Inhibition of HTLV-1 transcription by cyclin dependent kinase inhibitors.
HTLV-1 is the etiologic agent for adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), where viral replication and transformation are largely dependent upon modification of regulatory and host cell cycle proteins. The mechanism of HTLV-1 transformation appears to be distinct from that of many known chronic or acute leukemia viruses and is related to the viral activator Tax. Here we show that cyclin E, can associate tightly with the coactivator p300 and Pol II complex in HTLV-1 infected cells. The cyclin E associated complex is kinase active and phosphorylates the carboxy terminal domain of RNA Pol II. More importantly, p21/Waf1, a well-known cdk inhibitor at the G1/S border, inhibits transcription of HTLV-1 in both transfections and in in vitro transcription assays. Finally, specific cdk chemical inhibitors, functionally similar to cellular cdkIs, such as p21/Waf1 which inhibits cyclin E/cdk2 activity, also inhibit transcription of the HTLV-1 promoter. In particular, Purvalanol A, with an IC50 of 0.035 microm inhibits activated, but not basal transcription, as well as HTLV-1 infected cells. Collectively, the role of cyclin E/cdk2 in HTLV-1 infected cells and its involvement in RNA Pol II phosphorylation is discussed.
Wang
Lai
L
George Washington University, School of Medicine, Washington, DC 20037, USA.
Deng
Longwen
L
Wu
Kaili
K
de la Fuente
Cynthia
C
Wang
Dai
D
Kehn
Kylene
K
Maddukuri
Anil
A
Baylor
Shanese
S
Santiago
Francisco
F
Agbottah
Emmanuel
E
Trigon
Sylviane
S
Morange
Michel
M
Mahieux
Renaud
R
Kashanchi
Fatah
F
D000595:Amino Acid Sequence; D000818:Animals; D016367:Baculoviridae / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D007313:Insecta; D008214:Lymphocytes / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011687:Purines / Q000494:pharmacology; D012367:RNA, Viral; D014158:Transcription, Genetic; D014162:Transfection
C471843:6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D010455:Peptides; D011687:Purines; D012367:RNA, Viral; D015500:Chloramphenicol O-Acetyltransferase