CDK9 as an Appealing Target for Therapeutic Interventions

Cyclin Dependent Kinase 9 (CDK9) as a serine/threonine kinase belongs to a great number of CDKs. CDK9 is the main core of PTEF-b complex and phosphorylates RNA polymerase (RNAP) II besides other transcription factors which regulate gene transcription elongation in numerous physiological processes. Multi-functional nature of CDK9 in diverse cellular pathways proposes that it is as an appealing target. In this review, we summarized the recent findings on the molecular interaction of CDK9 with critical participant molecules to modulate their activity in various diseases. Furthermore, the presented review provides a rationale supporting the use of CDK9 as a therapeutic target in clinical developments for crucial diseases; particularly cancers will be reviewed.

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Keratin 19 interacts with GSK3β to regulate its nuclear accumulation and degradation of cyclin D3

10.1101/2021.07.28.454205 ◽

2021 ◽

Author(s):

Pooja Sharma ◽

Sarah Tiufekchiev ◽

Victoria Lising ◽

Seung Woo Chung ◽

Jung Soo Suk ◽

...

Keyword(s):

Cell Proliferation ◽

Cyclin D3 ◽

Nuclear Accumulation ◽

Cyclin Dependent Kinase ◽

Serine Threonine Kinase ◽

Threonine Kinase ◽

Keratin 19 ◽

Head Domain ◽

Cancer Types ◽

Potential Strategy

Cyclin D3 regulates the G1/S transition and is frequently overexpressed in several cancer types including breast cancer, where it promotes tumor progression. Here, we show that a cytoskeletal protein keratin 19 (K19) physically interacts with a serine/threonine kinase GSK3β and prevents GSK3β-dependent degradation of cyclin D3. The absence of K19 allowed active GSK3β to accumulate in the nucleus and degrade cyclin D3. Specifically, the head domain of K19 was required to sustain inhibitory phosphorylation of GSK3β Ser9, prevent nuclear accumulation of GSK3β, and maintain cyclin D3 levels and cell proliferation. K19 was found to interact with GSK3β and K19-GSK3β interaction was mapped out to require Ser10 and Ser35 residues on the head domain of K19. Unlike wildtype K19, S10A and S35A mutants failed to maintain total and nuclear cyclin D3 levels and induce cell proliferation. Finally, we show that the K19-GSK3β-cyclin D3 pathway affected sensitivity of cells towards inhibitors to cyclin dependent kinase 4 and 6 (CDK4/6). Overall, these findings establish a role for K19 in the regulation of GSK3β-cyclin D3 pathway and demonstrate a potential strategy for overcoming resistance to CDK4/6 inhibitors.

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WNK Protein Kinases Modulate Cellular Cl− Flux by Altering the Phosphorylation State of the Na-K-Cl and K-Cl Cotransporters

Physiology ◽

10.1152/physiol.00015.2006 ◽

2006 ◽

Vol 21 (5) ◽

pp. 326-335 ◽

Cited By ~ 83

Author(s):

Kristopher T. Kahle ◽

Jesse Rinehart ◽

Aaron Ring ◽

Ignacio Gimenez ◽

Gerardo Gamba ◽

...

Keyword(s):

The Body ◽

Entry And Exit ◽

Serine Threonine Kinase ◽

Phosphorylation State ◽

Human Hypertension ◽

Precise Control ◽

Threonine Kinase ◽

Physiological Processes ◽

Molecular Determinants ◽

Wnk Protein Kinases

Precise control of cellular Cl− transport is necessary for many fundamental physiological processes. For example, the intracellular concentration of Cl−, fine-tuned through the coordinated action of cellular Cl− influx and efflux mechanisms, determines whether a neuron’s response to GABA is excitatory or inhibitory. In epithelia, synchrony between apical and basolateral Cl− flux, and transcellular and paracellular Cl− transport, is necessary for efficient transepithelial Cl− reabsorption or secretion. In cells throughout the body, coordination of Cl− entry and exit mechanisms help defend against changes in cell volume. The Na-K-Cl and K-Cl cotransporters of the SLC12 gene family are important molecular determinants of Cl− entry and exit, respectively, in these systems. The WNK serine-threonine kinase family, members of which are mutated in an inherited form of human hypertension, are components of a signaling pathway that coordinates Cl− influx and efflux through SLC12 cotransporters to dynamically regulate intracellular Cl− activity.

