Role Of Cyclin-dependent Kinase Research Articles

The role of cyclin-dependent kinases in oral potentially malignant disorders and oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a major global health problem with a relatively low-moderate 5-year survival rate. OSCC is often preceded by lesions and conditions known as oral potentially malignant disorders (OPMDs) that have an increased risk of malignant transformation. Despite advances in diagnostic technology and cancer research, the prognosis of OSCC remains poor as it is frequently detected a late stage. Understanding the molecular pathways involved in oral carcinogenesis provides a platform to identify biomarkers that may allow the early detection of OSCC and accurate prediction of the malignant potential of OPMDs. In addition, specific molecular inhibitors can be developed to target these important pathways and allow advanced therapeutic management to improve the prognosis of this malignancy. A common feature across a number of different cancers is the dysfunction of cell cycle moderator proteins known as cyclin-dependent kinases. This review summarises the current literature regarding the role of cyclin-dependent kinases in oral carcinogenesis with a particular focus on cyclin-dependent kinases 4 (CDK4) and 6 (CDK6). This is of particular relevance as CDK4 and CDK6 inhibitors have shown some promising results in other cancer types and are interesting potential treatments for OSCC.

Role of cyclin-dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway.

Liver cancer is the fourth leading cause of cancer related mortality in the world, with hepatocellular carcinoma (HCC) representing the most common primary subtype. Two-thirds of HCC patients have advanced disease when diagnosed, and for these patients, treatment strategies remain limited. In addition, there is a high incidence of tumor recurrence after surgical resection with the current treatment regimens. The development of novel and more effective agents is required. Cyclin-dependent kinases (CDKs) constitute a family of 21 different protein kinases involved in regulating cell proliferation, apoptosis, and drug resistance, and are evaluated in preclinical and clinical trials as chemotherapeutics. To summarize and discuss the therapeutic potential of targeting CDKs in HCC, recent published articles identified from PubMed were comprehensively reviewed. The key words included hepatocellular carcinoma, cyclin-dependent kinases, and CDK inhibitors. This review focuses on the emerging evidence from studies describing the genetic and functional aspects of CDKs in HCC. We also present an overview of CDK inhibitors that have shown efficacy in laboratory studies of HCC. Although many of the studies assessing CDK-targeting therapies in HCC are at the preclinical stage, there is significant evidence that CDK inhibitors used alone or in combination with established chemotherapy drugs could have significant applications in HCC.

Endocrine-based targeted combination versus endocrine therapy alone as first-line treatment in elderly patients with hormone receptor-positive advanced breast cancer: Meta-analysis of phase II and III randomized clinical trials.

1046 Background: Combined endocrine approaches have been widely investigated as first-line treatment in hormone receptors positive metastatic breast cancer. In particular, multiple randomized trials showed that the addiction of CDK (cyclin-dependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged ≥65 years) are under represented in most of the clinical studies. Moreover, due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present meta-analysis aimed to understand the role of the new endocrine approaches in women aged ≥65 years. Methods: This meta-analysis included first line phase II/III randomized published trials comparing (ET) to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged ≥65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Results: 8 studies were included in the analysis. 4 trials (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found in elderly population subgroup. Conclusions: The novel experimental combo-strategies in the first line setting showed an improvement in PFS in the subgroup of elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone. The magnitude of PFS benefit due to addition of CDK4/6 inhibitors to ET is age-independent.

Third-generation CDK inhibitors: A review on the synthesis and binding modes of Palbociclib, Ribociclib and Abemaciclib

The role of cyclin-dependent kinases (CDKs) in regulating the transition of cell cycle steps makes this class of enzymes a suitable target for cancer therapy. Three different generations of CDKs inhibitors have been developed so far. Third-generation compounds (i.e. selective CDK4/6 inhibitors) are the most promising ones, due to their limited toxicity and high in vivo activity. To date, three compounds have entered the therapy, namely Palbociclib, Ribociclib and Abemaciclib. Herein we review the medicinal chemistry aspects of these drugs, with some references to very similar analogues that have been published.

Understanding the Role of Cyclin Dependent Kinase 5 (Cdk5) in Insulin Related Neurodegenerative Disease

Cyclin Dependent Kinase 5 (Cdk5) is a member of the cyclin dependent kinase family of proteins that play key roles in the regulation of the cell cycle. The activity of these enzymes is dependent upon association with a cyclin activating partner. Unlike other members of this family, however, Cdk5 appears to play no role in cell cycle regulation. Cdk5 is ubiquitously expressed in all cells. However maximum kinase activity is found in post‐mitotic neurons and glial cells, where Cdk5's cyclin activating partners exhibit high expression. Known substrates of Cdk5 include proteins that modulate cell morphology and motility. Our lab has shown that Cdk5 plays an essential role in the developing nervous system primarily through studies of chemical inhibition of Cdk5 in a neuronal model. Specifically, we employed the well‐known PC12 cell line which can be induced to transdifferentiate into neuronal‐like cells. Inhibition of Cdk5 during this process reduced the neuronal characteristics these cells typically exhibit, mimicking neuronal degradation or degeneration. Multiple published studies support Cdk5's role in the developing mammalian nervous system. Recent investigations have shown an increased correlation between the likelihood of developing neurodegenerative diseases and insulin resistance associated with Type 2 diabetes. Insulin resistance results in the over‐secretion of insulin (hyperinsulinemia) into the blood stream and causes a down regulation of insulin receptors in peripheral tissue. Although acute hyperinsulinemia in the central nervous system (CNS) may have cognitive enhancing effects, chronic hyperinsulinemia appears to be neurotoxic. We are exploring this potential relationship between insulin levels and the neuron by exploiting our neuronal model cell line, PC12. Using this model, we examine the role of normal and aberrant Cdk5 activity in the response of differentiated neuronal‐like PC12 cells to varying concentrations of insulin in culture. Our aim is to test the reports of deregulation of brain insulin signaling as an early marker in AD. Here we show our preliminary results of the transdifferentiation of PC12 cells while Cdk5 activity is manipulated under hyperinsulinemic conditions. Our findings underscore the value of this model as a means to examine the potential role of Cdk5 as a link between AD and Type 2 diabetes. Given the increased Type 2 Diabetes diagnosis and the aging of American society implications for this study are self‐evident.Support or Funding InformationThe Rose M. Badgely Charitable Trust, Joseph Alexander Foundation, Sister Colette Mahoney Science Research Grant and the Marymount Manhattan College Faculty Award.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Investigating the Role of Cdk5 in Alzheimer's Disease and Type‐2 Diabetes

