Cyclin-dependent kinase 9 may as a novel target in downregulating the atherosclerosis inflammation (Review)

Han, Yeming; Yang, Zhan; Hou, Guihua; Li, Li

doi:10.3892/br.2014.322

Cited by 12 publications

(9 citation statements)

References 50 publications

(55 reference statements)

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“…These factors may play an important role in phenotypic and functional plasticity of CDK9 that is associated with transcriptional control and can form distinct positive transcription elongation factors (P-TEFs). In addition, structural and dynamic adaptability of CDK9 is intimately connected with diverse therapeutic indications of this kinase client, as CDK9 inhibition contributes to the anticancer activity and is relevant for the treatment of inflammation-associated diseases [ 156 ].…”

Section: Resultsmentioning

confidence: 99%

Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone

2017

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The overarching goal of delineating molecular principles underlying differentiation of protein kinase clients and chaperone-based modulation of kinase activity is fundamental to understanding activity of many oncogenic kinases that require chaperoning of Hsp70 and Hsp90 systems to attain a functionally competent active form. Despite structural similarities and common activation mechanisms shared by cyclin-dependent kinase (CDK) proteins, members of this family can exhibit vastly different chaperone preferences. The molecular determinants underlying chaperone dependencies of protein kinases are not fully understood as structurally similar kinases may often elicit distinct regulatory responses to the chaperone. The regulatory divergences observed for members of CDK family are of particular interest as functional diversification among these kinases may be related to variations in chaperone dependencies and can be exploited in drug discovery of personalized therapeutic agents. In this work, we report the results of a computational investigation of several members of CDK family (CDK5, CDK6, CDK9) that represented a broad repertoire of chaperone dependencies—from nonclient CDK5, to weak client CDK6, and strong client CDK9. By using molecular simulations of multiple crystal structures we characterized conformational ensembles and collective dynamics of CDK proteins. We found that the elevated dynamics of CDK9 can trigger imbalances in cooperative collective motions and reduce stability of the active fold, thus creating a cascade of favorable conditions for chaperone intervention. The ensemble-based modeling of residue interaction networks and community analysis determined how differences in modularity of allosteric networks and topography of communication pathways can be linked with the client status of CDK proteins. This analysis unveiled depleted modularity of the allosteric network in CDK9 that alters distribution of communication pathways and leads to impaired signaling in the client kinase. According to our results, these network features may uniquely define chaperone dependencies of CDK clients. The perturbation response scanning and rigidity decomposition approaches identified regulatory hotspots that mediate differences in stability and cooperativity of allosteric interaction networks in the CDK structures. By combining these synergistic approaches, our study revealed dynamic and network signatures that can differentiate kinase clients and rationalize subtle divergences in the activation mechanisms of CDK family members. The therapeutic implications of these results are illustrated by identifying structural hotspots of pathogenic mutations that preferentially target regions of the increased flexibility to enable modulation of activation changes. Our study offers a network-based perspective on dynamic kinase mechanisms and drug design by unravelling relationships between protein kinase dynamics, allosteric communications and chaperone dependencies.

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Section: Resultsmentioning

confidence: 99%

Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone

2017

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“…Cyclin-dependent kinase 9 (CDK9), a transcriptional regulator that has few effects on cell cycle control, is activated by binding with cyclin T1 to form positive transcription elongation factor b (P-TEFb), which enhances transcription activity through RNA polymerase II to facilitate RNA synthesis for cell growth and differentiation. 15 , 16 , 17 In addition to its crucial role in cancer cell metabolism and cardiomyocyte proliferation, recent studies have shown that it may also play an important role in CVDs, as it was detected to be upregulated in artery plaque, serum, and monocyte samples of coronary heart disease (CHD) patients. 16 , 18 , 19 However, the regulatory function and mechanism of CDK9 in VSMC phenotypic conversion are mostly unknown.…”

Section: Introductionmentioning

confidence: 99%

Long Non-coding RNA PEBP1P2 Suppresses Proliferative VSMCs Phenotypic Switching and Proliferation in Atherosclerosis

Lian

Yang

et al. 2020

Molecular Therapy - Nucleic Acids

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Long non-coding RNAs (lncRNAs) play a crucial role in the growth of vascular smooth muscle cells (VSMCs), the dysfunction of which is closely associated with the initiation and progression of cardiovascular diseases (CVDs). Abnormal phenotypic switching and proliferation of VSMCs constitute a significant event in the progression of atherosclerosis. The present study identified a novel lncRNA, PEBP1P2, which serves as a valuable regulator of VSMCs in phenotypic transformation and proliferation. The expression of PEBP1P2 was remarkably decreased in proliferating VSMCs and pathological arteries when using a balloon injury model of rats. Furthermore, we found that PEBP1P2 represses proliferation, migration, and dedifferentiation during phenotype switching in VSMCs induced by platelet-derived growth factor BB (PDGF-BB). Mechanistically, cyclin-dependent kinase 9 (CDK9) was confirmed to be the direct target of PEBP1P2, which was proven to mediate phenotypic switching and proliferation of VSMCs and was rescued by PEBP1P2. Then, we explored the clinical significance, as we observed the decreased expression of PEBP1P2 in the serum of coronary heart disease (CHD) patients and human advanced carotid atherosclerotic plaques. Finally, PEBP1P2 overexpression distinctly suppressed neointima formation and VSMC phenotypic switching in vivo . Taken together, PEBP1P2 inhibits proliferation and migration in VSMCs by directly binding to CDK9, implying that it may be a promising therapeutic target for the treatment of proliferative vascular diseases.

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“…Cyclin‐dependent kinase 9 (CDK9), the kinase of positive transcription elongation factor b (P‐TEFb), is crucial in the cell cycle control and regulation of apoptosis . CDK9 interacts with many transcription factors (TFs) and regulates the expression of antiapoptotic proteins for the survival of cancer cells .…”

Section: Introductionmentioning

confidence: 99%

miR‐206 inhibits the growth of hepatocellular carcinoma cells via targeting CDK9

et al. 2017

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AbstractmiR‐206 plays an important role in regulating the growth of multiple cancer cells. Cyclin‐dependent kinase 9 (CDK9) stimulates the production of abundant prosurvival proteins, leading to impaired apoptosis of cancer cells. However, it is unknown whether CDK9 is involved in the miR‐206‐mediated growth suppression of hepatocellular carcinoma (HCC) cells. In this study, we found that the expression level of miR‐206 was significantly lower in HCC cell lines than that in normal hepatic cell line (L02). Meanwhile, CDK9 was upregulated in HCC cell lines. Moreover, miR‐206 downregulated CDK9 in HCC cells via directly binding to its mRNA 3′ UTR, which resulted in a decrease of RNA PolII Ser2 phosphorylation and Mcl‐1 level. Additionally, miR‐206 suppressed the cell proliferation, and induced cell cycle arrest and apoptosis. Similarly, silence or inhibition of CDK9 also repressed the cell proliferation, and induced cell cycle arrest and apoptosis. Taken together, the results demonstrated that miR‐206 inhibited the growth of HCC cells through targeting CDK9, suggesting that the miR‐206‐CDK9 pathway may be a novel target for the treatment of HCC.

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Cyclin-dependent kinase 9 may as a novel target in downregulating the atherosclerosis inflammation (Review)

Cited by 12 publications

References 50 publications

Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone

Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone

Long Non-coding RNA PEBP1P2 Suppresses Proliferative VSMCs Phenotypic Switching and Proliferation in Atherosclerosis

miR‐206 inhibits the growth of hepatocellular carcinoma cells via targeting CDK9

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