Transcriptional cyclin-dependent kinases as the mediators of inflammation-a review

Sundar, Vaishnavi; Vimal, Sanjana; Mithlesh, M.s. Sai; Dutta, Anupam; Tamizhselvi, Ramasamy; Manickam, Venkatraman

doi:10.1016/j.gene.2020.145200

Cited by 28 publications

(21 citation statements)

References 68 publications

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“…Cell proliferation is often linked to the signal transducer and activator of transcription 3 (STAT3) pathway, which has been implicated in proliferation and fibrosis, specifically in kidney diseases ( 18 , 19 ). The CDK family can directly modulate STAT3, and alterations in STAT3–CDK2/4/6 in human malignancies portend a worse prognosis ( 20 , 21 ). Thus, we hypothesized that palbociclib may ameliorate tubular injury and tubulointerstitial fibrosis through STAT3 suppression.…”

Section: Resultsmentioning

confidence: 99%

Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease

Osaki¹,

Manolopoulou²,

Ivanova³

et al. 2022

JCI Insight

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and genome-wide association studies identified dachshund homolog 1 (DACH1), which suppresses tubular cell cycle progression, as having protective effects on CKD (7). Though suggestive that ongoing tubular cell cycling may be detrimental, few studies have directly manipulated cell cycle progression in the chronically injured kidney to determine how tubular cell cycle alters tubular injury and fibrosis.Most proximal tubules in the uninjured kidney are quiescent (G0) but, upon injury, reenter the cell cycle at G1, which is the first cell cycle checkpoint. Actively cycling cells progress from G1/S phase (DNA synthesis); then to the second checkpoint, G2; and finally to M (mitosis). Work has established that some tubule cells arrest at G2/M following injury, and these G2-arrested cells play an important role in CKD progression through production of profibrotic growth factors like TGF-β and CTGF (8). However, little is known about the role of cell cycle progression at the G1/S transition in chronically injured tubules. Cyclin dependent kinases 4 and 6 (CDK4/6) combine with cyclin D1 to phosphorylate retinoblastoma protein (Rb), leading to the liberation of E2F, a transcription factor that promotes expression of genes related to G1/S phase progression. The FDA-approved drug palbociclib is a highly selective inhibitor of CDK4/6 that is currently used to treat patients with breast cancer and provides an important tool to assess how G1/S cell cycle progression alters CKD progression.In this manuscript, we use a cell cycle reporter mouse to confirm that cell cycle is persistently altered in the chronically injured proximal tubules. Blocking CDK4/6 in mice after 2 different models of CKD significantly reduced tubular cell cycle progression, ameliorated tubular injury, preserved renal function, and decreased tubulointerstitial fibrosis. Surprisingly, selective tubular deletion of cyclin D1 worsened, rather than improved, tubular injury in murine CKD. Human expression quantitative trait loci (eQTLs) and genome-wide association study (GWAS) data are consistent with the murine studies showing that inhibiting CDK4/6, but not cyclin D1, protects against CKD. Mechanistically, CDK4/6 inhibition reduced proximal tubule cell death through a pathway involving STAT3/IL-1β.

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Section: Resultsmentioning

confidence: 99%

Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease

Osaki¹,

Manolopoulou²,

Ivanova³

et al. 2022

JCI Insight

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“…Unlike most other CDKs, CDK9 specifically regulates the transcription of primary inflammatory response genes via RNA polymerase II. These include genes encoding inflammatory cytokines and the neutrophil pro-survival protein Mcl1 ( Sundar et al, 2021 ; Eyvazi et al, 2019 ; Lucas et al, 2014 ). Acute inhibition of CDK9 therefore provides a therapeutic opportunity to suppress the transcription of short-lived inflammatory disease drivers preferentially.…”

Section: Introductionmentioning

confidence: 99%

Selective Cdk9 inhibition resolves neutrophilic inflammation and enhances cardiac regeneration in larval zebrafish

et al. 2021

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Sustained neutrophilic inflammation is detrimental for cardiac repair and associated with adverse outcomes following myocardial infarction (MI). An attractive therapeutic strategy to treat MI is to reduce or remove infiltrating neutrophils to promote downstream reparative mechanisms. CDK9 inhibitor compounds enhance the resolution of neutrophilic inflammation, however, their effects on cardiac repair/regeneration are unknown. Our laboratory has devised a cardiac injury model to investigate inflammatory and regenerative responses in larval zebrafish using heartbeat-synchronised light sheet fluorescence microscopy. We used this model to test two clinically approved CDK9 inhibitors, AT7519 and Flavopiridol, examining their effects on neutrophils, macrophages and cardiomyocyte regeneration. We found AT7519 and Flavopiridol resolve neutrophil infiltration by inducing reverse migration from the cardiac lesion. While continuous exposure to AT7519 or Flavopiridol caused adverse phenotypes, transient treatment accelerated neutrophil resolution while avoiding these effects. Transient treatment with AT7519, but not Flavopiridol, augmented wound-associated macrophage polarisation, which enhanced macrophage-dependent cardiomyocyte number expansion and the rate of myocardial wound closure. Using cdk9−/- knockout mutants we showed AT7519 is a selective CDK9 inhibitor, revealing the potential of such treatments to promote cardiac repair/regeneration.

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“…Cyclins and cyclin-dependent kinases (CDKs) have important roles in cell cycle regulation ( Saeed et al, 2015 ; Ding et al, 2020 ; Sundar et al, 2021 ). Altering their expression can disrupt the cell cycle.…”

Section: Resultsmentioning

confidence: 99%

Functionalized Selenium Nanoparticles Synergizes With Metformin to Treat Breast Cancer Cells Through Regulation of Selenoproteins

Zhang

Chen

et al. 2021

Front. Bioeng. Biotechnol.

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Owing to high blood sugar level and chronic inflammation, diabetes tend to cause the overproduction of free radicals in body, which will damage tissue and cells, reduce autoimmunity, and greatly increase the incidence of tumors. Selenium nanoparticles (SeNPs) exhibit high antioxidant activity with anti-tumor ability. In addition, metformin is considered as a clinical drug commonly for the treatment of stage II diabetes. Therefore, in this study, different functionalized SeNPs combined with metformin were performed to detect the feasibility for cancer therapy. The combination of Tween 80 (TW80)-SeNPs and metformin was found to have a synergistic effect on MCF-7 cells. The mechanism of this synergistic effect involved in the induction of DNA damage by affecting the generation of reactive oxygen species through selenoproteins; the upregulation of DNA-damage-related proteins including p-ATM, p-ATR, and p38; the promotion of p21 expression; and the downregulation of cyclin-dependent kinases and cyclin-related proteins causing cell cycle arrest. Furthermore, the expression of AMPK was affected, which in turn to regulate the mitochondrial membrane potential to achieve the synergistic treatment effect.

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Transcriptional cyclin-dependent kinases as the mediators of inflammation-a review

Cited by 28 publications

References 68 publications

Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease

Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease

Selective Cdk9 inhibition resolves neutrophilic inflammation and enhances cardiac regeneration in larval zebrafish

Functionalized Selenium Nanoparticles Synergizes With Metformin to Treat Breast Cancer Cells Through Regulation of Selenoproteins

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