Alzheimer's disease (AD), a progressive, age‐related neurodegenerative disorder, affects more than 30 million people worldwide. The etiology of this disease remains unclear, although risks factors such as aging, type‐2 diabetes and obesity have been identified. Hallmarks of AD include extracellular amyloid‐b plaques and interneuronal neurofibrillary tangles of hyperphosphorylated tau protein. Our lab investigates the role of Cyclin dependent kinase 5 (Cdk5) in mammalian nervous system development using the well‐established neuronal cell model PC12. PC12 cells are derived pheochromcytoma of a rat adrenal medulla. Our early findings have shown that Cdk5 is essential for the establishment of crucial neuronal cell morphology and action. This is in good agreement with other published reports that show Cdk5 is required for proper central nervous system development and for neuronal patterning and migration. Given Cdk5's role in neuronal development and that one of its substrates is tau, we decided to explore a role for Cdk5 in neurodegeneration. Chemical inhibition of Cdk5 revealed extreme aberrations in nerve cell morphology, architecture and function in our PC12 cell line in the presence of neurotrophic factors. To characterize and quantify these physical changes, we devised a simple method to convert these qualitative results to quantitative results, allowing rigorous comparison of our data. Our findings align well with the reports of other labs demonstrating a role for Cdk5 in the formation of neurofibrillary tangles and other protein aggregation and misfolding events in neurodegenerative diseases like AD. Cdk5 has also been implicated in the differentiation of extra neural tissues, including the pancreas. Since some of the risk factors for AD includes obesity and Type 2 diabetes, we also investigated the effect of Cdk5 inhibition in pancreatic cell models. Our findings suggest a role for Cdk5 in insulin secretion, supporting published reports of a role for Cdk5 in exocytosis in the pancreas. Recent evidence that deregulation of brain insulin plays a role in the pathology of AD may explain the associated risk factors of obesity and Type 2 diabetes with AD. Therefore, we are exploring the neuronal phenotype under hyperglycemic conditions while manipulating Cdk5 activity. We are extending our research using another well‐known neuronal cell model, N2a, a murine neuroblastoma. Here we report our test results of the impact of normal and aberrant Cdk5 activity on the response of differentiated N2a cells to varying concentrations of glucose in culture. This has allowed us to draw broader conclusions regarding the role of Cdk5 in neuronal development and degeneration and the connection between type II diabetes and AD. Since a number of reports suggest that dysfunction in cerebral glucose metabolism are early abnormalities in AD, this model system provides a means to examine the potential role of Cdk5 as a link between AD and Type II diabetes.Support or Funding InformationThe Rose M. Badgely Charitable Trust, Joseph Alexander Foundation, Sister Colette Mahoney Science Research Grant and the Marymount Manhattan College Faculty Award.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2

AbstractA distinct hallmark of acute myeloid leukemia (AML) is the arrest of leukemic myeloblasts at an immature stage of development. Therapies that overcome differentiation arrest have emerged as a powerful strategy for treating AML, but targeting leukemia differentiation remains challenging, mainly because of an incomplete mechanistic understanding of the process. Here, we unveil a new role for cyclin-dependent kinase 2 (CDK2) in blocking myeloid differentiation in AML. We show that among several interphase CDK, only CDK2 undergoes ubiquitin-dependent proteasome degradation, which is accompanied by AML cell differentiation. By using the yeast 2-hybrid system and functional analyses, KLHL6 was identified as a specific E3 ubiquitin ligase regulating the degradation of CDK2. Importantly, inhibiting CDK2, but not other cyclin-dependent kinases CDK1/4/6, effectively induced granulocytic differentiation in AML cell lines and 5 major subtypes of primary patient-derived AML samples. Mechanistically, CDK2 depletion led to the reactivation of differentiation pathway translation, and the differentiation blockade function of CDK2 may be achieved directly by maintaining the activity of PRDX2. Finally, CDK2 depletion arrested tumor growth of AML cells in nude mice and extended survival in both AML cell line and PDX-AML cells derived xenograft mouse models. Thus, our work not only provides experimental evidence for validating CDK2 as a potential therapeutic target for differentiation, but also uncovers the biological function of the CDK2-PRDX2 axis in blocking AML differentiation.

Role of cyclin-dependent kinase 4/6 inhibitors in the current and future eras of cancer treatment.

Cyclin-dependent kinase 4/6 inhibitors, which act by inhibiting progression from the G1 to S phases of the cell cycle, include palbociclib, ribociclib, abemaciclib, and trilaciclib. Palbociclib and ribociclib are currently food and drug administration-approved for use in combination with aromatase inhibitors in postmenopausal women with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Palbociclib is also food and drug administration-approved for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Abemaciclib is the newest cyclin-dependent kinase 4/6 inhibitor to gain Food and Drug Administration (FDA) approval, specifically as monotherapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer previously treated with chemotherapy and endocrine therapy. Abemaciclib also shares a similar indication with palbociclib for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Trilaciclib use remains largely investigational at this time. However, despite FDA-approval for only metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, all four cyclin-dependent kinase 4/6 inhibitors have shown promise in hematologic malignancies and non-breast solid tumors. Although further research is needed, cyclin-dependent kinase 4/6 inhibitors represent intriguing developments in the treatment of various malignancies, including those with such poor prognoses as glioblastoma multiforme, mantle cell lymphoma, and metastatic melanoma. We discuss the approved indications, current research, and areas of future exploration for palbociclib, ribociclib, abemaciclib, and trilaciclib.

