Inhibition of methyltransferases results in induction of g2/m checkpoint and programmed cell death in human T-lymphotropic virus type 1-transformed cells.
Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia. The HTLV-1-encoded protein Tax transactivates the viral long terminal repeat and plays a critical role in virus replication and transformation. Previous work from our laboratory demonstrated that coactivator-associated arginine methytransferase 1, a protein arginine methytransferase, was important for Tax-mediated transactivation. To further investigate the role of methyltransferases in viral transcription, we utilized adenosine-2,3-dialdehyde (AdOx), an adenosine analog and S-adenosylmethionine-dependent methyltransferase inhibitor. The addition of AdOx decreased Tax transactivation in C81, Hut102, and MT-2 cells. Unexpectedly, we found that AdOx potently inhibited the growth of HTLV-1-transformed cells. Further investigation revealed that AdOx inhibited the Tax-activated NF-kappaB pathway, resulting in reactivation of p53 and induction of p53 target genes. Analysis of the NF-kappaB pathway demonstrated that AdOx treatment resulted in degradation of the IkappaB kinase complex and inhibition of NF-kappaB through stabilization of the NF-kappaB inhibitor IkappaBalpha. Our data further demonstrated that AdOx induced G(2)/M cell cycle arrest and cell death in HTLV-1-transformed but not control lymphocytes. These studies demonstrate that protein methylation plays an important role in NF-kappaB activation and survival of HTLV-1-transformed cells.
Dasgupta
Arindam
A
Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 41 Medlars Dr., Building 41, Room B201, Bethesda, MD 20892, USA.
Jung
Kyung-Jin
KJ
Jeong
Soo-Jin
SJ
Brady
John N
JN
D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016356:Gene Products, tax / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014779:Virus Replication / Q000502:physiology*
D004791:Enzyme Inhibitors; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D016159:Tumor Suppressor Protein p53; D000072000:NF-KappaB Inhibitor alpha; D008780:Methyltransferases; D051550:I-kappa B Kinase