Role Of Cyclin-dependent Kinase Research Articles

Role of Cyclin-Dependent Kinase 4/6 in Metastatic Breast Cancer: Real-World Data From a Tertiary Care Institute in Eastern India.

Introduction CDK4/6 inhibitors currently approved for patients with hormone-receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer include palbociclib, ribociclib, and abemaciclib. This study aims to report on the treatment outcomes and real-world data regarding the use of CDK4/6 inhibitors in the treatment of ER+/HER2- metastatic breast cancer at a tertiary care institute in Eastern India. Materials and methods The present study is a retrospective analysis of data from patients with metastatic HR+/HER2-breast cancer who were treated with CDK4/6 inhibitors at a tertiary care institute in Eastern India between 2015 and 2022. The data were collected from online records in the departmental files and analyzed for the primary baseline characteristics of the patients, tumors, and response rates, including partial response (PR), complete response (CR), progressive disease (PD), and stable disease (SD), as defined by the Response Evaluation Criteria in Solid Tumors (RECIST)criteriaversion 1.1. The treatment administered, progression-free survival (PFS), and toxicity were also evaluated. Results From 2015 to 2022, 24 eligible patients were treated with CDK4/6 inhibitors for metastatic HR+/HER2-breast cancer. The average duration of follow-up was 25 months. Out of the 24 patients, 15 (62.5%) were taking Tab. ribociclib, six (25%) were taking Tab. palbociclib, and three (12.5%) were taking Tab. abemaciclib. CDK4/6 was used as a first-line therapy for 16 patients, while eight patients received it as a second-line treatment. Out of the total number of patients, six (25%) had stable disease, 13 (54.2%) had a partial response, and four (16.7%) had progressive disease. In total, of the eligible patients, five (20.8%) had grade I neutropenia, seven (29.2%) had grade II neutropenia, and four (16.7%) had grade III neutropenia. At five years, the PFS rate estimated by the Kaplan-Meier method was 50% (95% CI: 47.89-69.31). Conclusion Ribociclib and palbociclib have improved PFS in patients with metastatic HR+/HER2-breast cancer. Both drugs have well-tolerated toxicity, allowing patients to continue taking them for an extended period of time. CDK4/6 inhibitors have a higher response rate than the other agents.

The Role of Cyclin-Dependent Kinases (CDK) 4/6 in the Ovarian Tissue and the Possible Effects of Their Exogenous Inhibition.

The combination of cyclin-dependent kinase (CDK) 4/6 inhibitors with endocrine therapy is the standard treatment for patients with HR+/HER2- advanced breast cancer. Recently, this combination has also entered the early setting as an adjuvant treatment in patients with HR+/HER2- disease at a high risk of disease recurrence following (neo)adjuvant chemotherapy. Despite their current use in clinical practice, limited data on the potential gonadotoxicity of CDK4/6 inhibitors are available. Hence, fully informed treatment decision making by premenopausal patients concerned about the potential development of premature ovarian insufficiency and infertility with the proposed therapy remains difficult. The cell cycle progression of granulosa and cumulus cells is a critical process for ovarian function, especially for ensuring proper follicular growth and acquiring competence. Due to the pharmacological properties of CDK4/6 inhibitors, there could be a potentially negative impact on ovarian function and fertility in women of reproductive age. This review aims to summarize the role of the cyclin D-CDK4 and CDK6 complexes in the ovary and the potential impact of CDK4/6 inhibition on its physiological processes.

Cdk12 maintains the integrity of adult axons by suppressing actin remodeling

The role of cyclin-dependent kinases (CDKs) that are ubiquitously expressed in the adult nervous system remains unclear. Cdk12 is enriched in terminally differentiated neurons where its conical role in the cell cycle progression is redundant. We find that in adult neurons Cdk12 acts a negative regulator of actin formation, mitochondrial dynamics and neuronal physiology. Cdk12 maintains the size of the axon at sites proximal to the cell body through the transcription of homeostatic enzymes in the 1-carbon by folate pathway which utilize the amino acid homocysteine. Loss of Cdk12 leads to elevated homocysteine and in turn leads to uncontrolled F-actin formation and axonal swelling. Actin remodeling further induces Drp1-dependent fission of mitochondria and the breakdown of axon-soma filtration barrier allowing soma restricted cargos to enter the axon. We demonstrate that Cdk12 is also an essential gene for long-term neuronal survival and loss of this gene causes age-dependent neurodegeneration. Hyperhomocysteinemia, actin changes, and mitochondrial fragmentation are associated with several neurodegenerative conditions such as Alzheimer’s disease and we provide a candidate molecular pathway to link together such pathological events.