Effects of cyclin-dependent kinase 9 (CDK9) on lytic replication of Kaposi′s sarcoma-associated herpesvirus (KSHV)

Objective To investigate the role of cyclin-dependent kinase 9 (CDK9) in regulating lytic replication of Kaposi′s sarcoma-associated herpesvirus (KSHV). Methods Percentages of red fluorescent protein (RFP) positive cells were counted after treating and stimulating iSLK.219 cells with FIT-039, a CDK9 specific inhibitor, and doxycycline (Dox), respectively, or transfecting and stimulating them with CDK9 siRNA (si-CDK9) and Dox, respectively. Quantitative real-time PCR was used to detect the expression of KSHV genes at mRNA level in TREx-K-Rta BCBL-1 cells treated with FIT-039 or transfected with si-CKD9 in the presence of Dox. Chromatin immunoprecipitation (ChIP) assay was used to examine the enrichment of RNA polymerase Ⅱ (RNA Pol Ⅱ) and phosphorylated CTD-S2 of RNA Pol Ⅱ on the PAN promoter in TREx-K-Rta BCBL-1 cells treated with FIT-039. Results Both FIT-039 intervention and CDK9 knockdown dramatically deceased the percentage of RFP-positive iSLK.219 cells and suppressed the expression of ORF50, PAN and K2 in TREx-K-Rta BCBL-1 cells at mRNA level. Furthermore, FIT-039 significantly inhibited the enrichment of RNA Pol Ⅱ and phosphorylated CTD-S2 of RNA Pol Ⅱ on the PAN promoter in TREx-K-Rta BCBL-1 cells. Conclusion CDK9 is involved in regulating the lytic replication of KSHV through promoting the phosphorylation of CTD-S2 of RNA Pol Ⅱ. Key words: Cyclin-dependent kinase 9; Kaposi′s sarcoma-associated herpesvirus; Lytic replication; Gene transcriptional elongation

Roles of CDK and DDK in Genome Duplication and Maintenance: Meiotic Singularities.

Cells reproduce using two types of divisions: mitosis, which generates two daughter cells each with the same genomic content as the mother cell, and meiosis, which reduces the number of chromosomes of the parent cell by half and gives rise to four gametes. The mechanisms that promote the proper progression of the mitotic and meiotic cycles are highly conserved and controlled. They require the activities of two types of serine-threonine kinases, the cyclin-dependent kinases (CDKs) and the Dbf4-dependent kinase (DDK). CDK and DDK are essential for genome duplication and maintenance in both mitotic and meiotic divisions. In this review, we aim to highlight how these kinases cooperate to orchestrate diverse processes during cellular reproduction, focusing on meiosis-specific adaptions of their regulation and functions in DNA metabolism.

Antitumor effects of cyclin dependent kinase 9 inhibition in esophageal adenocarcinoma.

Role of cyclin dependent kinase 9(CDK9) as a potential target in esophageal adenocarcinoma (EAC) is unknown. We investigated CDK9 protein expression in EAC and Barrett's esophagus and role of CDK9 in oncogenic processes of EAC in vitro and in murine xenografts. The CDK9 expression was significantly higher in EAC as compared to Barrett's esophagus in patient samples. Stable shCDK9 in SKGT4 reduced proliferation by 37% at day 4, increased apoptosis at 48 hours and induced G1 cell cycle arrest at 48 hours (58.4% vs. 45.8%) compared to controls SKGT4 cells. SKGT4-shCDK9 cell-derived tumors were significantly smaller than control SKGT4-derived tumors in xenografts (72.89mm3 vs. 270mm3). Pharmaceutical inhibition of CDK9 by Flavopiridol (0.1μm for 48 hours) and CAN508 (20 and 40μm for 72 hours) induced significant reduction in proliferation and 2-fold increase in apoptosis in SKGT4, FLO1 and OE33 cells. In xenograft models, CAN508 (60 mg/kg/dayx10 days) and Flavopiridol (4mg/kg/dayx10 days) caused 50.8% and 63.1% reduction in xenograft tumors as compared to control on post-treatment day 21. Reduction of MCL-1 and phosphorylated RNA polymerase II was observed with transient shCDK9 in SKGT4 cells but not with stable shCDK9. CAN508 (20 and 40 μm) and Flavopiridol (0.1, 0.2 and 0.3 μm) for 4 hours showed reduction in MCL-1 mRNA (84% and 96%) and protein. Mcl-1 overexpression conferred resistance to Flavopiridol (0.2 μm or 0.4 μm for 48 hours) and CAN 508 (20 or 40μm for 72 hours). Chromatin immunoprecipitation demonstrated significant reduction of binding of transcriptional factor HIF-1α to MCL-1 promoter in FLO-1 cells by CDK9 inhibitors.

A CDK2 activity signature predicts outcome in CDK2-low cancers.

The role of cyclin-dependent kinase 2 (CDK2) in cancer is controversial. A major hurdle is the availability of tools to easily assess its activity across many samples. Here, we introduce a transcriptional signature to specifically track CDK2 activity. It responds to genetic and chemical perturbations in the CDK-RB-E2F axis, correlates with mitotic rate in vitro and in vivo and reacts rapidly to changes in CDK2 activity during cell cycle progression. We find that CDK2 activity is specifically elevated in human testes, mirroring its critical function in mice, and report very distinct profiles across human cancers. Increased CDK2 activity decreases risk in colon cancer, but elevates poor outcome two- to fivefold in specific tumors, including low grade glioma, kidney, thyroid, adrenocortical and prostate cancer. These are typically 'CDK2-low' cancers, suggesting that above a certain threshold CDK2 promotes progression, but further increases do not influence outcome. Multivariate analysis revealed that the CDK2 signature is the most important predictive feature in these cancers versus dozens of other clinical parameters, such as tumor grade or mitotic index. Thus, transcriptome data provides a novel, straightforward method to monitor CDK2 activity, implicates key roles for the kinase in a subset of human tissues and tumors and enhances cancer risk prediction. The strategy used here for CDK2 could be applied to other kinases that influence transcription.

Cdk5-Dependent Activation of Neuronal Inflammasomes in Parkinson's Disease.

Inflammasomes, which mediate the activation of caspase-1 and maturation of IL-1β and IL-18, have been unambiguously verified to participate in many diseases, such as lung diseases, infectious diseases and Alzheimer's disease, but the relation between Parkinson's disease and inflammasomes is poorly understood. The expression, maturation, and secretion of inflammasomes in neurons were measured. The activation of inflammasomes in the substantia nigra of the brain was tested in acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and an α-synuclein transgenic mouse model. The levels of IL-1β and IL-18 in cerebrospinal fluid and serum samples of Parkinson's disease (PD) patients and control subjects were measured. The role of cyclin-dependent kinase 5 (Cdk5) in neuronal inflammasome activation was evaluated using the pharmacological Cdk5 inhibitor roscovitine or Cdk5-targeted deletion. Here, we observed the expression of core molecules of inflammasomes, including NALP3, ASC, caspase-1, and IL-1β, in neuronal cells. The PD inducer rotenone could activate neuronal inflammasomes and promote the maturation and secretion of the cleaved IL-1β and IL-18 in a dose- and time-dependent manner. We also detected the activation of inflammasomes in the substantia nigra of a PD mouse model and in cerebrospinal fluid of PD patients. Furthermore, Cdk5 is required for the activation of inflammasomes, and both inhibition and deletion of Cdk5 could efficiently block inflammasome activation in PD models. Together, our results indicated that Cdk5-dependent activation of neuronal inflammasomes was involved in the progression of PD.

