CDK8 inhibitors antagonize HIV-1 reactivation and promote provirus latency in T cells DOI Creative Commons
Riley M. Horvath, Zabrina L. Brumme, Ivan Sadowski

et al.

Journal of Virology, Journal Year: 2023, Volume and Issue: 97(9)

Published: Sept. 6, 2023

Latent HIV-1 provirus represents the barrier toward a cure for infection and is dependent upon host RNA Polymerase (Pol) II machinery reemergence. Here, we find that inhibitors of Pol mediator kinases CDK8/19, Senexin A BRD6989, inhibit induction expression in response to latency-reversing agents T cell signaling agonists. These were found impair recruitment LTR. Furthermore, several latency reversal was impaired disruption CDK8 by shRNA or gene knockout. However, effects depletion did not entirely mimic CDK8/19 kinase inhibition suggesting are functionally redundant. Additionally, treatment CD4+ peripheral blood mononuclear cells isolated from people living with who receiving antiretroviral therapy inhibited viral replication stimulation PMA ionomycin. observations indicate kinases, CDK19, play significant role regulation transcription small molecule these enzymes may contribute therapies designed promote deep involving durable suppression expression. IMPORTANCE will require novel can force elimination contain copies virus genome inserted into chromosome, but which shut off, silenced. known as latently-infected cells, represent main reason why current HIV/AIDS cannot because unaffected drugs. Our results chemical Cdk8 also latent HIV provirus. an important enzyme regulates genes signals need respond produced frequently mutated cancers. be employed prevent provirus, might eventually enable infected individuals cease

Language: Английский

Comprehensive Review of Uterine Fibroids: Developmental Origin, Pathogenesis, and Treatment DOI Creative Commons
Qiwei Yang, Michał Ciebiera, María Victoria Bariani

et al.

Endocrine Reviews, Journal Year: 2021, Volume and Issue: 43(4), P. 678 - 719

Published: Nov. 6, 2021

Abstract Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing most common tumors in women worldwide. To date, no long-term or noninvasive treatment option exists for hormone-dependent uterine fibroids, due to limited knowledge about molecular mechanisms underlying initiation and development fibroids. This paper comprehensively summarizes recent research advances on focusing risk factors, origin, pathogenetic mechanisms, options. Additionally, we describe current interventions Finally, future perspectives studies summarized. Deeper mechanistic insights into tumor etiology complexity can contribute progress newer targeted therapies.

Language: Английский

Citations

277
Structure and mechanism of the RNA polymerase II transcription machinery DOI Open Access

Allison C. Schier,

Dylan J. Taatjes

Genes & Development, Journal Year: 2020, Volume and Issue: 34(7-8), P. 465 - 488

Published: April 1, 2020

RNA polymerase II (Pol II) transcribes all protein-coding genes and many noncoding RNAs in eukaryotic genomes. Although Pol is a complex, 12-subunit enzyme, it lacks the ability to initiate transcription cannot consistently transcribe through long DNA sequences. To execute these essential functions, an array of proteins protein complexes interact with regulate its activity. In this review, we detail structure mechanism over dozen factors that govern initiation (e.g., TFIID, TFIIH, Mediator), pausing, elongation DSIF, NELF, PAF, P-TEFb). The structural basis for regulation has advanced rapidly past decade, largely due technological innovations cryoelectron microscopy. Here, summarize wealth functional data have enabled deeper understanding mechanisms; also highlight mechanistic questions remain unanswered or controversial.

Language: Английский

Citations

239
Transcription-Associated Cyclin-Dependent Kinases as Targets and Biomarkers for Cancer Therapy DOI
Jonathan Chou, David A. Quigley, Troy M. Robinson

et al.

Cancer Discovery, Journal Year: 2020, Volume and Issue: 10(3), P. 351 - 370

Published: Feb. 18, 2020

Drugs targeting the cell cycle-regulatory cyclin-dependent kinase (CDK) 4 and 6 have been approved for treatment of hormone receptor-positive breast cancer, inhibitors other cell-cycle CDKs are currently in clinical trials. Another class CDKs, transcription-associated including CDK7, CDK8, CDK9, CDK12 CDK13, critical regulators gene expression. Recent evidence suggests several novel functions these regulation epigenetic modifications, intronic polyadenylation, DNA-damage responses, genomic stability. Here, we summarize our current understanding transcriptional their utility as biomarkers, potential therapeutic targets. SIGNIFICANCE: CDK CDK4 CDK6 Several studies now point to opportunities by inhibiting well vulnerabilities with PARP immunotherapy tumors deficient CDKs.

