Human FKBP5 Negatively Regulates Transcription through Inhibition of P-TEFb Complex Formation
- 1 January 2022
- journal article
- research article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 42 (1), e0034421
- https://doi.org/10.1128/mcb.00344-21
Abstract
Although large number of recent studies indicate strong association of FKBP5 (aka FKBP51) functions with various stress-related psychiatric disorder, the overall mechanisms are poorly understood. Beyond a few studies indicating its functions in regulating glucocorticoid receptor-, and AKT-signalling pathways, other functional roles (if any) are unclear. In this study, we report an anti-proliferative role of human FKBP5 through negative regulation of expression of proliferation-related genes. Mechanistically, we show that, owing to same region of interaction on CDK9, human FKBP5 directly competes with CyclinT1 for functional P-TEFb complex formation. In vitro biochemical coupled with cell-based assays, showed strong negative effect of FKBP5 on P-TEFb-mediated phosphorylation of diverse substrates. Consistently, FKBP5 knockdown showed enhanced P-TEFb complex formation leading to increased global RNA polymerase II CTD phosphorylation and expression of proliferation-related genes and subsequent proliferation. Thus, our results show an important role of FKBP5 in negative regulation of P-TEFb functions within mammalian cells.Keywords
Funding Information
- Council of Scientific and Industrial Research, India
- University Grants Commission
- Council of Scientific and Industrial Research, India
- Department of Biotechnology, Ministry of Science and Technology, India
- Department of Science and Technology, Ministry of Science and Technology, India
- Department of Science and Technology, Ministry of Science and Technology, India (EMR/2016/001593)
- University Grants Commission
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