Cdk5-Mediated Brain Unfolded Protein Response Upregulation Associated with Cognitive Impairments in Type 2 Diabetes and Ameliorative Action of NAC.

The role of cyclin-dependent kinase 5 (Cdk5) in the normal functioning of the central nervous system and synaptic plasticity is well established. However, dysregulated kinase activity can have a significant impact on neurodegeneration and cognitive impairment. Cdk5 hyperactivation is linked to diabetes-associated neurodegeneration, but the underlying mechanism is not fully understood. Our study reveals that oxidative stress can lead to Cdk5 hyperactivity, which in turn is linked to neurodegeneration and cognitive impairment. Specifically, our experiments with N2A cells overexpressing Cdk5 and its activators p35 and p25 show ER stress, resulting in activation of the unfolded protein response (UPR) pathway. We identified Cdk5 as the epicenter of this regulatory process, leading to the activation of the CDK5-IRE1-XBP1 arm of UPR. Moreover, our study demonstrated that Cdk5 hyperactivation can lead to ER stress and activation of the UPR pathway, which may contribute to cognitive impairments associated with diabetes. Our findings also suggest that antioxidants such as NAC and GSH can decrease deregulated Cdk5 kinase activity and rescue cells from UPR-mediated ER stress. The accumulation of phosphorylated Tau protein in AD brain protein has been widely described earlier. Notably, we observed that oral treatment with NAC decreased Cdk5 kinase activity in the hippocampus, attenuated high levels of phospho-tau (ser396), and ameliorated memory and learning impairments in a type 2 diabetic (T2D) mouse model. Additionally, the high-fat-induced T2D model exhibits elevated phospho-tau levels, which are rescued by the NAC treatment. Taken together, these results suggest that targeting Cdk5 may be a promising therapeutic strategy for treating diabetes-associated cognitive impairments.

Role of cyclin-dependent kinase 5 in psychosis and the modulatory effects of cannabinoids

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEP/c) and without (FEP/nc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212–2 (WIN: 1 mg/kg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP: 10 mg/kg) during 10 days. FEP/c showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEP/nc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEP/nc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95/CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.

Palbociclib enhances the effect of doxorubicin-induced apoptosis in activated B-cell-like diffuse large B-cell lymphoma cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma around the world. While R-CHOP has significantly improved patient outcomes, a subset of patients still has poor outcome. Here, the oncogenic roles of cyclin dependent kinase 4/6 (CDK4/6)-Cyclin D (CCND) signaling axis in DLBCL and its potential mechanism were investigated to explore the possibility of targeting CDK4/6-CCND signaling axis for DLBCL therapy. The transcription levels, functional enrichment analysis, mutation analysis, and prognostic values were performed via the Oncomine, GEPIA, UALCAN, cBioPortal, and Metascape and GenomicScape databases. Expression of CDK4/6-CCND signaling axis in DLBCL patients and DLBCL cell lines was evaluated by qRT-PCR. Additionally, the impact of CDK4/6-CCND signaling axis on cell viability and apoptosis in DLBCL cell lines were evaluated in vitro . The transcription levels of CDK4/6-CCND signaling were increased in DLBCL patients. Meanwhile, in Gene Expression Omnibus dataset, the expression of CDK4 and CCND2 was higher in ABC-DLBCL, whereas the expression of CCND1 and CCND3 was higher in GCB-DLBCL. Moreover, according to the results of qRT-PCR, the expression of CDK4/6-CCND signaling axis in ABC-DLBCL cell line is higher than that in GCB-DLBCL cell lines. Prognostic analysis indicated that upregulation of CDK4, CCND2, and CCND3 was significantly associated with poor survival. Cell function experiments showed that palbociclib could enhance the apoptosis-promoting and cell viability-inhibiting effects of doxorubicin on ABC-DLBCL (SU-DHL-2) cells. Doxorubicin accumulation experiment showed that palbociclib promoted doxorubicin accumulation in ABC-DLBCL cells. Additionally, Western blot analysis demonstrated that palbociclib prevented antiapoptotic protein BCL2 expression in ABC-DLBCL cell line. Our study provides novel insights into targeted therapies for ABC-DLBCL patients.

