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 tumor-suppressor protein pRb, the G1 cyclins, the cyclin-dependent kinases, and their inhibitors. These regulators are targeted by negative growth regulatory signals, such as that provided by TGF-beta. Here, we show that the presence of either wild-type EBV or its transforming latent membrane protein-1 (LMP-1) results in the loss of TGF-beta 1-mediated growth inhibition in human B cells. Chemical cross-linking with 125I-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 signals, as evidenced by the TGF-beta 1-mediated modulation of junB gene expression. However, TGF-beta 1 did not induce dephosphorylation of pRb in EBV (or LMP-1)-positive cells as opposed to EBV-negative cells, suggesting a dichotomy in the TGF-beta 1 signaling pathway leading to separable gene regulatory and growth inhibitory responses. Furthermore, LMP-1 was found to induce the expression of cyclin D2; normal B cells or 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 key cell cycle regulators by LMP-1 can lead to pRb hyperphosphorylation and uncontrolled cell proliferation.
Arvanitakis
L
L
Department of Pathology, Roger Williams Medical Center-Brown University, Providence, RI 02908, USA.
Yaseen
N
N
Sharma
S
S
D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D002051:Burkitt Lymphoma / Q000473:pathology; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D003432:Cross-Linking Reagents / Q000494:pharmacology; D056742:Cyclin D2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D006566:Herpesviridae Infections / Q000473:pathology; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000473:pathology; D014763:Viral Matrix Proteins / Q000502:physiology*
C080336:CCND2 protein, human; D003432:Cross-Linking Reagents; D056742:Cyclin D2; D016213:Cyclins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D014763:Viral Matrix Proteins; D015847:Interleukin-4; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases