Epstein-Barr virus latent membrane protein 1 induces and causes release of fibroblast growth factor-2

N Wakisaka, S Murono, T Yoshizaki, M Furukawa… - Cancer research, 2002 - AACR
N Wakisaka, S Murono, T Yoshizaki, M Furukawa, JS Pagano
Cancer research, 2002AACR
We have shown that the EBV oncoprotein, latent membrane protein 1 (LMP1), induces a
constellation of tumor-invasiveness factors. Fibroblast growth factor (FGF)-2 is angiogenic as
well mitogenic. Although FGF-2 does not contain a hydrophobic signal sequence for
secretion, FGF-2 is released extracellularly. However, the mechanism by which FGF-2 is
released is unclear. Here we show first that LMP1 induces in epithelial cells the expression
of FGF-2 mRNA and protein through both LMP1 COOH-terminal activation domains, CTAR 1 …
Abstract
We have shown that the EBV oncoprotein, latent membrane protein 1 (LMP1), induces a constellation of tumor-invasiveness factors. Fibroblast growth factor (FGF)-2 is angiogenic as well mitogenic. Although FGF-2 does not contain a hydrophobic signal sequence for secretion, FGF-2 is released extracellularly. However, the mechanism by which FGF-2 is released is unclear. Here we show first that LMP1 induces in epithelial cells the expression of FGF-2 mRNA and protein through both LMP1 COOH-terminal activation domains, CTAR 1 and CTAR 2, which can activate nuclear factor (NF)-κB signaling and also the p38 mitogen-activated protein kinase pathway. Coexpression of IκBα (S32A/S36A), which cannot be phosphorylated and prevents NF-κB activation, with LMP1 inhibited induction of FGF-2 by LMP1, which suggests that LMP1 induces FGF-2 via NF-κB signaling. Moreover, unlike phorbol 12-myristate 13-acetate LMP1 also induced the release of the Mr 18,000 isoform of FGF-2 protein. Transfection of Ad-AH cells with LMP1 deletion mutants lacking either CTAR 1 or CTAR 2 also induced the release of the protein. Secretion was confirmed in 293 cells, which do not contain detectable endogenous FGF-2 protein, cotransfected with FGF-2 and LMP1. Finally, Na+/K+-ATPase participates in FGF-2 release, independently of the classical endoplasmic reticulum/Golgi pathway. In this study, the release of Mr 18,000 FGF-2 protein was partially suppressed by ouabain, which inhibits the activity of Na+/K+-ATPase α1 subunit, but not by Brefeldin A, which inhibits the endoplasmic reticulum/Golgi-dependent secretory pathway. In contrast, the release of Mr 18,000 FGF-2 protein was almost completely inhibited by IκBα (S32A/S36A). These results suggest that FGF-2 release is independently mediated by NF-κB signaling, not simply a consequence of induction itself. Thus, NF-κB signaling is involved in induction of expression and release of FGF-2 by LMP1.
AACR