Loss of functional transforming growth factor (TGF)-β type II receptor results in insensitivity to TGF-β1-mediated apoptosis and Epstein–Barr virus reactivation

Transforming growth factor (TGF)-β1 induces not only cell growth inhibition or apoptosis but also Epstein–Barr virus (EBV) reactivation in some Burkitt's lymphoma (BL) cell lines. The purpose of this study was to define the role of TGF-β signaling molecules in response to TGF-β1-mediated cell growth inhibition, apoptosis, and EBV reactivation in BL cell lines. First, we confirmed the effect of TGF-β1 on the cell growth and EBV reactivation in six BL cell lines. TGF-β1 induced cell growth inhibition and EBV reactivation in these cell lines but did not in Akata cells. To elucidate the mechanism of TGF-β1 unresponsiveness in Akata cells, we studied the expression of TGF-β receptors and the intracellular signaling molecules Smads. All cell lines expressed TGF-β type I receptor, Smad2, Smad3, and Smad4. TGF-β type II receptor (R-II) was expressed in all cell lines except Akata cells. Introduction of the TGF-β R-II into Akata cells results in sensitivity to TGF-β1-mediated growth inhibition, apoptosis, and EBV reactivation. In addition, to test a possibility to the transcriptional repression of the TGF-β R-II gene in Akata cells, the effect of histone deacetylation (HDAC) inhibitor, trichostatin A (TSA) was examined. The expression of TGF-β R-II in Akata cells was induced by TSA treatment. These results suggest that the lack of functional TGF-β R-II impedes the progression of signals through TGF-β1 and becomes a determinant of unresponsiveness to TGF-β1-mediated growth inhibition and EBV reactivation. J. Med. Virol. 78:1456–1464, 2006. © 2006 Wiley-Liss, Inc.