176 research outputs found
Treating Transcriptional Addiction in Small Cell Lung Cancer
Small cell lung cancer (SCLC) is a devastating tumor type with great therapeutic need. In this issue of Cancer Cell, Christensen and colleagues identify THZ1, a CDK7 inhibitor, as a potential therapy for SCLC. Using cells and mouse models, the authors show exquisite sensitivity of SCLC to transcriptional inhibition
Immunosenescence and Senescence Immunosurveillance: One of the Possible Links Explaining the Cancer Incidence in Ageing Population
Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence
Regulation of ploidy and senescence by the AMPK-related kinase NUAK1.
Senescence is an irreversible cell-cycle arrest that is elicited by a wide range of factors, including replicative exhaustion. Emerging evidences suggest that cellular senescence contributes to ageing and acts as a tumour suppressor mechanism. To identify novel genes regulating senescence, we performed a loss-of-function screen on normal human diploid fibroblasts. We show that downregulation of the AMPK-related protein kinase 5 (ARK5 or NUAK1) results in extension of the cellular replicative lifespan. Interestingly, the levels of NUAK1 are upregulated during senescence whereas its ectopic expression triggers a premature senescence. Cells that constitutively express NUAK1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator LATS1, whereas depletion of NUAK1 with shRNA exerts opposite effects. Interestingly, a dominant-negative form of LATS1 phenocopies NUAK1 effects. Moreover, we show that NUAK1 phosphorylates LATS1 at S464 and this has a role in controlling its stability. In summary, our work highlights a novel role for NUAK1 in the control of cellular senescence and cellular ploidy.We thank the members of the Laboratory for helpful discussions. We also thank Virginie Glippa and Julie Bertout for technical assistance. We thank H Esumi for the NUAK1 cDNA, E Hara and H Saya for the LATS1âencoding vector. This work was carried out with the support of the âAssociation pour la Recherche sur le Cancerâ, the âFondation pour la Recherche MĂ©dicale Nord Pas de Calaisâ, the âComitĂ© du Pas de Calais de la Ligue Nationale contre le Cancerâ, the RTRS Fondation Synergie Lyon Cancer, and the Medical Research Council, UK.S
Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth
Loss of secreted phospholipase A2 receptor (PLA2R1) has recently been found to render human primary cells more resistant to senescence whereas increased PLA2R1 expression is able to induce cell cycle arrest, cancer cell death or blockage of cancer cell transformation in vitro, suggesting that PLA2R1 displays tumor suppressive activities. Here we report that PLA2R1 expression strongly decreases in samples of human renal cell carcinoma (RCC). Knockdown of PLA2R1 increases renal cancer cell tumorigenicity supporting a role of PLA2R1 loss to promote in vivo RCC growth. Most RCC result from Von Hippel-Lindau (VHL) tumor suppressor loss-of-function and subsequent gain-of-function of the oncogenic HIF-2alpha/c-MYC pathway. Here, by genetically manipulating VHL, HIF-2alpha and c-MYC, we demonstrate that loss of VHL, stabilization of HIF-2alpha and subsequent increased c-MYC activity, binding and transcriptional repression, through induction of PLA2R1 DNA methylation closed to PLA2R1 transcriptional start site, results in decreased PLA2R1 transcription. Our results describe for the first time an oncogenic pathway leading to PLA2R1 transcriptional repression and the importance of this repression for tumor growth
Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone
BMP7 released by bone marrow stromal cells induces reversible senescence of prostate cancer stem-like cells, and BMPR2 expression inversely correlates with bone metastasis and recurrence in prostate cancer patients
