c-Crk proto-oncogene contributes to transcriptional repression of p120-catenin in non-small cell lung cancer cells
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Fariborz Mortazavi Steven Dubinett Matthew Rettig
- چاپ و سال / کشور: 2011
Description
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.
Clin Exp Metastasis (2011) 28:391–404 DOI 10.1007/s10585-011-9378-8 Received: 13 December 2010 / Accepted: 6 February 2011 / Published online: 20 February 2011
