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J Biol Chem, Vol. 275, Issue 1, 279-287, January 7, 2000
From the Department of Molecular and Cell Biology, University of
California at Berkeley, Berkeley, California 94720-3206
Tat activation of HIV-1 transcription is mediated
by human transcription elongation factor P-TEFb, which interacts with
Tat and phosphorylates the C-terminal domain of RNA polymerase II. The
catalytic subunit of the P-TEFb complex, Cdk9, has been shown to
interact with cyclin T and several other proteins of unknown identity.
Consequently, the exact subunit composition of active P-TEFb has not
been determined. Here we report the affinity purification and
identification of the Cdk9-associated proteins. In addition to forming
a heterodimer with cyclin T1, Cdk9 interacted with the molecular
chaperone Hsp70 or a kinase-specific chaperone complex, Hsp90/Cdc37, to
form two separate chaperone-Cdk9 complexes. Although the Cdk9/cyclin T1
dimer was exceptionally stable and produced slowly in the cell, free
and unprotected Cdk9 appeared to be degraded rapidly. Several lines of
evidence indicate the heterodimer of Cdk9/cyclin T1 to be the mature,
active form of P-TEFb responsible for phosphorylation of the C-terminal
domain of RNA polymerase II interaction with the Tat activation domain,
and mediation of Tat activation of HIV-1 transcription. Pharmacological
inactivation of Hsp90/Cdc37 function by geldanamycin revealed an
essential role for the chaperone-Cdk9 complexes in generation of
Cdk9/cyclin T1. Our data suggest a previously unrecognized
chaperone-dependent pathway involving the sequential
actions of Hsp70 and Hsp90/Cdc37 in the stabilization/folding of
Cdk9 as well as the assembly of an active Cdk9/cyclin T1 complex
responsible for P-TEFb-mediated Tat transactivation.
Requirement for a Kinase-specific Chaperone Pathway in the
Production of a Cdk9/Cyclin T1 Heterodimer Responsible for
P-TEFb-mediated Tat Stimulation of HIV-1 Transcription*
*
This work was supported by National Institutes of Health
Grant AI-41757, University of California Universitywide AIDS Research Program Grant R97-B-113, and U. S. Army Breast Cancer Research Program
Grant DAMD17-96-1-6137 (to Q. Z.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: 206 Stanley Hall,
#3206, University of California, Berkeley, Berkeley, CA 94720. E-mail:
qzhou@uclink4.berkeley.edu.
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