Off the Clock: the Non-canonical Roles of Cyclin-Dependent Kinases in Neural and Glioma Stem Cell Self-Renewal.

Glioma stem cells (GSCs) are thought to drive growth and therapy resistance in glioblastoma (GBM) by "hijacking" at least a subset of signaling pathways active in normal neural stem cells (NSCs). Though the origins of GSCs still remain elusive, uncovering the mechanisms of self-renewing division and cell differentiation in normal NSCs has shed light on their dysfunction in GSCs. However, the distinction between self-renewing division pathways utilized by NSC and GSC becomes critical when considering options for therapeutically targeting signaling pathways that are specifically active or altered in GSCs. It is well-established that cyclin-dependent kinases (CDKs) regulate the cell cycle, yet more recent studies have shown that CDKs also play important roles in the regulation of neuronal survival, metabolism, differentiation, and self-renewal. The intimate relationship between cell cycle regulation and the cellular programs that determine self-renewing division versus cell differentiation is only beginning to be understood, yet seems to suggest potential differential vulnerabilities in GSCs. In this timely review, we focus on the role of CDKs in regulating the self-renewal properties of normal NSCs and GSCs, highlighting novel opportunities to therapeutically target self-renewing signaling pathways specifically in GBM.

Role of cyclin-dependent kinase 5 in early brain injury following experimental subarachnoid hemorrhage.

Increasing evidence indicates that early brain injury (EBI) can contribute to poor outcomes following subarachnoid hemorrhage (SAH), and is associated with apoptosis. Cyclin-dependent kinase 5 (Cdk5) is a key mediator of neuronal viability. The role of Cdk5 in several neurological disorders has been elucidated; however, its role in EBI after SAH remains unclear. The present study aimed to explore the involvement of Cdk5 in EBI after SAH. The expression levels of Cdk5, Cdk5 phosphorylated at Tyr15 (Cdk5-pTyr15) and p25 (a Cdk5 activator) were assessed by western blotting, and the cell distribution of Cdk5 was demonstrated by double immunofluorescence. The expression levels of caspase-3 and cytochrome c were evaluated by western blotting to assess the severity of neuronal apoptosis. Nissl and TUNEL staining experiments were performed to observe the effects of roscovitine, a Cdk5 inhibitor, on EBI following SAH. The results indicated that the expression levels of Cdk5, p25 and Cdk5-pTyr15 significantly increased in the rat temporal cortex following SAH. Immunofluorescence staining indicated that Cdk5 was expressed in the neurons and astrocytes of the rat cortex after SAH and that Cdk5 underwent nuclear translocation in neurons. Roscovitine administration effectively inhibited Cdk5 activation. In conclusion, roscovitine treatment significantly mitigated EBI and alleviated cerebral edema following SAH. These findings suggest that Cdk5 is an important target in SAH therapy.

CDK1 promotes the stemness of lung cancer cells through interacting with Sox2.

The promoting roles of cyclin dependent kinase 1 (CDK1) have been revealed in various tumors, however, its effects in the progression of cancer stem cells are still confusing. This work aims to explore the roles of CDK1 in regulating the stemness of lung cancer cells. Online dataset analysis was performed to evaluate the correlation between CDK1 exression and the survival of lung cancer patients. RT-qPCR, western blot, cell viability, sphere-formation analysis and ALDH activity detection were used to investigate the roles of CDK1 on lung cancer cell stemness, viability and chemotherapeutic sensitivity. Immunocoprecipitation (Co-IP) analysis and rescuing experiments were performed to reveal the underlying mechanisms contributing to CDK1-mediated effects on lung cancer cell stemness. CDK1 mRNA expression was negatively correlated with the overall survival of lung cancer patients and remarkably increased in tumor spheres formed by lung cancer cells compared to the parental cells. Additionally, CDK1 positively regulated the stemness of lung cancer cells. Mechanistically, CDK1 could interact with Sox2 protein, but not other stemness markers (Oct4, Nanog and CD133). Furthermore, CDK1 increased the phosphorylation, cytoplasm-nuclear translocation and transcriptional activity of Sox2 protein in lung cancer cells. Moreover, CDK1 positively regulated the stemness of lung cancer cells in a Sox2-dependent manner. Finally, we revealed that inhibition of CDK1 enhanced the chemotherapeutic sensitivity, which was also rescued by Sox2 overexpression. This work reveals a novel CDK1/Sox2 axis responsible for maintaining the stemness of lung cancer cells.

