title: c-Crk proto-oncogene contributes to transcriptional repression of p120-catenin in non-small cell lung cancer cells.
abstract: As a member of adherens junction, p120-catenin (p120ctn) plays a major role in cell adhesions through stabilization of E-cadherin. p120ctn is transcriptionally down-regulated in non-small cell lung cancer (NSCLC), although the molecular mechanisms underlying p120ctn repression are incompletely defined. Here we further investigated transcriptional regulation of p120ctn in NSCLC. We prepared a promoter reporter plasmid construct that contained p120ctn promoter region from position -1082 to +320 relative to transcription start site. Through serial deletion mutation analysis of the p120ctn promoter, we pinpointed cis-acting elements involved in regulation of p120ctn. We identified transcription factor SP1 as a transcriptional repressor of p120ctn that directly binds to segment (-9 to +36) of the p120ctn promoter. SP1 can receive multiple signals from several intracellular signaling pathways. Through examination of SP1 binding partners, we identified proto-oncogene c-Crk to be involved in transcriptional down-regulation of p120ctn. RNAi mediated silencing of CRK in A549, H157 and H358 cells increased p120ctn protein levels. On the other hand, over-expression of CRK-I and CRK-II in NSCLC cells down-regulated p120ctn, an effect that was abrogated by simultaneous silencing of SP1. In summary, our data provide evidence for the role of c-Crk proto-oncogene in transcriptional repression of p120ctn that further clarifies the mechanism by which this biochemical signal promotes metastasis in NSCLC.
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. fredmortazavi@ucla.edu
authors.forename: Fariborz
authors.initials: F
authors.lastname: Mortazavi
authors.forename: Steven
authors.initials: S
authors.lastname: Dubinett
authors.forename: Matthew
authors.initials: M
authors.lastname: Rettig
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D051177:Catenins / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics; D000090063:Proto-Oncogene Mas; D050737:Proto-Oncogene Proteins c-crk / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured; D000095002:Delta Catenin
chemical_list: D051177:Catenins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D050737:Proto-Oncogene Proteins c-crk; D000095002:Delta Catenin; C000722347:CTNND1 protein, human