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Deficiency of cyclin-dependent kinase-like 5 causes spontaneous epileptic seizures in neonatal mice

10.1101/2020.03.09.983981 ◽

2020 ◽

Author(s):

Wenlin Liao ◽

Kun-Ze Lee ◽

San-Hua Su ◽

Yuju Luo

Keyword(s):

Mouse Models ◽

Early Onset ◽

Epileptic Seizures ◽

Cyclin Dependent Kinase ◽

Serine Threonine Kinase ◽

Gene Encoding ◽

Linked Gene ◽

Threonine Kinase ◽

Spontaneous Seizures ◽

Deficient Mice

AbstractCyclin-dependent kinase-like 5 (CDKL5), an X-linked gene encoding a serine-threonine kinase, is enriched in the mammalian forebrain and critical for neuronal maturation and synaptic function. Mutations in this gene cause CDKL5 deficiency disorder (CDD) that is characterized by early-onset epileptic seizures, autistic behaviors and intellectual disability. Although numerous CDD symptoms have been recapitulated in mouse models, spontaneous seizures have not been reported in mice with CDKL5 deficiency. Here, we present the first systematic study of spontaneous seizures in a mouse model of CDD. Through wireless electroencephalographic (EEG) recording and simultaneous videotaping, we observed epileptiform discharges accompanied with ictal behaviors in pups lacking CDKL5 at a selective time window during the pre-weaning period. The seizure-like patterns of EEG showed robust increase in total number of spike events, the total number and duration of bursts in Cdkl5 null pups compared to wild-type littermate controls at the age of postnatal day 12 (P12). The mutants displayed not only jerky and spasm-like movements during the prolonged bursts of discharges at P12, but also strengthened ictal grasping in both juvenile stage and adulthood. In addition, loss of CDKL5 remarkably reduced the phosphorylation of K+/Cl- co-transporter 2, which may impede GABA-mediated inhibition, in the cortex of P12 mouse pups. Our study reveals previously unidentified phenotypes of early-onset seizures in CDKL5-deficient mice, highlights the translational value of mouse models of CDD and provides a potential molecular target for early diagnosis and treatment for CDD.Significance StatementCyclin-dependent kinase-like 5 (CDKL5) is an X-linked gene encoding a serine-threonine kinase. Mutations in this gene cause CDKL5 deficiency disorder (CDD), a rare disease characterized by developmental delays, autistic behaviors and early-onset epilepsy. Even though many symptoms of CDD patients have been phenocopied in mice, spontaneous seizures are yet to be reported in mouse models of CDD. Here, for the first time, we identified early-onset seizures and ictal behaviors in neonatal pups of CDKL5-deficient mice. Loss of CDKL5 also selectively reduced protein levels of phosphorylated K+/Cl-cotransporter 2 in neonatal cortex of mice. Our study reveals an indispensible role of CDKL5 in regulating neuronal excitability in developing brains and highlights the translational significance of the CDD mouse models.

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What We Know and Would Like to Know about CDKL5 and Its Involvement in Epileptic Encephalopathy

Neural Plasticity ◽

10.1155/2012/728267 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 49

Author(s):

Charlotte Kilstrup-Nielsen ◽

Laura Rusconi ◽

Paolo La Montanara ◽

Dalila Ciceri ◽

Anna Bergo ◽

...

Keyword(s):

Clinical Symptoms ◽

Intractable Epilepsy ◽

Epileptic Encephalopathy ◽

Neuronal Morphology ◽

Cyclin Dependent Kinase ◽

Serine Threonine Kinase ◽

Nuclear Compartment ◽

Threonine Kinase ◽

Current State ◽

Activity Dependent

In the last few years, the X-linked serine/threonine kinase cyclin-dependent kinase-like 5 (CDKL5) has been associated with early-onset epileptic encephalopathies characterized by the manifestation of intractable epilepsy within the first weeks of life, severe developmental delay, profound hypotonia, and often the presence of some Rett-syndrome-like features. The association of CDKL5 with neurodevelopmental disorders and its high expression levels in the maturing brain underscore the importance of this kinase for proper brain development. However, our present knowledge of CDKL5 functions is still rather limited. The picture that emerges from the molecular and cellular studies suggests that CDKL5 functions are important for regulating both neuronal morphology through cytoplasmic signaling pathways and activity-dependent gene expression in the nuclear compartment. This paper surveys the current state of CDKL5 research with emphasis on the clinical symptoms associated with mutations inCDKL5, the different mechanisms regulating its functions, and the connected molecular pathways. Finally, based on the available data we speculate that CDKL5 might play a role in neuronal plasticity and we adduce and discuss some possible arguments supporting this hypothesis.

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Silencing MASTL Inhibits Cell Proliferation and Migration of Gastric Cancer MGC-803 Cells Via Suprressing AKT, mTOR, p38 Signal Pathways

10.21203/rs.3.rs-55295/v1 ◽

2020 ◽

Author(s):

caixia An ◽

hailong li ◽

Rong Niu ◽

xiaoguang liu ◽

Yonghua Hu ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Signal Pathways ◽

Cyclin Dependent Kinase ◽

Serine Threonine Kinase ◽

Threonine Kinase ◽

Mrna Microarray ◽

And Migration

Abstract Background: Microtubule-associated serine/threonine kinase (MASTL) functions to regulate chromosome condensation and mitotic progression. Emerging reports showed that aberrant MASTL expression is commonly implicated in various human cancers and act as an oncogene. This study aimed to discover the potential significance of MASTL in gastric cancer, and to uncover relevant mechanisms. Methods: Lentivirus MASTL-shRNA was constructed and infected into MGC-803 cells to analysis its influences on cell proliferation by Green fluorescent protein (GFP)-based cellomics and colony formation assay, cell invasion and migration by transwell assay, apoptosis and cell cycle by flow cytometry detection, respectively. Nude mice and fluorescence imaging were used to characterize the regulation of tumor growth in vivo. Affymetrix mRNA microarray assay combined KEGG enrichment analysis were used to screen relevant molecules related to MASTL silencing. Finally，several aberrantly expressed genes were validated by quantitative reverse transcription PCR(RT-qPCR)and western blot detection. Results: Silencing MASTL significantly inhibited cell proliferation, migration and invasion, arrested cell cycle at G1 stage. Silencing MASTL reduced tumor growth in nude mice, and fluorescence imaging indicated that the total radiant efficiency of mice in the Lv-shMAST group was markedly reduced compared with in mice in the Lv-shCtrl group in vivo. Affymetrix mRNA microarray assay revealed that 124 genes upregulated, 167 genes downregulated. RT-qPCR and western blotting validation showed that cyclin dependent kinase 6(CDK6), bone morphogenetic protein 2(BMP2), snail family transcriptional repressor 2(SNAI2), phosphorylation-mechanistic target of rapamycin kinase (p-mTOR), phosphorylation-AKT serine/threonine kinase (p-AKT) and phosphorylation-p38 kinase (p-p38) are downregulated, and cyclin dependent kinase inhibitor 1A (CDKN1A) is upregulated. Conclusions: Silencing MASTL could significantly inhibit cell growth, migration ability, induce apoptosis, arrest cell cycle at G1 stage, and the mechanisms of which were mediated via inactivation of mTOR, AKT, p38 signal pathways.

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