Ribociclib and everolimus in well-differentiated foregut neuroendocrine tumors.

The mammalian target of rapamycin inhibitor everolimus is an established therapy for well-differentiated (WD) foregut neuroendocrine tumors (NETs). Pre-clinical data demonstrates a potential synergistic role for cyclin dependent kinase 4/6 inhibition and everolimus to treat this disease. In this phase II multicenter study, patients with advanced foregut WDNETs received combination ribociclib and everolimus until confirmed disease progression or unacceptable toxicity. The first 12 patients received ribociclib 300 mg three weeks in a row with a 1 week break and everolimus 2.5 mg daily (recommended phase II dose). Due to unexpected hematologic and infectious toxicities, the trial was put on hold, modified, and an additional 9 patients received ribociclib 200 mg and everolimus 2.5 mg daily. The primary end point was progression-free survival. Archived pre-treatment tumor was profiled by next-generation sequencing to evaluate for genomic markers of drug response. Twenty-one patients were treated (median age, 56; range, 24 to 77). The study did not meet the pre-specified criteria to advance to stage two. No patients experienced an objective response. Thirteen patients (62%) experienced stable disease. Median progression-free survival was 7.7 months (95% CI, 2.8 months to not reached). Eleven of the first 12 patients (92%) developed grade 2 or more myelosuppression. Ten patients (84%) experienced treatment interruption and 8 patients (67%) required dose reduction. Genetic testing in archival tumor tissue samples failed to identify a predictive biomarker of disease stabilization. The combination of ribociclib and everolimus had insufficient activity to warrant further investigation in foregut WDNETs.

Cellular and Molecular Mechanisms of R/S-Roscovitine and CDKs Related Inhibition under Both Focal and Global Cerebral Ischemia: A Focus on Neurovascular Unit and Immune Cells.

Ischemic stroke is the second leading cause of death worldwide. Following ischemic stroke, Neurovascular Unit (NVU) inflammation and peripheral leucocytes infiltration are major contributors to the extension of brain lesions. For a long time restricted to neurons, the 10 past years have shown the emergence of an increasing number of studies focusing on the role of Cyclin-Dependent Kinases (CDKs) on the other cells of NVU, as well as on the leucocytes. The most widely used CDKs inhibitor, (R)-roscovitine, and its (S) isomer both decreased brain lesions in models of global and focal cerebral ischemia. We previously showed that (S)-roscovitine acted, at least, by modulating NVU response to ischemia. Interestingly, roscovitine was shown to decrease leucocytes-mediated inflammation in several inflammatory models. Specific inhibition of roscovitine majors target CDK 1, 2, 5, 7, and 9 showed that these CDKs played key roles in inflammatory processes of NVU cells and leucocytes after brain lesions, including ischemic stroke. The data summarized here support the investigation of roscovitine as a potential therapeutic agent for the treatment of ischemic stroke, and provide an overview of CDK 1, 2, 5, 7, and 9 functions in brain cells and leucocytes during cerebral ischemia.

The role of cyclin-dependent kinase 5 in neuropathic pain.

The chronification of pain can be attributed to changes in membrane receptors and channels underlying neuronal plasticity and signal transduction largely within nociceptive neurons that initiate and maintain pathological pain states. These proteins are subject to dynamic modification by posttranslational modifications, creating a code that controls protein function in time and space. Phosphorylation is an important posttranslational modification that affects ∼30% of proteins in vivo. Increased phosphorylation of various nociceptive ion channels and of their modulators underlies sensitization of different pain states. Cyclin-dependent kinases are proline-directed serine/threonine kinases that impact various biological and cellular systems. Cyclin-dependent kinase 5 (Cdk5), one member of this kinase family, and its activators p35 and p39 are expressed in spinal nerves, dorsal root ganglia, and the dorsal horn of the spinal cord. In neuropathic pain conditions, expression and/or activity of Cdk5 is increased, implicating Cdk5 in nociception. Experimental evidence suggests that Cdk5 is regulated through its own phosphorylation, through increasing p35's interaction with Cdk5, and through cleavage of p35 into p25. This narrative review discusses the molecular mechanisms of Cdk5-mediated regulation of target proteins involved in neuropathic pain. We focus on Cdk5 substrates that have been linked to nociceptive pathways, including channels (eg, transient receptor potential cation channel and voltage-gated calcium channel), proteins involved in neurotransmitter release (eg, synaptophysin and collapsin response mediator protein 2), and receptors (eg, glutamate, purinergic, and opioid). By altering the phosphoregulatory "set point" of proteins involved in pain signaling, Cdk5 thus appears to be an attractive target for treating neuropathic pain conditions.

