TY - JOUR
T1 - Flavopiridol inhibits P-TEFb and blocks HIV-1 replication
AU - Chao, Sheng Hao
AU - Fujinaga, Koh
AU - Marion, Jon E.
AU - Taube, Ran
AU - Sausville, Edward A.
AU - Senderowicz, Adrian M.
AU - Peterlin, B. Matija
AU - Price, David H.
PY - 2000/9/15
Y1 - 2000/9/15
N2 - Flavopiridol (L86-8276, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid potently inhibited transcription by RNA polymerase II in vitro by blocking the transition into productive elongation, a step controlled by P-TEFb. The ability of P-TEFb to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II was inhibited by fiavopiridol with a K(i) of 3 nM. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 is a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat. Consistent with its ability to inhibit P-TEFb, flavopiridol blocked Tat transactivation of the viral promoter in vitro. Furthermore, flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC50 of less than 10 nM.
AB - Flavopiridol (L86-8276, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid potently inhibited transcription by RNA polymerase II in vitro by blocking the transition into productive elongation, a step controlled by P-TEFb. The ability of P-TEFb to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II was inhibited by fiavopiridol with a K(i) of 3 nM. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 is a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat. Consistent with its ability to inhibit P-TEFb, flavopiridol blocked Tat transactivation of the viral promoter in vitro. Furthermore, flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC50 of less than 10 nM.
UR - http://www.scopus.com/inward/record.url?scp=0034665961&partnerID=8YFLogxK
U2 - 10.1074/jbc.C000446200
DO - 10.1074/jbc.C000446200
M3 - Article
C2 - 10906320
AN - SCOPUS:0034665961
SN - 0021-9258
VL - 275
SP - 28345
EP - 28348
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -
