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

Objectives 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. Methods 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. Results 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. Conclusions This work reveals a novel CDK1/Sox2 axis responsible for maintaining the stemness of lung cancer cells (AU)

Phosphate: from stardust to eukaryotic cell cycle control

Phosphorus is a pivotal element in all biochemical systems: it serves to store metabolic energy as ATP, it forms the backbone of genetic material such as RNA and DNA, and it separates cells from the environment as phospholipids. In addition to this 'big hits', phosphorus has recently been shown to play an important role in other important processes such as cell cycle regulation. In the present review, we briefly summarize the biological processes in which phosphorus is involved in the yeast Saccharomyces cerevisiae before discussing our latest findings on the role of this element in the regulation of DNA replication in this eukaryotic model organism. We describe both the role of phosphorus in the regulation of G1 progression by means of the Cyclin Dependent Kinase (CDK) Pho85 and the stabilization of the cyclin Cln3, as well as the role of other molecule composed of phosphorus-the polyphosphate-in cell cycle progression, dNTP synthesis, and genome stability. Given the eminent role played by phosphorus in life, we outline the future of phosphorus in the context of one of the main challenges in human health: cancer treatment (AU)

No disponible

Glucose and glutamine metabolism control by APC and SCF during the G1-to-S phase transition of the cell cycle

Recent studies have given us a clue as to how modulations of both metabolic pathways and cyclins by the ubiquitin system influence cell cycle progression. Among these metabolic modulations, an aerobic glycolysis and glutaminolysis represent an initial step for metabolic machinery adaptation. The enzymes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and glutaminase-1 (GLS1) maintain a high abundance in glycolytic intermediates (for synthesis of non-essential amino acids, the use of ribose for the synthesis of nucleotides and hexosamine biosynthesis), as well as tricarboxylic acid cycle intermediates (replenishing the loss of mitochondrial citrate), respectively. On the one hand, regulation of these key metabolic enzymes by ubiquitin ligases anaphase-promoting complex/cyclosome (APC/C) and Skp1/cullin/F-box (SCF) has revealed the importance of anaplerosis by both glycolysis and glutaminolysis to overcome the restriction point of the G1 phase by maintaining high levels of glycolytic and glutaminolytic intermediates. On the other hand, only glutaminolytic intermediates are necessary to drive cell growth through the S and G2 phases of the cell cycle. It is interesting to appreciate how this reorganization of the metabolic machinery, which has been observed beyond cellular proliferation, is a crucial determinant of a cell’s decision to proliferate. Here, we explore a unifying view of interactions between the ubiquitin system, metabolic activity, and cyclin-dependent kinase complexes activity during the cell cycle

Therapeutic opportunities to control tumor cell cycles

No disponible

Tumor cell proliferation is frequently associated togenetic or epigenetic alterations in key cell cycleregulators. Most human tumors deregulate thispathway to sustain proliferation with independenceof external mitogenic factors. In addition, the alterationof cell cycle proteins may confer genomic instabilitythat results in additional mutations inthese tumor cells. The frequent alteration of the cellcycle in tumor cells has launched the identificationfor critical cell cycle regulators as anticancer targets.The inhibition of some cell cycle kinases suchas cyclin-dependent kinases (CDKs) or the Auroraand Polo mitotic kinases is currently under study inseveral preclinical and clinical trials. Similarly, theclinical success of microtubule poisons such as taxolhas promoted new applied research in mitosisregulation. Recent investigations have suggestednew targets of interest including additional kinases,phosphatases and other mitotic regulators such asmicrotubule motor proteins (kinesins). Currrent researchin this area will undoubtedly result in newand improved targeted therapies for cancer treatment

Molecular biology of exocrine pancreatic cancer

Exocrine pancreatic cancer is one of the neoplasiaswith a worse prognosis, with conventional treatmentshaving little impact on disease outcome.Research and genomic high-throughput technologyis continuously expanding our knowledge of pancreascancer biology. Characterization of geneticand epigenetic alterations in pancreatic tumors hasallowed a better understanding of the progressionmodel of the disease at the molecular level. The developmentof new therapeutic approaches with target-oriented agents is been tested in the preclinicaland clinical settings. This review updates the currentavailable data on pancreatic cancer molecularbiology

