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Expression of PP1 inhibitor inhibits CDK9 and HIV‐1 transcription
Author(s) -
Ammosova Tatiana,
Yedavalli Venkat R.K.,
Jerebtsova Marina,
Van Eynde Aleyde,
Beullens Monique,
Bollen Mathieu,
Jeang KuanTeh,
Nekhai Sergei
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.756.1
CDK9/cyclin T1 is a key enzyme in HIV‐1 transcription. Dephosphorylation of CDK9 on Thr186 by protein phosphatase‐1 (PP1) in stress‐induced cells or by protein phosphatase M1A in normally growing cells activates CDK9. Previously we showed that HIV‐1 Tat protein binds to protein phosphatase‐1 (PP1) through Q 35 VCF 38 sequence in Tat, which is similar to the PP1‐binding RVxF motif and that this interaction assists HIV‐1 transcription. Nuclear Inhibitor of PP1 (NIPP1) binds to PP1 through RVCF sequence in the central domain of NIPP1 (cdNIPP1) with the high efficiency. Here we analyzed the effect of cdNIPP1 expression in stable cell line and also as part of HIV‐1 genome in place of nef . Stable expression of cdNIPP1 increased CDK9 phosphorylation on Thr186, induced the association of CDK9 with 7SK RNA and inhibited CDK9 activity. The stable expression of cdNIPP1 disrupted the interaction of Tat and PP1, and inhibited HIV‐1 transcription. Expression of cdNIPP1 as a part of the HIV‐1 genome inhibited HIV‐1 replication. Our results strongly indicate that redistribution of PP1 can be used as a future approach to disrupt Tat‐induced HIV‐1 transcription and to inhibit of HIV‐1 replication. This study was supported by NIH grants 2 R25 HL003679‐08, 1SC1GM082325 and 2G12RR003048.