal thyroidtissues, 22 follicular adenomas, and 15 papillary carcinomas. Thesemiquantitative scoring of the immunohistochemical staining was comparedwith the prognostic factors for thyroid carcinoma to evaluate theprognostic significance in 87 papillary carcinoma patients. RESULTS: TheMUC1 mRNA of the papillary carcinoma tissue showed an increased expressionlevel compared with the other tissues. However, the expression level ofMUC4 mRNA was weak in all the specimens, and this was not significantlydifferent among the three groups. MUC1 immunoreactivity was more intensein papillary carcinoma but not in the other tissues. MUC4 was notexpressed in all thyroid tissues. The expression of MUC1 was significantlyassociated with tumor size, extrathyroidal spread, and TNM stage (P <.05). CONCLUSIONS: Up-regulation of MUC1 may play a more important rolethan that of MUC4 in the development of thyroid papillary carcinoma, andit may have some significance as a prognostic factor.

• Pino V, Ramsauer VP, Salas P, Carothers Carraway CA, Carraway KL
• Membrane mucin Muc4 induces density-dependent changes in ERK activation inmammary epithelial and tumor cells: role in reversal of contactinhibition.
• J Biol Chem. 2006; 281: 29411-20
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• The membrane mucin Muc4 has been shown to alter cellular behavior throughboth anti-adhesive effects on cell-cell and cell-extracellular matrixinteractions and its ability to act as an intramembrane ligand for thereceptor tyrosine kinase ErbB2. The ERK pathway is regulated by bothcell-matrix and cell-cell adhesion. An analysis of the effects of Muc4expression on ERK phosphorylation in mammary tumor and epithelial cells,which exhibit both adhesion-dependent growth and contact inhibition ofgrowth, showed that the effects are density dependent, with opposingeffects on proliferating cells and contact-inhibited cells. In thesecells, cell-matrix interactions through integrins are required foractivation of the ERK mitogenesis pathway. However, cell-cell interactionsvia cadherins inhibit the ERK pathway. Expression of Muc4 reverses both ofthese effects. In contact-inhibited cells, Muc4 appears to activate theERK pathway at the level of Raf-1; this activation does not depend on Rasactivation. The increase in ERK activity correlates with an increase incyclin D(1) expression in these cells. This abrogation of contactinhibition is dependent on the number of mucin repeats in the mucinsubunit of Muc4, indicative of an anti-adhesive effect. The mechanism bywhich Muc4 disrupts contact inhibition involves a Muc4-inducedrelocalization of E-cadherin from adherens junctions at the lateralmembrane of the cells to the apical membrane. Muc4-induced abrogation ofcontact inhibition may be an important mechanism by which tumors progressfrom an early, more benign state to invasiveness.

• Diaz A et al.
• Lipopolysaccharide-induced expression of multiple alternatively splicedMEFV transcripts in human synovial fibroblasts: a prominent splice isoformlacks the C-terminal domain that is highly mutated in familialMediterranean fever.
• Arthritis Rheum. 2004; 50: 3679-89
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• OBJECTIVE: To investigate the expression of the familial Mediterraneanfever (FMF) gene (MEFV) in human synovial fibroblasts. METHODS: MEFVmessenger RNA in synovial fibroblasts, chondrocytes, and peripheral bloodleukocytes (PBLs) was analyzed by semiquantitative and real-timepolymerase chain reaction and ribonuclease protection assay. Thesubcellular localization of pyrin, the MEFV product, was determined intransfected synovial fibroblasts and HeLa cells with plasmids encodingpyrin isoforms. Native pyrin was detected with an antipyrin antibody.RESULTS: MEFV was expressed in synovial fibroblasts, but not inchondrocytes. Four alternatively spliced transcripts were identified: anextension of exon 8 (exon 8ext) resulting in a frameshift that predicts atruncated protein lacking exons 9 and 10, the addition of an exon (exon4a) predicting a truncated protein at exon 5, the in-frame substitution ofexon 2a for exon 2, and the previously described removal of exon 2 (exon2Delta). Exon 8ext transcripts represented 27% of the total messagepopulation in synovial fibroblasts. All other alternatively splicedtranscripts were rare. Consensus and alternatively spliced transcriptswere induced by lipopolysaccharide in synovial fibroblasts and PBLs. Intransfected cells, the proteins encoded by all highly expressed spliceforms were cytoplasmic. In contrast, native pyrin was predominantlynuclear in synovial fibroblasts, neutrophils, and dendritic cells, but wascytoplasmic in monocytes. CONCLUSION: Several MEFV transcripts areexpressed and inducible in synovial fibroblasts. A prominent isoform lacksthe C-terminal domain that contains the majority of mutations found inpatients with FMF. While recombinant forms of all major pyrin isoforms arecytoplasmic, native pyrin is nuclear in several cell types. Thus,mechanisms in addition to splicing patterns must control pyrin'ssubcellular distribution.

• Escande F, Lemaitre L, Moniaux N, Batra SK, Aubert JP, Buisine MP
• Genomic organization of MUC4 mucin gene. Towards the characterization ofsplice variants.
• Eur J Biochem. 2002; 269: 3637-44
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• The human MUC4 gene encodes a large membrane-associated mucin,characterized by a mucin tandem repeat domain and a growth factor-liketransmembrane domain. In addition to the originally published sequence(sv0-MUC4), several MUC4 cDNA sequences (called sv1-MUC4 to sv21-MUC4,MUC4/X, MUC4/Y) from various tissues and cell lines have been recentlydescribed. They differ from sv0-MUC4 by deletions and/or insertionslocated in the 3' region or, for two of them, by deletion of the centralrepetitive domain. To establish the nature of the mechanisms responsiblefor the diversity of MUC4 transcripts, the genomic structure of the 3'region of the human MUC4 gene was determined. Our results show that itspans approximately 30.8 kb of genomic DNA and is composed of 24 exons,including one alternative exon which was exclusively reported forsv1-MUC4. Moreover, we have shown that the different MUC4 transcripts aregenerated by several mechanisms, including the alternative use of cassetteexons, exon skipping or use of cryptic splice donor/acceptor sites.