Modulation au niveau musculaire des effets de l'insuline pour l'exercice ou l'immobilisation
SIGLECNRS T 58014 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc
Le récepteur aux phospholipases A2 (PLA2R1) est un nouveau régulateur inattendu de la sénescence cellulaire et un gÚne suppresseur de tumeurs
ActivĂ©e dans les stades prĂ©coces du dĂ©veloppement tumoral, la sĂ©nescence empĂȘche la progression tumorale en induisant un arrĂȘt de prolifĂ©ration cellulaire. Ainsi, tout comme lâapoptose, ce mĂ©canisme doit ĂȘtre altĂ©rĂ© pour quâune cellule devienne tumorale. MalgrĂ© ce rĂŽle crucial de protection contre la progression tumorale, nous connaissons peu les mĂ©canismes molĂ©culaires qui rĂ©gulent lâĂ©chappement Ă la sĂ©nescence. A lâaide dâune banque de shRNA ciblant 8000 gĂšnes, nous avons rĂ©alisĂ© un criblage gĂ©nĂ©tique dans le but dâisoler de nouveaux rĂ©gulateurs, qui lors quâils sont inhibĂ©s, favorisent un Ă©chappement Ă la sĂ©nescence. Ce criblage nous a ainsi permis dâisoler PLA2R1 comme un nouveau rĂ©gulateur de la sĂ©nescence. Nous avons montrĂ© que ce gĂšne rĂ©gulait la sĂ©nescence par lâactivation du gĂšne suppresseur de tumeurs p53. Un deuxiĂšme travail nous a ensuite permis dâidentifier PLA2R1 comme un nouveau gĂšne suppresseur de tumeurs. Dans un futur proche PLA2R1 pourra, peut-ĂȘtre, ĂȘtre utilisĂ© comme bio-marqueur. De plus nous avons rĂ©cemment dĂ©montrĂ© que cette protĂ©ine pourrait avoir un potentiel Ă visĂ©e thĂ©rapeutique Ă©tant donnĂ© son potentiel dâaction sur les cellules tumorales. Lâensemble de ces travaux nous ont donc permis dâisoler PLA2R1 comme un nouveau rĂ©gulateur de la sĂ©nescence et gĂšne suppresseur de tumeurs.Activated in early stages of tumorigenesis, senescence, by blocking proliferation, inhibits tumour growth. Therefore, just like other fails safe mechanisms such as apoptosis, its escape is a property that cancer cell acquire. Although senescence plays a crucial role in tumour suppression and blockade, there is still much to learn about the mechanisms regulating this phenomenon. Using a shRNA library targeting 8000 human genes, we performed a loss of function genetic screen in order to identify genes that when down-regulated, would allow a senescence escape. Using this strategy, we were able to identify PLA2R1 as a novel regulator of cellular senescence by modulating the activation of the p53 tumour suppressor gene. In a second work, we demonstrated that PLA2R1 is a candidate tumour suppressor gene. In the future, PLA2R1 might be used as a biomarker. Finally, we have demonstrated that PLA2R1 could have therapeutic potential as it induces apoptosis in a myriad of cancer cell lines. Altogether, the work performed during my thesis as enabled us to identify PLA2R1 as a novel cellular senescence regulator and a putative new tumour suppressor gene with therapeutic potential
Tissus durs et ùge individuel des vertébrés
Chez la grenouille rousse (#Rana temporaria$ L.), la squelettochronologie appliquĂ©e sur les phalanges est une mĂ©thode efficace de dĂ©termination de l'Ăąge individuel. Cette mĂ©thode permet d'Ă©tablir certains paramĂštres dĂ©mographiques (longĂ©vitĂ©, survie) lorsque d'autres mĂ©thodes sont rendues inefficaces Ă cause d'effectifs elevĂ©s. Les problĂšmes d'interprĂ©tation des coupes histologiques sont rares. Leur lecture apporte des informations non seulement sur la structure d'Ăąge, mais aussi sur la croissance et la maturation. L'estimation de ce dernier paramĂštre est problĂ©matique chez certains individus Ă la seule lecture de leurs squelettogrammes. En effet, le rapprochement des Lignes d'ArrĂȘt de Croissance (LAC) ne signifie sans doute pas toujours que la maturitĂ© sexuelle a Ă©tĂ© atteinte l'annĂ©e prĂ©cĂ©dente. (RĂ©sumĂ© d'auteur
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