No disponible

Protein kinases and phosphatases as therapeutic targets in cancer

No disponible

Protein phosphorylation plays key roles in many physiologicalprocesses and is often deregulated in pathologicalconditions. Our current understanding of howprotein kinases and phosphatases orchestrate thephosphorylation changes that control cellular functionshas made these enzymes potential drug targetsfor the treatment of many diseases. The success of thetyrosine kinase inhibitor Gleevec in the treatment ofsome cancers has further invigorated the developmentof kinase inhibitors as anti-cancer drugs. Alarge number of these compounds are currently undergoingclinical trials and there is much expectationon the therapeutic potential of these molecules, asmore specific and less toxic drugs than currentlyused generic chemotherapeutic agents. In this manuscript,we review the current status of more than 30protein kinase inhibitors with proven or potentialtherapeutic value for cancer treatment. These includeinhibitors of receptor and cytosolic tyrosine kinasesas well as compounds that target different families ofserine/threonine kinases involved in signalling andcell cycle regulation. We also briefly touch on theprospects of phosphatase inhibitors. The combinationof kinase inhibitors to target different components ofsignalling pathways that are found deregulated in tumoursis also emerging as an interesting approach forcancer therapy

The TGFβ pathway in basic oncology

La familia del factor de crecimiento transformante-β (TGFβ) se destaca particularmente entre los factores de crecimiento como regulador de la proliferación y diferenciación celular. El TGFβ promueve el crecimiento de los tejidos y la morfogénesis durante la embriogénesis en organismos tan diversos como nematodos, mosca de la fruta y humanos. Para elucidar las bases de esta gran diversidad de respuestas del TGFβ en diferentes tipos celulares, hemos trazado la vía que comunica los receptores de membrana del TGFβ con los genes diana. El TGFβ forma un complejo receptor en el cual la quinasa del receptor tipo II fosforila y activa el receptor tipo I. Este receptor tipo I fosforila y activa los factores de transcripción Smad. Una vez activados, los factores Smad entran en el núcleo con el fin de formar complejos para el reconocimiento y regulación (activación o represión) de genes específicos. La señalización del TGFβ hace disminuir la actividad CDK y provoca la represión de distintos genes promotores del crecimiento. La vía del TGFβ, cuando se altera, juega un papel esencial en la tumorigénesis y en la metástasis

The transforming growth factor-β (TGFβ) family is particularly prominent among growth factors controlling cell proliferation and differentiation, and fosters tissue growth and morphogenesis during embryogenesis in organisms as diverse as the nematode, fruit fly, and human. To elucidate the basis for the great diversity of TGFβ responses in different cell types, we delineated the pathway linking membrane TGFβ receptors to target genes. TGFβ assembles a receptor complex in which the type II receptor kinase phosphorylates and activates the type I receptor. This type I receptor phosphorylates and activates Smad transcription factors. A receptor-activated Smad complex enters the nucleus to find partners for the recognition and regulation (activation of repression) of specific genes. TGFβ signaling decreases CDK activity and causes the repression of several growthpromoting genes. The TGFβ pathway, when altered, plays an essential role in tumorigenesis and metastasis

Aceleración y frenado de la proliferación celular / Aceleration and brake of cell proliferation

Las células de plantas poseen análogos estructurales y funcionales de los complejos CDK-ciclina de levaduras y animales que permiten iniciar o avanzar la proliferación celular. Las células vegetales presentan además versiones específicas de CDKs y ciclinas sin homología con las del hombre, tales como las implicadas en citocinesis, un proceso que difiere en ambos reinos. Finalmente, las plantas no sólo poseen homólogos de la CAK humana (CDKDs) que activan otras CDKs por fosforilación de una treonina situada en su lazo T, sino también otra segunda CAK (CDKF1) y un grupo de ciclinas, las P, que son homólogas de las existentes en levaduras. Ello apoya una historia de endosimbiosis ocasional entre levaduras y la célula precursora de plantas, con transmisión horizontal de genes. Las plantas también conservan los mecanismos de frenado por rutas de chequeo que retrasan la activación de CDKs, generalmente al evitar la defosforilación de la treonina14 y la tirosina 15 mediante inhibición de la fosfatasa Cdc25 o sus homólogos funcionales, cuando las condiciones de la propia célula son inadecuadas para afrontar sin riesgos una transición irreversible entre fases consecutivas del ciclo

Plants possess the structural and functional homologs of the yeast and human CDK-cyclin complexes, apart from some specific ones as those that participate in cytokinesis, a process that differs essentially in plant and animal cells. Apart from the human CAK homologue that activates CDKs by phosphorylating the threonine residue in the T-loop, plant cells have an additional CAK (CDKGF1) and a whole group of cyclins, the P ones, that are orthologues of the yeast ones. This unveils an occasional endosymbiotic process with a horizontal gene transfer between yeast and plant genomes. Plant cells also possess the braking mechanisms that prevent CDK activation to face an irreversible transition between subsequent cycle phases when the cell is not completely ready for it. Such mechanisms mostly prevent CDK activation by inhibiting dephosphorylation of the CDK threonine14-tyrosine15 residues brought about by the Cdc25 phosphatase plant homolog

