The epigenetic reader BRD4 plays a vital role in transcriptional regulation, cellular growth control, and cell-cycle progression. Dysregulation of BRD4 function has been implicated in the pathogenesis of a wide range of cancers. However, how BRD4 is regulated to maintain its normal function in healthy cells and how alteration of this process leads to cancer remain poorly understood. In this study, we discovered that BRD4 is hyperphosphorylated in NUT midline carcinoma and identified CDK9 as a potential kinase mediating BRD4 hyperphosphorylation. Disruption of BRD4 hyperphosphorylation using both chemical and molecular inhibitors led to the repression of BRD4 downstream oncogenes and abrogation of cellular transformation. BRD4 hyperphosphorylation is also observed in other cancers displaying enhanced BRD4 oncogenic activity. Our study revealed a mechanism that may regulate BRD4 biological function through phosphorylation, which, when dysregulated, could lead to oncogenesis. Our finding points to strategies to target the aberrant BRD4 signaling specifically for cancer intervention.
The human papillomavirus (HPV) vaccines effectively protect against new infections of up to four HPV subtypes. However, these vaccines are not protective against many other clinically relevant HPV subtypes and are ineffective at treating established HPV infections. There is therefore a significant need for antiviral treatments for persistent HPV infections. A promising anti-HPV drug target is the interaction between the HPV E2 protein and cellular bromodomain-containing protein 4 (Brd4) since this protein complex mediates several processes important for the viral life cycle including viral genome maintenance, replication, and transcription. Using bimolecular fluorescence complementation (BiFC) technology, we demonstrate the E2 and Brd4 interaction on both interphase chromatin and mitotic chromosomes throughout mitosis. The E2-Brd4 BiFC was significantly diminished by mutating the Brd4 binding sites in E2 or by a dominant negative inhibitor of the E2-Brd4 interaction, demonstrating the potential of BiFC for identifying inhibitors of this important virus-host interaction. Importantly, when Brd4 was released from chromatin using the bromodomain inhibitor JQ1(+), the E2-Brd4 interacting complex relocated into foci that no longer associate with mitotic chromosomes, pointing to JQ1(+) as a promising antiviral inhibitor of HPV genome maintenance during HPV persistent infection.
Pathogen-associated molecular patterns (PAMPs) trigger plant innate immunity that acts as the first line of inducible defense against pathogen infection. A receptor-like cytoplasmic kinase BOTRYTIS-INDUCED KINASE 1 (BIK1) functions as a signaling hub immediately downstream of multiple pattern recognition receptors (PRRs). It is known that PLANT U-BOX PROTEIN 25 (PUB25) and PUB26 ubiquitinate BIK1 and mediate BIK1 degradation. However, how BIK1 homeostasis is maintained is not fully understood. Here, we show that two closely related ubiquitin ligases, RING DOMAIN LIGASE 1 (RGLG1) and RGLG2, preferentially associate with the hypo-phosphorylated BIK1 and promote the association of BIK1 with the co-receptor for several PRRs, BRI1-ASSOCIATED RECEPTOR KINASE1 (BAK1). PUB25 interacts with RGLG2 and mediates its degradation. In turn, RGLG2 represses the ubiquitin ligase activity of PUB25. RGLG1/2 suppress PUB25-mediated BIK1 degradation, promote BIK1 protein accumulation, and positively regulate immune signaling in a ubiquitin ligase activity-dependent manner. Our work reveals how BIK1 homeostasis is maintained by the interplay of different ubiquitin ligases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.