title: Decoding c-Myc networks of cell cycle and apoptosis regulated genes in a transgenic mouse model of papillary lung adenocarcinomas.
abstract: The c-Myc gene codes for a basic-helix-loop-helix-leucine zipper transcription factor protein and is reported to be frequently over-expressed in human cancers. Given that c-Myc plays an essential role in neoplastic transformation we wished to define its activity in lung cancer and therefore studied its targeted expression to respiratory epithelium in a transgenic mouse disease model. Using histological well-defined tumors, transcriptome analysis identified novel c-Myc responsive cell cycle and apoptosis genes that were validated as direct c-Myc targets using EMSA, Western blotting, gene reporter and ChIP assays.Through computational analyses c-Myc cooperating transcription factors emerged for repressed and up-regulated genes in cancer samples, namely Klf7, Gata3, Sox18, p53 and Elf5 and Cebpα, respectively. Conversely, at promoters of genes regulated in transgenic but non-carcinomatous lung tissue enriched binding sites for c-Myc, Hbp1, Hif1 were observed. Bioinformatic analysis of tumor transcriptomic data revealed regulatory gene networks and highlighted mortalin and moesin as master regulators while gene reporter and ChIP assays in the H1299 lung cancer cell line as well as cross-examination of published ChIP-sequence data of 7 human and 2 mouse cell lines provided strong evidence for the identified genes to be c-Myc targets. The clinical significance of findings was established by evaluating expression of orthologous proteins in human lung cancer. Taken collectively, a molecular circuit for c-Myc-dependent cellular transformation was identified and the network analysis broadened the perspective for molecularly targeted therapies.
authors.affiliation: Centre for Integrative Biology (CIBIO), University of Trento, 38123 Mattarello, Italy.
authors.forename: Yari
authors.initials: Y
authors.lastname: Ciribilli
authors.affiliation: Centre for Pharmacology and Toxicology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Prashant
authors.initials: P
authors.lastname: Singh
authors.affiliation: Centre for Pharmacology and Toxicology, Hannover Medical School, 30625 Hannover, Germany.|Institute of Pathology, 41747 Viersen, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Spanel
authors.affiliation: Centre for Integrative Biology (CIBIO), University of Trento, 38123 Mattarello, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
authors.affiliation: Centre for Pharmacology and Toxicology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Borlak
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000231:Adenocarcinoma, Papillary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D024202:Electrophoretic Mobility Shift Assay; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc
keywords: c-Myc regulated cell cycle and apoptotic genes; c-Myc regulatory gene networks; c-Myc transgenic mouse model of papillary lung adenocarcinomas; gene reporter assays; whole genome scans