Phosphorylation by JNK switches BRD4 functions.
Autor: | Devaiah BN; Experimental Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA., Singh AK; Experimental Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA., Mu J; Experimental Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA., Chen Q; Center for Biomedical Informatics and Information Technology, NCI, NIH, Bethesda, MD 20892, USA., Meerzaman D; Center for Biomedical Informatics and Information Technology, NCI, NIH, Bethesda, MD 20892, USA., Singer DS; Experimental Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA. Electronic address: dinah.singer@nih.gov. |
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Jazyk: | angličtina |
Zdroj: | Molecular cell [Mol Cell] 2024 Nov 21; Vol. 84 (22), pp. 4282-4296.e7. Date of Electronic Publication: 2024 Oct 24. |
DOI: | 10.1016/j.molcel.2024.09.030 |
Abstrakt: | Bromodomain 4 (BRD4), a key regulator with pleiotropic functions, plays crucial roles in cancers and cellular stress responses. It exhibits dual functionality: chromatin-bound BRD4 regulates remodeling through its histone acetyltransferase (HAT) activity, while promoter-associated BRD4 regulates transcription through its kinase activity. Notably, chromatin-bound BRD4 lacks kinase activity, and RNA polymerase II (RNA Pol II)-bound BRD4 exhibits no HAT activity. This study unveils one mechanism underlying BRD4's functional switch. In response to diverse stimuli, c-Jun N-terminal kinase (JNK)-mediated phosphorylation of human BRD4 at Thr1186 and Thr1212 triggers its transient release from chromatin, disrupting its HAT activity and potentiating its kinase activity. Released BRD4 directly interacts with and phosphorylates RNA Pol II, PTEFb, and c-Myc, thereby promoting transcription of target genes involved in immune and inflammatory responses. JNK-mediated BRD4 functional switching induces CD8 expression in thymocytes and epithelial-to-mesenchymal transition (EMT) in prostate cancer cells. These findings elucidate the mechanism by which BRD4 transitions from a chromatin regulator to a transcriptional activator. Competing Interests: Declaration of interests The authors declare no competing interests. (Published by Elsevier Inc.) |
Databáze: | MEDLINE |
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