title: Relaxation of glycine receptor and onconeural gene transcription control in NRSF deficient small cell lung cancer cell lines.
abstract: Negative regulation of many neuronal genes is mediated by the neuron-restrictive silencer factor (NRSF/repressor element-1 binding transcription factor, REST), which binds to the neuron-restrictive silencer element (NRSE/repressor element-1, RE-1) and thereby represses transcription of neuronal genes in non-neuronal cells. Sequence analysis of 5'-flanking regions of glycine receptor (GlyR) subunit genes revealed a consensus motif for NRSE in the GLRA1 and GLRA3, but not in GLRB, genes. In this study, we examined tumor cell lines for the expression of NRSF, GlyR subunits and onconeural genes. We identified two small cell lung cancer (SCLC) cell lines lacking full-length NRSF/REST as well as its neuronal splice variants. Presence or absence of NRSF as well as its functionality in different SCLC cell lines was additionally shown in reporter gene assays. As GlyR alpha1 is selectively transcribed in NRSF/REST free cells, GlyR alpha1 transcripts might serve as positive signals for NRSF deficient cells. In contrast, GlyR beta is nearly ubiquitously transcribed in the cell lines analyzed and, therefore, should represent a useful marker for neoplastic cells. Sequence analysis of GlyR beta transcripts led to the identification of a new splice variant lacking exon 8, GlyR beta Delta8. This suggests that the lack of NRSF in SCLC cells, resulting in the relaxation of neuronal gene suppression, is an important mechanism underlying paraneoplastic expression.
authors.affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054, Erlangen, Germany. cmb@biochem.uni-erlangen.de
authors.forename: Sabine B
authors.initials: SB
authors.lastname: Neumann
authors.forename: Randolf
authors.initials: R
authors.lastname: Seitz
authors.forename: Anke
authors.initials: A
authors.lastname: Gorzella
authors.forename: Angelien
authors.initials: A
authors.lastname: Heister
authors.forename: Magnus von Knebel
authors.initials: Mv
authors.lastname: Doeberitz
authors.forename: Cord Michael
authors.initials: CM
authors.lastname: Becker
mesh_terms: D015153:Blotting, Western / Q000379:methods; D018288:Carcinoma, Small Cell; D045744:Cell Line, Tumor; D004274:DNA, Recombinant / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000502:physiology; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms; D008214:Lymphocytes / Q000378:metabolism; D009154:Mutation; D021122:Protein Subunits / Q000378:metabolism*; D012333:RNA, Messenger; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000099229:RE1-Silencing Transcription Factor
chemical_list: D004274:DNA, Recombinant; D021122:Protein Subunits; D012333:RNA, Messenger; D018009:Receptors, Glycine; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor