Epstein-Barr Virus latent membrane protein 1 overcomes all-trans retinoic acid-induced apoptosis by inhibiting retinoic acid receptor-β₂ expression.
Nasopharyngeal carcinoma is closely associated with infection with Epstein-Barr Virus (EBV); however, the mechanism is still unclear. Here, we report that the EBV oncoprotein, latent membrane protein 1 (LMP1), suppresses apoptotic cell death provoked by all-trans retinoic acid (ATRA) in NPC cells. For this purpose, LMP1 downregulated levels of Bak whilst it upregulated levels of Bcl2, lowering the ratio of Bak to Bcl2. In addition, LMP1 suppressed ATRA-mediated activation of Caspase 9, Caspase 3, and PARP but not Caspase 8 in Ad-AH cells, suggesting that LMP1 acts by blocking the activation of intrinsic apoptosis pathway by ATRA. These effects were almost completely abolished when levels of retinoic acid receptor-β(2) (RAR-β(2)) in the LMP1-expressing cells were recovered by either exogenous gene expression or treatment with a universal DNMT inhibitor, 5-Aza-2'dC, indicating that LMP1 executes its antiapoptotic effects by downregulating levels of RAR-β(2) via DNA methylation.
Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
Hyehyeon
H
Lee
So Young
SY
Seo
Indira
I
Tiwari
Kyung Lib
KL
Jang
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002277:Carcinoma / Q000378:metabolism / Q000821:virology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation; D006801:Humans; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000821:virology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014763:Viral Matrix Proteins / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
C494772:BAK1 protein, human; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018168:Receptors, Retinoic Acid; D014763:Viral Matrix Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; C540966:retinoic acid receptor, beta2, human; D014212:Tretinoin; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases