Página 1 dos resultados de 2140 itens digitais encontrados em 0.011 segundos

The impact of MAO-A in cellular senescence

Sequeiros, Pedro Emanuel de Magalhães
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Dissertação de Mestrado
Português
Relevância na Pesquisa
48.03967%
Senescência celular é um mecanismo de supressão tumoral e um contribuinte para a perda de função tecidual, a medida que envelhecemos, relacionado assim com o processo a que chamamos envelhecimento. Ele tem sido e caracterizado in vitro, como o resultado de uma resposta a danos no ADN em virtude de telómeros não disfuncionais. Senescência também pode ser induzida por vários outros mecanismos, incluindo a ativação de oncogenes, agentes que alteram a estrutura da cromatina ou danos no DNA, com o stress oxidativo a ser o agente de degradação mais importante. No entanto, estudos recentes revelaram que a senescência é, de facto, um processo complexo, que envolve a ativação sequencial de vários processos celulares, que têm se mostrado necessários para o estabelecimento e manutenção do fenótipo. Um desses múltiplos processos celulares, inclui a geração de espécies reativas de oxigênio (ROS) e seu papel no estabelecimento do fenótipo senescente, no entanto, a complexidade das vias de sinalização envolvidas e suas consequências para a senescência in vitro e in vivo estão longe de serem compreendidos. MAO-A é uma enzima mitocondrial que catalisa a desaminação oxidativa de monoaminas e produz peróxido de hidrogénio...

Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence.

Zwerschke, Werner; Mazurek, Sybille; Stöckl, Petra; Hütter, Eveline; Eigenbrodt, Erich; Jansen-Dürr, Pidder
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/12/2003 Português
Relevância na Pesquisa
48.01412%
Cellular senescence is considered a major tumour-suppressor mechanism in mammals, and many oncogenic insults, such as the activation of the ras proto-oncogene, trigger initiation of the senescence programme. Although it was shown that activation of the senescence programme involves the up-regulation of cell-cycle regulators such as the inhibitors of cyclin-dependent kinases p16INK4A and p21CIP-1, the mechanisms underlying the senescence response remain to be resolved. In the case of stress-induced premature senescence, reactive oxygen species are considered important intermediates contributing to the phenotype. Moreover, distinct alterations of the cellular carbohydrate metabolism are known to contribute to oncogenic transformation, as is best documented for the phenomenon of aerobic glycolysis. These findings suggest that metabolic alterations are involved in tumourigenesis and tumour suppression; however, little is known about the metabolic pathways that contribute to these processes. Using the human fibroblast model of in vitro senescence, we analysed age-dependent changes in the cellular carbohydrate metabolism. Here we show that senescent fibroblasts enter into a metabolic imbalance, associated with a strong reduction in the levels of ribonucleotide triphosphates...

DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis*

Schmitt, Estelle; Paquet, Claudie; Beauchemin, Myriam; Bertrand, Richard
Fonte: Zhejiang University Press Publicador: Zhejiang University Press
Tipo: Artigo de Revista Científica
Publicado em /06/2007 Português
Relevância na Pesquisa
48.047236%
Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities. Cellular senescence is a safeguard program limiting the proliferative competence of cells in living organisms. Apoptosis eliminates unwanted cells by the coordinated activity of gene products that regulate and effect cell death. The intimate link between the cell cycle, cellular senescence, apoptosis regulation, cancer development and tumor responses to cancer treatment has become eminently apparent. Extensive research on tumor suppressor genes, oncogenes, the cell cycle and apoptosis regulatory genes has revealed how the DNA damage-sensing and -signaling pathways, referred to as the DNA-damage response network, are tied to cell proliferation, cell-cycle arrest, cellular senescence and apoptosis. DNA-damage responses are complex, involving “sensor” proteins that sense the damage, and transmit signals to “transducer” proteins, which, in turn, convey the signals to numerous “effector” proteins implicated in specific cellular pathways, including DNA repair mechanisms, cell-cycle checkpoints, cellular senescence and apoptosis. The Bcl-2 family of proteins stands among the most crucial regulators of apoptosis and performs vital functions in deciding whether a cell will live or die after cancer chemotherapy and irradiation. In addition...

