Up-regulation of Bcl-xl by hepatocyte growth factor in human mesothelioma cells involves ETS transcription factors

Xiaobo Cao, James Littlejohn, Charles Rodarte, Lidong Zhang, Benjamin Martino, Philip Rascoe, Kamran Hamid, Daniel Jupiter, W. Roy Smythe

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15 Scopus citations

Abstract

Bcl-xl and the hepatocyte growth factor (HGF) receptor c-Met are both highly expressed in mesotheliomas, where they protect cells from apoptosis and can confer resistance to conventional therapeutic agents. In our current study, we investigate a model for the transcriptional control of Bcl-xl that involves ETS transcription factors and the HGF/Met axis. In addition, the effects of activated c-Met on the phosphorylation of the ETS family transcriptional factors were examined. The transient expression of ETS-2 and PU.1 cDNAs in mesothelioma cell lines resulted in an increase in the promoter activity of Bcl-xl and consequently in its mRNA and protein expression levels, whereas the transcriptional repressor Tel suppressed Bcl-xl transcription. The activation of the HGF/Met axis led to rapid phosphorylation of ETS family transcription factors in mesothelioma cells through the mitogen-activated protein kinase pathway and via nuclear accumulation of ETS-2 and PU.1. A chromatin immunoprecipitation assay further demonstrated that the activation of c-Met enhanced the binding of ETS transcriptional factors to the Bcl-x promoter. Finally, we determined the Bcl-xl and phosphorylated c-Met expression levels in mesothelioma patient samples; these data suggest a strong correlation between Bcl-xl and phosphorylated c-Met levels. Taken together, these findings support a role for c-Met as an inhibitor of apoptosis and an activator of Bcl-xl.

Original languageEnglish (US)
Pages (from-to)2207-2216
Number of pages10
JournalAmerican Journal of Pathology
Volume175
Issue number5
DOIs
StatePublished - 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Cao, X., Littlejohn, J., Rodarte, C., Zhang, L., Martino, B., Rascoe, P., Hamid, K., Jupiter, D., & Smythe, W. R. (2009). Up-regulation of Bcl-xl by hepatocyte growth factor in human mesothelioma cells involves ETS transcription factors. American Journal of Pathology, 175(5), 2207-2216. https://doi.org/10.2353/ajpath.2009.090070