Abstract IA28: Immunological insights from tracking dynamic cellular behavior in lymph nodes and tissues

Abstract A unique feature of the vertebrate immune system is its dependency on the migratory capacity of individual immune cells for proper development, differentiation and functional execution in vivo. High-resolution dynamic live-animal imaging has allowed scientists to decipher novel immunological insights, which is aided by increasing imaging sophistication, availability of in vivo experimental models, and high throughput multi-parameter data collection and analyses. Intravital imaging, combined with mathematical modeling and other immunological tools, has revealed an asymmetric role for MHC interactions in modulating CD4+ vs. CD8+ T lymphocyte surveillance strategies for cognate antigens in lymph nodes (LNs) [1]. Furthermore, naïve CD8+ T cells are preferentially attracted in a CCR5-dependent manner to LN niche sites where cognate antigen recognition occurs between DCs and CD4+ T cells via CCL3 / CCL4 gradient [2]. Additional data suggest that naïve CD8+ T cells regulate transient expression of preformed inflammatory chemokine receptors via integrin engagement early upon entry into inflamed LNs, suggesting a context-specific orchestration of immune responses in LNs. Once activated in the LNs, T cells travel to various anatomic compartments for delivery of their acquired effector function. Recent imaging experiments revealed that extravascular, CNS-resident CX3CR1+ APCs dynamically extend their cellular processes across intact vessel wall into vascular lumen. The frequency of projections increased in experimental autoimmune encephalomyelitis (EAE), whereas the number of projections remained stable compared to baseline days after other tissue injury such as CNS tumor infiltration and aseptic spinal cord trauma [3]. This unique behavior by CNS parenchymal CX3CR1+ cells may represent their unexplored functional role in antigen sampling and immune cell recruitment across the BBB. Lastly, we reported a novel role for cyclin-dependent kinase 5 (Cdk5), a proline-directed serine-threonine kinase, in T cell activation and persistence [4]. Cdk5 enzymatic activity has been found to be aberrantly up-regulated in a wide spectrum of tumors. Disruption of Cdk5 activity sensitizes tumor cells to elimination in a T cell-dependent manner, a process that is associated with an attenuated response in PD-L1 up-regulation upon interferon-γ exposure. Our additional emerging data further support a synergistic role of anti-Cdk5 agents in modulating tumor sensitivity to immunotherapeutic approaches. In conclusion, the tissue microenvironment plays a critical role in regulating host immune cell tumor crosstalk, and recent new advances in imaging modalities and in vivo experimental methodologies provided new insights that hold promises to propel the field of cancer immunotherapy forward.

A Chemical Screening Approach to Identify Novel Key Mediators of Erythroid Enucleation.

Erythroid enucleation is critical for terminal differentiation of red blood cells, and involves extrusion of the nucleus by orthochromatic erythroblasts to produce reticulocytes. Due to the difficulty of synchronizing erythroblasts, the molecular mechanisms underlying the enucleation process remain poorly understood. To elucidate the cellular program governing enucleation, we utilized a novel chemical screening approach whereby orthochromatic cells primed for enucleation were enriched ex vivo and subjected to a functional drug screen using a 324 compound library consisting of structurally diverse, medicinally active and cell permeable drugs. Using this approach, we have confirmed the role of HDACs, proteasomal regulators and MAPK in erythroid enucleation and introduce a new role for Cyclin-dependent kinases, in particular CDK9, in this process. Importantly, we demonstrate that when coupled with imaging analysis, this approach provides a powerful means to identify and characterize rate limiting steps involved in the erythroid enucleation process.

Evolutionary conservation of the CDK targets in eukaryotic DNA replication initiation

A fundamental requirement for all organisms is the faithful duplication and transmission of the genetic material. Failure to accurately copy and segregate the genome during cell division leads to loss of genetic information and chromosomal abnormalities. Such genome instability is the hallmark of the earliest stages of tumour formation. Cyclin-dependent kinase (CDK) plays a vital role in regulating the duplication of the genome within the eukaryotic cell cycle. Importantly, this kinase is deregulated in many cancer types and is an emerging target of chemotherapeutics. In this review, I will consider recent advances concerning the role of CDK in replication initiation across eukaryotes. The implications for strict CDK-dependent regulation of genome duplication in the context of the cell cycle will be discussed.