Significance of Cellular Senescence in Aging and Cancer

Grimes, Angela; Chandra, Sathees B.C.
Fonte: Korean Cancer Association Publicador: Korean Cancer Association
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
48.099263%
Cellular senescence is a mechanism that induces an irreversible growth arrest in all somatic cells. Senescent cells are metabolically active but lack the capacity to replicate. Evolutionary theories suggest that cellular senescence is related to the organismal decline occurring in aging organisms. Also, such theories describe senescence as an antagonistically pleiotropic process that can have beneficial or detrimental effect on the organism. Cellular senescence is believed to be involved in the cellular changes observed as aging progresses. Accumulation of senescent cells appears to occur widely as the organism ages. Furthermore, senescence is a key element of the tumor suppressor pathways. Therefore, it is part of the natural barrier against the uncontrolled proliferation observed in cellular development of malignancies in multicellular organisms. Activation of the senescence process guarantees a limited number of cellular replications. The genetic network led by p53 is responsible for activation of senescence in response to DNA damage and genomic instability that could lead to cancer. A better comprehension of the genetic networks that control the cell cycle and induce senescence is important to analyze the association of senescence to longevity and diseases related to aging. For these reasons...

p53 isoforms, Δ133p53 and p53β, are endogenous regulators of replicative cellular senescence

Fujita, Kaori; Mondal, Abdul M.; Horikawa, Izumi; Nguyen, Giang H.; Kumamoto, Kensuke; Sohn, Jane J.; Bowman, Elise D.; Mathe, Ewy A.; Schetter, Aaron J.; Pine, Sharon R.; Ji, Helen; Vojtesek, Borivoj; Bourdon, Jean-Christophe; Lane, David P.; Harris, Cur
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
48.02331%
The finite proliferative potential of normal human cells leads to replicative cellular senescence, which is a critical barrier to tumour progression in vivo1–3. We show that human p53 isoforms (Δ133p53 and p53β)4 constitute an endogenous regulatory mechanism for p53-mediated replicative senescence. Induced p53β and diminished Δ133p53 were associated with replicative senescence, but not oncogene-induced senescence, in normal human fibroblasts. The replicatively senescent fibroblasts also expressed increased levels of miR-34a, a p53-induced microRNA5–9, the antisense inhibition of which delayed the onset of replicative senescence. The siRNA-mediated knockdown of endogenous Δ133p53 induced cellular senescence, which was attributed to the regulation of p21WAF1 and other p53 transcriptional target genes. In overexpression experiments, while p53β cooperated with full-length p53 to accelerate cellular senescence, Δ133p53 repressed miR-34a expression and extended cellular replicative lifespan, providing a functional connection of this microRNA to the p53 isoform-mediated regulation of senescence. The senescence-associated signature of p53 isoform expression (i.e., elevated p53β and reduced Δ133p53) was observed in vivo in colon adenomas with senescent phenotypes10...

A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis

Alimonti, Andrea; Nardella, Caterina; Chen, Zhenbang; Clohessy, John G.; Carracedo, Arkaitz; Trotman, Lloyd C.; Cheng, Ke; Varmeh, Shohreh; Kozma, Sara C.; Thomas, George; Rosivatz, Erika; Woscholski, Rudiger; Cognetti, Francesco; Scher, Howard I.; Pandol
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
48.00374%
Irreversible cell growth arrest, a process termed cellular senescence, is emerging as an intrinsic tumor suppressive mechanism. Oncogene-induced senescence is thought to be invariably preceded by hyperproliferation, aberrant replication, and activation of a DNA damage checkpoint response (DDR), rendering therapeutic enhancement of this process unsuitable for cancer treatment. We previously demonstrated in a mouse model of prostate cancer that inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (Pten) elicits a senescence response that opposes tumorigenesis. Here, we show that Pten-loss–induced cellular senescence (PICS) represents a senescence response that is distinct from oncogene-induced senescence and can be targeted for cancer therapy. Using mouse embryonic fibroblasts, we determined that PICS occurs rapidly after Pten inactivation, in the absence of cellular proliferation and DDR. Further, we found that PICS is associated with enhanced p53 translation. Consistent with these data, we showed that in mice p53-stabilizing drugs potentiated PICS and its tumor suppressive potential. Importantly, we demonstrated that pharmacological inhibition of PTEN drives senescence and inhibits tumorigenesis in vivo in a human xenograft model of prostate cancer. Taken together...