Estudio teórico del modo de unión entre CDK2 y butirolactona I / Theoretical study of the binding mode between CDK2 and butirolactone I

Las quinasas dependientes de ciclinas (CDKs) juegan un papel importante en la regulación de la división del ciclo celular, lo que supone una prometedora diana para el desarrollo de nuevos agentes terapéuticos frente al cáncer. Se ha realizado un gran esfuerzo durante los últimos años en la búsqueda de pequeñas moléculas que pueden actuar como inhibidores químicos de las CDKs. Estos inhibidores bloquean la progresión del ciclo celular y presentan una interesante actividad antitumoral. La butirolactona I, un producto natural aislado de Aspergillus terreus, que ha mostrado actividad antiproliferativa frente a carcinoma de colon y de páncreas en líneas celulares. Se comporta como un inhibidor competitivo del ATP, mostrando alta afinidad y selectividad frente a CDK1 (cdc2) y CDK2. Debido a la complejidad de la estructura de dicho compuesto, no se conoce bien su modo de unión a la diana farmacológica. Mediante técnicas de modelización molecular, hemos llevado a cabo un estudio que nos ha permitido proponer un modo de unión de dicho compuesto a su diana farmacológica. El complejo de más baja energía obtenido por este procedimiento fue posteriormente sometido a una simulación de dinámica molecular en presencia explícita del disolvente en torno al sitio de unión del ligando. El análisis de dicha simulación indica la formación de un complejo estable, que proponemos como posible modo de unión, y que ha servido como base para el diseño racional de otros ligandos que han sido sintetizados en nuestro laboratorio (AU)

Cyclin dependent kinases (CDKs) play a central role in the regulation of the cell division cycle, which makes them a promising target for the development of therapeutic agents in cancer. Efforts have been made in the last few years in the search for small molecules that can act as chemical inhibitors of CDKs. These inhibitors block cell cycle progression and display interesting antitumor activities. Butirolactone I, a natural product isolated from Aspergillus terreus, has shown antiproliferative activity against colon and pancreatic carcinoma cell lines; it behaves as an ATP competitive inhibitor, displaying a high affinity and selectivity towards CDK1 (cdc2) and CDK2. Due to the structural complexity of this compound, little is known about its binding mode to the pharmacological target. In this work, computer-based design techniques have been used to study the binding mode of butirolactone I to CDK2. The lowest energy complex predicted by these means was later submitted to molecular dynamics simulations in the presence of solvent around the ligandís binding site. The analysis of this simulation indicates the formation of a stable complex, which we propose as a possible binding mode. This has been used as a starting point for the rational design of other ligands that have been synthesized in our laboratory (AU)

Factores de crecimiento, lesión celular, proteincinasas dependientes de ciclinas y sus inhibidores: su relevancia en la patología molecular del cáncer humano / Growth factors, cell damage, cyclin-dependent kinases and their inhibitors: relevance in molecular pathology of human cancer

No disponible

La regulación del Ciclo Celular: modelos experimentales sencillos que resultan en Premios Nobel / Cell Cycle regulation: easy experimental model resulting in Nobel prizes

No disponible

CDKs y cáncer: nuevas dianas terapéuticas / CDKs y cáncer: nuevas dianas terapéuticas

Las quinasas ciclino-dependientes (CDKs) juegan un papel trascendental en la regulación del ciclo celular y constituyen, por tanto, una de las dianas moleculares de mayor actualidad en el desarrollo de nuevos fármacos con actividad antineoplásica. En el presente trabajo se muestran algunos aspectos del mecanismo de acción de estas enzimas, y se describen los inhibidores químicos de pequeño tamaño molecular que han mostrado, hasta el momento, mayor actividad y selectividad frente a CDKs, y que por lo tanto pueden considerarse como modelos para el diseño de nuevos fármacos (AU)

Nuevos caminos y nuevos fármacos en las demencias de Alzheimer / New ways and new generation of Alzheimer´s disease drugs

Ultimamente se han hecho grandes progresos en el desarrollo de nuevas estrategias y tratamientos en las Demencias de Alzheimer, en las que acaso lo más importante sea la transición del tratamiento sintomático a agentes modificadores de los mecanismos implicados en la patogenia de la enfermedad, de interferir las alteración o malfunción de sus múltiples vías neurobioquímicas, con esta esperanza se están desarrollando nuevos fármacos ya no paliativos de unos sistemas penosos, sino capaces de lentificar o detener la progresión de la enfermedad, lo cual implica el diseño de nuevos modelos clínicos que nos permitan comprobar la utilidad de los nuevos medicamentos (AU)

Patología molecular de los gliomas / Molecular biology of gliomas

No disponible