The Role of CDKs and CDKIs in Murine Development.

Cyclin-dependent kinases (CDKs) and their inhibitors (CDKIs) play pivotal roles in the regulation of the cell cycle. As a result of these functions, it may be extrapolated that they are essential for appropriate embryonic development. The twenty known mouse CDKs and eight CDKIs have been studied to varying degrees in the developing mouse, but only a handful of CDKs and a single CDKI have been shown to be absolutely required for murine embryonic development. What has become apparent, as more studies have shone light on these family members, is that in addition to their primary functional role in regulating the cell cycle, many of these genes are also controlling specific cell fates by directing differentiation in various tissues. Here we review the extensive mouse models that have been generated to study the functions of CDKs and CDKIs, and discuss their varying roles in murine embryonic development, with a particular focus on the brain, pancreas and fertility.

Biological Role of CDK 11 and 12 in Cell Cycle and its Function in Tumorigenesis

Uninhibited proliferation and abnormal cell cycle regulation are the hallmarks of cancer. The main role of cyclin dependent kinases is to regulate the cell cycle and cell proliferation. These protein kinases are frequently down regulated or up regulated in various cancers. Two CDK family members, CDK 11 and 12, have contradicting views about their roles in different cancers. For example, one study suggests that the CDK 11 isoforms, p58, inhibits growth of breast cancer whereas, the CDK 11 isoform, p110, is highly expressed in breast tumor. Studies regarding CDK 12 show variation of opinion towards different parts of the body, however there is a consensus that upregulation of cdk12 increases the risk of breast cancer. Hence, CDK 11 and CDK 12 need to be analyzed to confirm their mechanism and their role regarding therapeutics, prognostic value, and ethnicity in cancer. This article gives an outline on both CDKs of information known up to date from Medline, PubMed, Google Scholar and Web of Science search engines, which were explored and thirty relevant researches were finalized.

Role of Cyclin-Dependent Kinase 1 in Translational Regulation in the M-Phase.

Cyclin dependent kinase 1 (CDK1) has been primarily identified as a key cell cycle regulator in both mitosis and meiosis. Recently, an extramitotic function of CDK1 emerged when evidence was found that CDK1 is involved in many cellular events that are essential for cell proliferation and survival. In this review we summarize the involvement of CDK1 in the initiation and elongation steps of protein synthesis in the cell. During its activation, CDK1 influences the initiation of protein synthesis, promotes the activity of specific translational initiation factors and affects the functioning of a subset of elongation factors. Our review provides insights into gene expression regulation during the transcriptionally silent M-phase and describes quantitative and qualitative translational changes based on the extramitotic role of the cell cycle master regulator CDK1 to optimize temporal synthesis of proteins to sustain the division-related processes: mitosis and cytokinesis.

Phenotypic Characterization of Targeted Knockdown of Cyclin-Dependent Kinases in the Intestinal Epithelial Cells.

Cyclin-dependent kinases (CDKs) are serine/threonine kinases that regulate cell cycle and have been vigorously pursued as druggable targets for cancer. There are over 20 members of the CDK family. Given their structural similarity, selective inhibition by small molecules has been elusive. In addition, collateral damage to highly proliferative normal cells by CDK inhibitors remains a safety concern. Intestinal epithelial cells are highly proliferative and the impact of individual CDK inhibition on intestinal cell proliferation has not been well studied. Using the rat intestinal epithelial (IEC6) cells as an in vitro model, we found that the selective CDK4/6 inhibitor palbociclib lacked potent anti-proliferative activity in IEC6 relative to the breast cancer cell line MCF7, indicating the absence of intestinal cell reliance on CDK4/6 for cell cycle progression. To further illustrate the role of CDKs in intestinal cells, we chose common targets of CDK inhibitors (CDK 1, 2, 4, 6, and 9) for targeted gene knockdown to evaluate phenotypes. Surprisingly, only CDK1 and CDK9 knockdown demonstrated profound cell death or had moderate growth effects, respectively. CDK2, 4, or 6 knockdowns, whether single, double, or triple combinations, did not have substantial impact. Studies evaluating CDK1 knockdown under various cell seeding densities indicate direct effects on viability independent of proliferation state and imply a potential noncanonical role for CDK1 in intestinal epithelial biology. This research supports the concept that CDK1 and CDK9, but not CDKs 2, 4, or 6, are essential for intestinal cell cycle progression and provides safety confidence for interphase CDK inhibition.