YPEL3, a p53-regulated gene that induces cellular senescence

Kelley, Kevin; Miller, Kelly R.; Todd, Amber; Kelley, Amy; Tuttle, Rebecca; Berberich, Steven J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
48.01412%
Cellular senescence, the limited ability of cultured normal cells to divide, can result from cellular damage triggered through oncogene activation (premature senescence) or the loss of telomeres following successive rounds of DNA replication (replicative senescence). While both processes require a functional p53 signaling pathway, relevant downstream p53 targets have been difficult to identify. Discovery of senescence activators is important because induction of tumor cell senescence may represent a therapeutic approach for the treatment of cancer. In microarray studies where p53 was reactivated in MCF7 cells, we discovered that YPEL3 (Yippee-like-3), a member of a recently discovered family of putative zinc finger motif coding genes consisting of YPEL1-5, is a p53-regulated gene. YPEL3 expression induced by DNA damage leads to p53 recruitment to a cis-acting DNA response element located near the human YPEL3 promoter. Physiological induction of YPEL3 results in a substantial decrease in cell viability associated with an increase in cellular senescence. Through the use of RNAi and H-ras induction of cellular senescence, we demonstrate that YPEL3 activates cellular senescence downstream of p53. Consistent with its growth suppressive activity...

Distinct roles for p107 and p130 in Rb-independent cellular senescence

Lehmann, Brian D.; Brooks, Adam M.; Paine, Matthew S.; Chappell, William H.; McCubrey, James A.; Terrian, David M.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
48.03967%
Telomere attrition, DNA damage and constitutive mitogenic signaling can all trigger cellular senescence in normal cells and serve as a defense against tumor progression. Cancer cells may circumvent this cellular defense by acquiring genetic mutations in checkpoint proteins responsible for regulating permanent cell cycle arrest. A small family of tumor suppressor genes encoding the retinoblastoma susceptibility protein family (Rb, p107, p130) exerts a partially redundant control of entry into S phase of DNA replication and cellular proliferation. Here we report that activation of the p53-dependent DNA damage response has been found to accelerate senescence in human prostate cancer cells lacking a functional Rb protein. This novel form of irradiation-induced premature cellular senescence reinforces the notion that other Rb family members may compensate for loss of Rb protein in the DNA damage response pathway. Consistent with this hypothesis, depletion of p107 potently inhibits the irradiation-induced senescence observed in DU145 cells. In contrast, p130 depletion triggers a robust and unexpected form of premature senescence in unirradiated cells. The dominant effect of depleting both p107 and p130, in the absence of Rb, was a complete blockade of irradiation-induced cellular senescence. Onset of the p107-dependent senescence was temporally associated with p53-mediated stabilization of the cyclin-dependent kinase inhibitor p27 and decreases in c-myc and cks1 expression. These results indicate that p107 is required for initiation of accelerated cellular senescence in the absence of Rb and introduces the concept that p130 may be required to prevent the onset of terminal growth arrest in unstimulated prostate cancer cells lacking a functional Rb allele.

A New p53 Target Gene, RKIP, Is Essential for DNA Damage-Induced Cellular Senescence and Suppression of ERK Activation12

Lee, Su-Jin; Lee, Sun-Hye; Yoon, Min-Ho; Park, Bum-Joon
Fonte: Neoplasia Press Inc. Publicador: Neoplasia Press Inc.
Tipo: Artigo de Revista Científica
Publicado em /07/2013 Português
Relevância na Pesquisa
48.083076%
p53, a strong tumor suppressor protein, is known to be involved in cellular senescence, particularly premature cellular senescence. Oncogenic stresses, such as Ras activation, can initiate p53-mediated senescence, whereas activation of the Ras-mitogen-activated protein kinase (MAPK) pathway can promote cell proliferation. These conflicting facts imply that there is a regulatory mechanism for balancing p53 and Ras-MAPK signaling. To address this, we evaluated the effects of p53 on the extracellular signal-regulated kinase (ERK) activation and found that p53 could suppress ERK activation through de novo synthesis. Through several molecular biologic analyses, we found that RKIP, an inhibitor of Raf kinase, is responsible for p53-mediated ERK suppression and senescence. Overexpression of RKIP can induce cellular senescence in several types of cell lines, including p53-deficient cells, whereas the elimination of RKIP by siRNA or forced expression of ERK blocks p53-mediated cellular senescence. These results suggested that RKIP is an essential protein for cellular senescence. Moreover, modification of the p53 serine 46 residue was critical for RKIP induction and ERK suppression as well as cellular senescence. These results indicated that RKIP is a novel p53 target gene that is responsible for p53-mediated cellular senescence and tumor suppressor protein expression.

Another Facet to the Anticancer Response to Lamellarin D: Induction of Cellular Senescence through Inhibition of Topoisomerase I and Intracellular Ros Production

Ballot, Caroline; Martoriati, Alain; Jendoubi, Manel; Buche, Sébastien; Formstecher, Pierre; Mortier, Laurent; Kluza, Jérome; Marchetti, Philippe
Fonte: MDPI Publicador: MDPI
Tipo: Artigo de Revista Científica
Publicado em 27/01/2014 Português
Relevância na Pesquisa
48.00374%
Lamellarin D (LamD) is a marine alkaloid with broad spectrum antitumor activities. Multiple intracellular targets of LamD, which affect cancer cell growth and induce apoptosis, have been identified. These include nuclear topoisomerase I, relevant kinases (such as cyclin-dependent kinase 2) and the mitochondrial electron transport chain. While we have previously demonstrated that LamD at micromolar range deploys strong cytotoxicity by inducing mitochondrial apoptosis, mechanisms of its cytostatic effect have not yet been characterized. Here, we demonstrated that induction of cellular senescence (depicted by cell cycle arrest in G2 associated with β-galactosidase activity) is a common response to subtoxic concentrations of LamD. Cellular senescence is observed in a large panel of cancer cells following in vitro or in vivo exposure to LamD. The onset of cellular senescence is dependent on the presence of intact topoisomerase I since topoisomerase I-mutated cells are resistant to senescence induced by LamD. LamD-induced senescence occurs without important loss of telomere integrity. Instead, incubation with LamD results in the production of intracellular reactive oxygen species (ROS), which are critical for senescence as demonstrated by the inhibitory effect of antioxidants. In addition...

NF-κB in Cellular Senescence and Cancer Treatment

Jing, Hua; Lee, Soyoung
Fonte: Korean Society for Molecular and Cellular Biology Publicador: Korean Society for Molecular and Cellular Biology
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
57.489883%
The NF-κB pathway transcriptionally controls a large set of target genes that play important roles in cell survival, inflammation, and immune responses. While many studies showed anti-tumorigenic and pro-survival role of NF-κB in cancer cells, recent findings postulate that NF-κB participates in a senescence-associated cytokine response, thereby suggesting a tumor restraining role of NF-κB. In this review, we discuss implications of the NF-κB signaling pathway in cancer. Particularly, we emphasize the connection of NF-κB with cellular senescence as a response to chemotherapy, and furthermore, present examples how distinct oncogenic network contexts surrounding NF-κB produce fundamentally different treatment outcomes in aggressive B-cell lymphomas as an example.

Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence

Tran, Duc; Bergholz, Johann; Zhang, Haibo; He, Hanbing; Wang, Yang; Zhang, Yujun; Li, Qintong; Kirkland, James L; Xiao, Zhi-Xiong
Fonte: BlackWell Publishing Ltd Publicador: BlackWell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
48.059663%
Cellular senescence, which is known to halt proliferation of aged and stressed cells, plays a key role against cancer development and is also closely associated with organismal aging. While increased insulin-like growth factor (IGF) signaling induces cell proliferation, survival and cancer progression, disrupted IGF signaling is known to enhance longevity concomitantly with delay in aging processes. The molecular mechanisms involved in the regulation of aging by IGF signaling and whether IGF regulates cellular senescence are still poorly understood. In this study, we demonstrate that IGF-1 exerts a dual function in promoting cell proliferation as well as cellular senescence. While acute IGF-1 exposure promotes cell proliferation and is opposed by p53, prolonged IGF-1 treatment induces premature cellular senescence in a p53-dependent manner. We show that prolonged IGF-1 treatment inhibits SIRT1 deacetylase activity, resulting in increased p53 acetylation as well as p53 stabilization and activation, thus leading to premature cellular senescence. In addition, either expression of SIRT1 or inhibition of p53 prevented IGF-1-induced premature cellular senescence. Together, these findings suggest that p53 acts as a molecular switch in monitoring IGF-1-induced proliferation and premature senescence...