CDK2 transcriptional repression is an essential effector in p53-dependent cellular senescence-implications for therapeutic intervention.

Cellular senescence, a form of cell-cycle arrest, is a tumor-suppressor mechanism triggered by multiple tumor-promoting insults, including oncogenic stress and DNA damage. The role of cyclin-dependent kinase 2 (CDK2) regulation has been evaluated in models of replicative senescence, but little is known regarding its role in other senescence settings. Using in vitro and in vivo models of DNA damage-and oncogene-induced cellular senescence, it was determined that activation of the tumor-suppressor protein p53 (TP53) resulted in repression of the CDK2 transcript that was dependent on intact RB. Ectopic CDK2 expression was sufficient to bypass p53-dependent senescence, and CDK2-specific inhibition, either pharmacologically (CVT313) or by use of a dominant-negative CDK2, was sufficient to induce early senescence. Pharmacologic inhibition of CDK2 in an in vivo model of pineal tumor decreased proliferation and promoted early senescence, and it also decreased tumor penetrance and prolonged time to tumor formation in animals lacking p53. In conclusion, for both oncogene- and DNA damage-induced cellular senescence, CDK2 transcript and protein are decreased in a p53- and RB-dependent manner, and this repression is necessary for cell-cycle exit during senescence. These data show that CDK2 inhibition may be useful for cancer prevention in premalignant hyperproliferative lesions, as well as established tumors.

Cyclin-dependent kinase 4/6 inhibitors in breast cancer therapy.

To review the latest preclinical and clinical findings on the role of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in breast cancer and update on the studies investigating the predictive biomarkers of response to CDK4/6 inhibitors. The retinoblastoma tumor suppressor (Rb) pathway is frequently deregulated in breast cancer and strategies to target this pathway have recently been proven to be effective in breast cancer patients. Preclinical and clinical data suggest that CDK4/6 inhibitors might be particularly useful in patients with hormone-receptor-positive or HER2-positive tumors, whereas the role of such inhibitors in triple-negative breast cancer is still controversial. Clinical trials are now investigating the safety and efficacy of different CDK4/6 inhibitors, mostly in breast cancer patients with hormone-receptor-positive tumors. Recent studies demonstrated that alterations in the cyclin D-CDK4-Rb pathway may have a role in primary resistance to CDK4/6 inhibitors. Target therapies have brought great improvements in the management of breast cancer patients. CDK4/6 inhibitors look promising in the treatment of patients with hormone-receptor-positive breast cancer, but it is of pivotal importance to identify which subgroup of patients would mostly benefit from CDK4/6 inhibition with biomarker-driven clinical trials.

C0485: Role of Cyclin-Dependent Kinase 6 (Cdk6) in Platelet Function and Hemostasis in Mice

Trabajo presentado en el 23rd International Congress on Thrombosis, celebrado en Valencia, Espana, del 14 al 17 de mayo de 2014

Modelling the CDK-dependent transcription cycle in fission yeast

CDKs (cyclin-dependent kinases) ensure directionality and fidelity of the eukaryotic cell division cycle. In a similar fashion, the transcription cycle is governed by a conserved subfamily of CDKs that phosphorylate Pol II (RNA polymerase II) and other substrates. A genetic model organism, the fission yeast Schizosaccharomyces pombe, has yielded robust models of cell-cycle control, applicable to higher eukaryotes. From a similar approach combining classical and chemical genetics, fundamental principles of transcriptional regulation by CDKs are now emerging. In the present paper, we review the current knowledge of each transcriptional CDK with respect to its substrate specificity, function in transcription and effects on chromatin modifications, highlighting the important roles of CDKs in ensuring quantity and quality control over gene expression in eukaryotes.