LATENT MEMBRANE PROTEIN-1 INDUCES CYCLIN D2 EXPRESSION, PRB HYPERPHOSPHORYLATION, AND LOSS OF TGF-BETA-1-MEDIATED GROWTH-INHIBITION IN EBV-POSITIVE B-CELLS

The normal cell cycle is regulated by several molecules, such as the t umor-suppressor protein pRb, the G1 cyclins, the cyclin-dependent kina ses, and their inhibitors. These regulators are targeted by negative g rowth regulatory signals, such as that provided by TGF-beta. Here, we show that the presence oi either wild-type EBV or its transforming lat ent membrane protein-1 (LMP-1) results in the loss of TGF-beta 1-media ted growth inhibition in human B cells. Chemical cross-linking with I- 125-labeled TGF-beta 1 showed an essentially normal TGF-beta receptor profile in EBV-positive and EBV-negative Burkitt's lymphoma cell lines , and these receptors were shown to be functional in transducing signa ls, as evidenced by the TGF-beta 1-mediated modulation of junB gene ex pression. However, TGF-beta 1 did not induce dephosphorylation of pRb in EBV (or LMP-1)-positive cells as opposed to EBV-negative cells, sug gesting a dichotomy in the TGF-beta 1 signaling pathway leading to sep arable gene regulatory and growth inhibitory responses. Furthermore, L MP-1 was found to induce the expression of cyclin D2; normal B cells o r EBV-negative Burkitt's lymphoma cells do not express D-type cyclins. Taken together, these data point to a potential mechanism underlying EBV-mediated B cell transformation whereby constitutive induction of k ey cell cycle regulators by LMP-1 can lead to pRb hyperphosphorylation and uncontrolled cell proliferation.