Dynamic Modelling of Pathways to Cellular Senescence Reveals Strategies for Targeted Interventions

Dalle Pezze, Piero; Nelson, Glyn; Otten, Elsje G.; Korolchuk, Viktor I.; Kirkwood, Thomas B. L.; von Zglinicki, Thomas; Shanley, Daryl P.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 28/08/2014 Português
Relevância na Pesquisa
48.11926%
Cellular senescence, a state of irreversible cell cycle arrest, is thought to help protect an organism from cancer, yet also contributes to ageing. The changes which occur in senescence are controlled by networks of multiple signalling and feedback pathways at the cellular level, and the interplay between these is difficult to predict and understand. To unravel the intrinsic challenges of understanding such a highly networked system, we have taken a systems biology approach to cellular senescence. We report a detailed analysis of senescence signalling via DNA damage, insulin-TOR, FoxO3a transcription factors, oxidative stress response, mitochondrial regulation and mitophagy. We show in silico and in vitro that inhibition of reactive oxygen species can prevent loss of mitochondrial membrane potential, whilst inhibition of mTOR shows a partial rescue of mitochondrial mass changes during establishment of senescence. Dual inhibition of ROS and mTOR in vitro confirmed computational model predictions that it was possible to further reduce senescence-induced mitochondrial dysfunction and DNA double-strand breaks. However, these interventions were unable to abrogate the senescence-induced mitochondrial dysfunction completely, and we identified decreased mitochondrial fission as the potential driving force for increased mitochondrial mass via prevention of mitophagy. Dynamic sensitivity analysis of the model showed the network stabilised at a new late state of cellular senescence. This was characterised by poor network sensitivity...

Deleted in Breast Cancer 1 regulates cellular senescence during obesity

Escande, Carlos; Nin, Veronica; Pirtskhalava, Tamar; Chini, Claudia C; Thereza Barbosa, Maria; Mathison, Angela; Urrutia, Raul; Tchkonia, Tamar; Kirkland, James L; Chini, Eduardo N
Fonte: BlackWell Publishing Ltd Publicador: BlackWell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
48.075737%
Chronic obesity leads to inflammation, tissue dysfunction, and cellular senescence. It was proposed that cellular senescence during obesity and aging drives inflammation and dysfunction. Consistent with this, clearance of senescent cells increases healthspan in progeroid mice. Here, we show that the protein Deleted in Breast Cancer-1 (DBC1) regulates cellular senescence during obesity. Deletion of DBC1 protects preadipocytes against cellular senescence and senescence-driven inflammation. Furthermore, we show protection against cellular senescence in DBC1 KO mice during obesity. Finally, we found that DBC1 participates in the onset of cellular senescence in response to cell damage by mechanism that involves binding and inhibition of HDAC3. We propose that by regulating HDAC3 activity during cellular damage, DBC1 participates in the fate decision that leads to the establishment of cellular senescence and consequently to inflammation and tissue dysfunction during obesity.

Stable Cellular Senescence Is Associated with Persistent DDR Activation

Fumagalli, Marzia; Rossiello, Francesca; Mondello, Chiara; d’Adda di Fagagna, Fabrizio
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 23/10/2014 Português
Relevância na Pesquisa
48.03967%
The DNA damage response (DDR) is activated upon DNA damage generation to promote DNA repair and inhibit cell cycle progression in the presence of a lesion. Cellular senescence is a permanent cell cycle arrest characterized by persistent DDR activation. However, some reports suggest that DDR activation is a feature only of early cellular senescence that is then lost with time. This challenges the hypothesis that cellular senescence is caused by persistent DDR activation. To address this issue, we studied DDR activation dynamics in senescent cells. Here we show that normal human fibroblasts retain DDR markers months after replicative senescence establishment. Consistently, human fibroblasts from healthy aged donors display markers of DDR activation even three years in culture after entry into replicative cellular senescence. However, by extending our analyses to different human cell strains, we also observed an apparent DDR loss with time following entry into cellular senescence. This though correlates with the inability of these cell strains to survive in culture upon replicative or irradiation-induced cellular senescence. We propose a model to reconcile these results. Cell strains not suffering the prolonged in vitro culture stress retain robust DDR activation that persists for years...

