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Clin Exp Metastasis. 2011 Apr;28(4):391-404. doi: 10.1007/s10585-011-9378-8. Epub 2011 Feb 20.

c-Crk proto-oncogene contributes to transcriptional repression of p120-catenin in non-small cell lung cancer cells.

Author information

1
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. fredmortazavi@ucla.edu

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.

PMID:
21336985
PMCID:
PMC3081060
DOI:
10.1007/s10585-011-9378-8
[Indexed for MEDLINE]
Free PMC Article

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