The Role of Cyclin-Dependent Kinases on the Metastasis of Breast Cancer

The Role of Cyclin-Dependent Kinases on the Metastasis of Breast Cancer

Role of cyclin-dependent kinase 2 in the progression of mouse juvenile cystic kidney disease

AbstractA hallmark of polycystic kidney diseases (PKDs) is aberrant proliferation, which leads to the formation and growth of renal cysts. Proliferation is mediated by cyclin-dependent kinases (Cdks), and the administration of roscovitine (a pan-Cdk inhibitor) attenuates renal cystic disease in juvenile cystic kidney (jck) mice. Cdk2 is a key regulator of cell proliferation, but its specific role in PKD remains unknown. The aim of this study was to test the hypothesis that Cdk2 deficiency reduces renal cyst growth in PKD. Three studies were undertaken: (i) a time course (days 28, 56, and 84) of cyclin and Cdk activity was examined in jck mice and compared with wild-type mice; (ii) the progression was compared in jck mice with or without Cdk2 ablation from birth; and (iii) the effect of sirolimus (an antiproliferative agent) on Cdk2 activity in jck mice was investigated. Renal disease in jck mice was characterized by diffuse tubular cyst growth, interstitial inflammation and fibrosis, and renal impairment, peaking on day 84. Renal cell proliferation peaked during earlier stages of disease (days 28–56), whereas the expression of Cdk2-cyclin partners (A and E) and Cdk1 and 2 activity, was maximal in the later stages of disease (days 56–84). Cdk2 ablation did not attenuate renal disease progression and was associated with persistent Cdk1 activity. In contrast, the postnatal treatment of jck mice with sirolimus reduced both Cdk2 and Cdk1 activity and reduced renal cyst growth. In conclusion, (i) the kinetics of Cdk2 and Cdk2-cyclin partners did not correlate with proliferation in jck mice; and (ii) the absence of Cdk2 did not alter renal cyst growth, most likely due to compensation by Cdk1. Taken together, these data suggest that Cdk2 is dispensable for the proliferation of cystic epithelial cells and progression of PKD.

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer.

Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.

The role of cyclin-dependent kinases in miR-193a5p regulating ovarian cancer cell proliferation and epithelial mesenchymal transformation

Objective: To investigate whether miR-193a-5p targets CDK14 and regulates the proliferation and epithelial-mesenchymal transition (EMT) of ovarian cancer cell line OVAC. Methods: TargetScanHuman was used to analyze the match between miR-193a-5p and CDK14, and then miRNA assay was used to detect whether miR-193a-5p targeting CDK14; miR-193a-5p mimics overexpression or miR-193a-5p inhibitor knockdown in the case of low miR-193a-5p, the expression levels of CDK14, EMT-related proteins E-cadherin, vimentin, fibronectin and N-cadherin were detected by immunoblotting, and the proliferation of ovarian cancer cells OVAC was detected by CCK-8, and the cell viability of cancer cell OVAC was detected by MMT. Results: miR-193a-5p targeted the 3'UTR of CDK14; after overexpression of miR-193a-5, the expression of CDK14 was decreased, the expression of EMT-related protein E-cadherin was increased, and the expressions of vimentin, fibronectin and N-cadherin were decreased. The proliferation and cell viability of ovarian cancer cell line OVAC were increased. Meanwhile, after knocking down miR-193a-5p, the expression of CDK14 was increased, and the expression of EMT-related protein E-cadherin was decreased, while the expression levels of vimentin, fibronectin and N-cadherin were increased, and the proliferation and cell viability of ovarian cancer cell line OVAC were decreased. Conclusion: miR-193a-5p reduces the proliferation, cell viability and EMT of ovarian cancer cell line OVAC by targeting the 3 'UTR of CDK14.