Translation-Dependent Mechanisms Lead to PML Upregulation and Mediate Oncogenic K-RAS-Induced Cellular Senescence

Scaglioni, Pier Paolo; Rabellino, Andrea; Bernardi, Rosa; Choi, Sooyeon; Konstantinidou, Georgia; Nardella, Caterina; Cheng, Ke; Pandolfi, Pier Paolo; Yung, Thomas M.
Fonte: Wiley Publicador: Wiley
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
67.489883%
Expression of oncogenic K-RAS in primary cells elicits oncogene-induced cellular senescence (OIS), a form of growth arrest that potently opposes tumourigenesis. This effect has been largely attributed to transcriptional mechanisms that depend on the p53 tumour suppressor protein. The PML tumour suppressor was initially identified as a component of the (PML-RARalpha) oncoprotein of acute promyelocytic leukaemia (APL). PML, a critical OIS mediator, is upregulated by oncogenic K-RAS in vivo and in vitro. We demonstrate here that oncogenic K-RAS induces PML protein upregulation by activating the RAS/MEK1/mTOR/eIF4E pathway even in the absence of p53. Under these circumstances, PML mRNA is selectively associated to polysomes. Importantly, we find that the PML 5′ untranslated mRNA region plays a key role in mediating PML protein upregulation and that its presence is essential for an efficient OIS response. These findings demonstrate that upregulation of PML translation plays a central role in oncogenic K-RAS-induced OIS. Thus, selective translation initiation plays a critical role in tumour suppression with important therapeutic implications for the treatment of solid tumours and APL.

Fonctions antitumorales de la voie ERK/MAPK et développement rationnel de nouvelles stratégies thérapeutiques

Deschênes-Simard, Xavier
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
Português
Relevância na Pesquisa
48.03753%
Les kinases régulées par les signaux extracellulaires (ERK1/2) régulent une multitude de processus cellulaires, incluant la prolifération, la survie et la différenciation. Ces kinases représentent l’élément terminal de la voie ERK/MAPK, laquelle est activée dans près de 30% de tous les cancers humains et donc généralement perçue comme étant un effecteur critique de la progression tumorale. Cependant, une accumulation d’observations suggèrent que les kinases ERK pourraient également induire la suppression tumorale. Le but premier de cette thèse est de démontrer comment la signalisation par ERK peut contribuer à la suppression tumorale et de concilier les mécanismes impliqués avec son rôle dans la progression du cancer. Puisque nos travaux ont une incidence sur les bénéfices attendus de certaines thérapies actuellement en développement, le deuxième objectif de la thèse est de proposer de nouvelles stratégies thérapeutiques pour combattre le cancer. Nous avons démontré qu’une hyperactivation des kinases ERK induit la sénescence cellulaire. Le mécanisme implique la dégradation sélective et dépendante du protéasome de nombreuses protéines, ce que nous avons nommé le SAPD (Senescence-Associated Protein Degradation). Ce processus cible des protéines requises pour différentes fonctions cellulaires...

Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor suppressor activities

Kagawa, Shingo; Natsuizaka, Mitsuteru; Whelan, Kelly A.; Facompre, Nicole; Naganuma, Seiji; Ohashi, Shinya; Kinugasa, Hideaki; Egloff, Ann Marie; Basu, Devraj; Gimotty, Phyllis A.; Klein-Szanto, Andres J; Bass, Adam; Wong, Kwok-Kin; Diehl, J. Alan; Rustgi
Fonte: Harvard University Publicador: Harvard University
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
58.07371%
Notch activity regulates tumor biology in a context-dependent and complex manner. Notch may act as an oncogene or a tumor suppressor gene even within the same tumor type. Recently, Notch signaling has been implicated in cellular senescence. Yet, it remains unclear as to how cellular senescence checkpoint functions may interact with Notch-mediated oncogenic and tumor suppressor activities. Herein, we used genetically engineered human esophageal keratinocytes and esophageal squamous cell carcinoma cells to delineate the functional consequences of Notch activation and inhibition along with pharmacological intervention and RNA interference (RNAi) experiments. When expressed in a tetracycline-inducible manner, the ectopically expressed activated form of Notch1 (ICN1) displayed oncogene-like characteristics inducing cellular senescence corroborated by the induction of G0/G1 cell-cycle arrest, Rb dephosphorylation, flat and enlarged cell morphology and senescence-associated β-galactosidase activity. Notch-induced senescence involves canonical CSL/RBPJ-dependent transcriptional activity and the p16INK4A-Rb pathway. Loss of p16INK4A or the presence of human papilloma virus (HPV) E6/E7 oncogene products not only prevented ICN1 from inducing senescence...

Participación de p19INK4d en la inducción de senescencia genotóxica y replicativa; Role of p19INK4d in the induction of genotoxic-induced and replicative senescence

Sonzogni, Silvina Verónica
Fonte: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires Publicador: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires
Tipo: info:eu-repo/semantics/doctoralThesis; tesis doctoral; info:eu-repo/semantics/publishedVersion Formato: application/pdf
Publicado em //2012 Português
Relevância na Pesquisa
48.14638%
A lo largo de la evolución, los organismos con tejidos renovables han desarrollado mecanismos para prevenir la tumorigénesis. Entre ellos, podemos mencionar a la senescencia celular y a la apoptosis. La senescencia se caracteriza por el arresto permanente del ciclo celular en respuesta a insultos tanto endógenos como exógenos. En los últimos años se han estudiando las moléculas involucradas en la activación de este mecanismo, destacándose la participación de los inhibidores de quinasas dependientes de ciclinas (CKIs) p21Cip1, p16INK4a y p15INK4b. En nuestro laboratorio se ha demostrado que la proteína p19INK4d (p19), un miembro de la familia INK4 de CKIs, se induce significativamente en respuesta a diversos genotóxicos aumentando la eficiencia de la reparación del ADN. El daño al ADN es un agente causal común de la respuesta senescente, independientemente del estímulo que le da origen. Los efectos provocados por diferentes inductores, tales como las especies reactivas de oxigeno (considerablemente aumentadas a lo largo del envejecimiento), los agentes genotóxicos (frecuentemente empleados en quimioterapia) o la activación de oncogenes, culminan dañando al ADN y activando en consecuencia mecanismos de arresto del ciclo celular. El arresto es dependiente de factores que controlan la progresión del ciclo tales como p53 y pRb-p16. Si bien estos son lo principales efectores moleculares involucrados en la iniciación y mantenimiento del estado de senescencia...

CDK2 and CKI targeting can significantly lower the cellular senescence bar - reveals a mathematical model of G1/S checkpoint pathway

Hong Ling; Sandhya Samarasinghe; Don Kulasiri
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
Relevância na Pesquisa
48.011167%
Cellular senescence, a mechanism employed by cells for thwarting proliferation, has shown to play an important role in protecting cells against cancer development in recent experimental observations, indicating that a deeper understanding of the cellular senescence pathway can help exploit its capacity for more effective cancer treatment. Furthermore, some experimental evidence points out that inhibition of CDK2 or Skp2 can be the critical trigger for cellular senescence. However, no mathematical model has been developed to highlight cellular senescence until now. In this study, we first implement a mathematical model of G1/S transition involving the DNA-damage pathway to highlight cellular senescence by lowering the critical trigger- CDK2. For this, we focus on the behaviour of two important proteins (E2F and CycE) for several reduced CDK2 levels under two DNA-damage conditions by calculating the probability (β) of DNA-damaged cells passing the G1/S. Our recently published results from the same model indicated that a large percentage of damaged cells pass G1/S under normal CDK2 levels, reaching β values of up to 65% under high level of DNA damage. The current study reveals that reduced CDK2 levels can significantly lower the percentage of damaged cells passing the G1/S; in particular...