Casein kinase II is a selective target of HIV-1 transcriptional inhibitors

被引:124
作者
Critchfield, JW
Coligan, JE
Folks, TM
Butera, ST
机构
[1] CTR DIS CONTROL & PREVENT, TB LAB RES, ATLANTA, GA 30333 USA
[2] NIAID, MOL STRUCT LAB, NATL INST HLTH, ROCKVILLE, MD 20852 USA
关键词
D O I
10.1073/pnas.94.12.6110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The identification of cellular factors that are required to complete various steps of the HIV-1 life cycle may lead to the development of new therapeutics. One key step, transcription from the integrated provirus, is inhibited by members of two distinct classes of compounds, the flavonoids and the benzothiophenes, via an unknown mechanism, possibly involving a cellular factor, A marked specificity toward inhibiting HIV-1 transcription is evidenced by the ability of drug-treated cells to retain their proliferative and differentiation capabilities, In addition, the compounds do not impede the activation and function of the transcriptional factor NF-kappa B. Here we report on the identification of several cellular proteins that mediate the HIV-1 transcriptional inhibitory property of the flavonoid chrysin, Chemical and immunologic analyses identified these cellular proteins as the individual subunits of casein kinase II (CKII), Though structurally unrelated to chrysin, an HIV-1 inhibitory benzothiophene also bound selectively to CKII, Both chrysin and the benzothiophenes inhibited human recombinant CKII enzymatic activity and showed competitive kinetics with respect to ATP, analogous to the classic CKII inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), Moreover, DRB potently inhibited HIV-1 expression in chronically infected cells, CKII may regulate HIV-1 transcription by phosphorylating cellular proteins involved in HIV-1 transactivation that contain multiple CKII phosphorylation consensus sequences.
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页码:6110 / 6115
页数:6
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