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Published ahead of print on September 13, 2007, doi:10.1165/rcmb.2007-0206OC

Am. J. Respir. Cell Mol. Biol., Volume 38, Number 2, February 2008, 209-217

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Submitted on June 6, 2007
Revised on September 13, 2007

HGF Mediates Cell Proliferation of Human Mesothelioma Cells Through a PI3K/MEK5/Fra-1 Pathway

Maria E Ramos-Nino1*, Steven R Blumen1, Tara Sabo-Attwood2, Harvey Pass3, Michele Carbone4, Joseph Testa5, Deborah A Altomare5, and Brooke T Mossman1

1 Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA, 2 Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA, 3 Department of Cardiothoracic Surgery, New York University School of Medicine, New York, NY, USA, 4 Cancer Research Center of Hawaii, Honolulu, HI, USA, 5 Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: Maria.Ramos{at}uvm.edu.

The ligand hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase, c-Met, are highly expressed in most human malignant mesotheliomas (MMs) and may contribute to their increased growth and viability. Based upon our observation that RNA silencing of fos-related antigen 1 (fra-1) inhibited c-met expression in rat mesotheliomas (1), we hypothesized that Fra-1 was a key player in HGF-induced proliferation in human MMs. In 3 of 7 human MM lines evaluated, HGF increased Fra-1 levels and phosphorylation of both extracellular signal-regulated kinase 5 (ERK5) and AKT that were inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY29004. HGF-dependent phosphorylation and Fra-1 expression were decreased after knockdown of Fra-1 whereas overexpression of Fra-1 blocked the expression of MEK5 at the mRNA and protein levels. Stable MM cell lines using a dnMEK5 showed that basal Fra-1 levels were increased in comparison to empty vector control lines. HGF also caused increased MM cell viability and proliferating cell nuclear antigen (PCNA) expression that were abolished by knockdown of MEK5 or Fra-1. Data suggest that HGF-induced effects in the some MM cells are mediated via activation of a novel PI3K/ERK5/Fra-1 feedback pathway that might explain tumor-specific effects of c-Met inhibitors on MM and other tumors.




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M. E. Ramos-Nino and B. Littenberg
A novel combination: ranpirnase and rosiglitazone induce a synergistic apoptotic effect by down-regulating Fra-1 and Survivin in cancer cells
Mol. Cancer Ther., July 1, 2008; 7(7): 1871 - 1879.
[Abstract] [Full Text] [PDF]


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