Language: Английский

Citations

238
Cyclin-dependent protein kinases and cell cycle regulation in biology and disease DOI Creative Commons
Ilenia Pellarin, Alessandra Dall’Acqua, Andrea Favero

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 12, 2025

Abstract Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as kinases able drive division. In reality, human genome contains 20 different CDKs, which can be divided in at least three sub-family with functions, mechanisms regulation, expression patterns and subcellular localization. Most these play fundamental roles normal physiology eucaryotic cells; therefore, their deregulation is associated onset and/or progression multiple disease including but not limited neoplastic neurodegenerative conditions. Here, we describe functions categorized into main functional groups they classified, highlighting most relevant pathways that functions. We then discuss potential CDKs pathologies, a particular focus on cancer, have extensively studied explored therapeutic targets. Finally, how inhibitors become standard therapies selected cancers propose novel ways investigation export targeting from cancer other chronic diseases. hope effort made collecting all available information both prominent lesser-known CDK family members will help identify develop areas research improve lives patients affected by debilitating

Language: Английский

Citations

23
The cell biology of HIV-1 latency and rebound DOI Creative Commons
Uri Mbonye, Jonathan Karn

Retrovirology, Journal Year: 2024, Volume and Issue: 21(1)

Published: April 5, 2024

Abstract Transcriptionally latent forms of replication-competent proviruses, present primarily in a small subset memory CD4 + T cells, pose the primary barrier to cure for HIV-1 infection because they are source viral rebound that almost inevitably follows interruption antiretroviral therapy. Over last 30 years, many factors essential initiating transcription have been identified studies performed using transformed cell lines, such as Jurkat T-cell model. However, highlighted this review, several poorly understood mechanisms still need be elucidated, including molecular basis promoter-proximal pausing transcribing complex and detailed mechanism delivery P-TEFb from 7SK snRNP. Furthermore, central paradox remains unsolved: how initial rounds achieved absence Tat? A critical limitation models is do not recapitulate transitions between active effector cells quiescent cells. Therefore, investigation latency reversal LRA efficacy proper physiological context requires utilization models. Recent mechanistic latently infected recovered donors ex vivo cellular demonstrated blocks restrictive epigenetic features at proviral promoter, cytoplasmic sequestration key initiation NFAT NF-κB, vanishingly low expression elongation factor P-TEFb. One foremost schemes eliminate residual reservoir deliberately reactivate proviruses enable clearance persisting cells—the “Shock Kill” strategy. For become efficient, effective, non-toxic latency-reversing agents (LRAs) must discovered. Since multiple restrictions limit reactivation understanding signaling stimulating biogenesis, activation, reversing prerequisite development more effective LRAs.

Language: Английский

Citations

20
Targeting transcription cycles in cancer DOI
Stephin J. Vervoort, Jennifer R. Devlin, Nicholas Kwiatkowski

et al.

Nature reviews. Cancer, Journal Year: 2021, Volume and Issue: 22(1), P. 5 - 24

Published: Oct. 21, 2021

Language: Английский

Citations

103
Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update DOI

Tizhi Wu,

Zhen Qin, Yucheng Tian

et al.

Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 63(22), P. 13228 - 13257

Published: Aug. 31, 2020

Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially cancers driven by dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal regulation that frequently dysregulated cancers. Emerging evidence indicates selective inhibition or degradation may provide benefit against certain Indeed, the development of modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides overview recent advances general, special emphasis on compounds evaluation new emerging strategies, such as proteolysis targeting chimeras (PROTACs).

Language: Английский

Citations

82
Dissecting the Pol II transcription cycle and derailing cancer with CDK inhibitors DOI
Pabitra K. Parua, Robert P. Fisher

Nature Chemical Biology, Journal Year: 2020, Volume and Issue: 16(7), P. 716 - 724

Published: June 22, 2020

Language: Английский

Citations

80
From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy DOI
Zhenfeng Shi, Lei Tian, Taotao Qiang

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(9), P. 6390 - 6418

Published: April 29, 2022

Herein, we discuss more than 50 cyclin-dependent kinase (CDK) inhibitors that have been approved or undergone clinical trials and their therapeutic application in multiple cancers. This review discusses the design strategies, structure–activity relationships, efficacy performances of these selective nonselective CDK inhibitors. The theoretical basis early broad-spectrum is similar to scope chemotherapy, but because toxicity greater benefit, there no window. notion a safer potential pan-CDK has widely recognized during research process. Four CDK4/6 for treatment breast cancer prophylactic administration chemotherapy protect bone marrow immune system function. Furthermore, emerging strategies field are summarized briefly, CDKs continue be pursued as anticancer drug targets discovery.

Language: Английский

Citations

40
Cyclin-dependent kinase 7 (CDK7) inhibitors as a novel therapeutic strategy for different molecular types of breast cancer DOI
Xue Song, Fang Chen, Yan Dai

et al.

British Journal of Cancer, Journal Year: 2024, Volume and Issue: 130(8), P. 1239 - 1248

Published: Feb. 14, 2024

Language: Английский

Citations

12