La régulation négative de la biogenèse des ribosomes : Une nouvelle voie de contrôle du cycle cellulaire par le suppresseur de tumeurs Arf ?

La prolifération cellulaire est intimement liée à la biogenèse des ribosomes dont dépendent les mécanismes fondamentaux de réplication, transcription, traduction. Toutefois, les arguments expérimentaux démontrant un lien direct entre la voie de biogenèse des ribosomes et le contrôle de la prolifération sont rares. Est-ce la prolifération anarchique des cellules qui induit l’activation de la synthèse des ribosomes ou, au contraire, est-ce qu’une synthèse accrue de ribosomes a pour conséquence une perte de contrôle de la prolifération ? Plusieurs suppresseurs de tumeurs sont connus aujourd’hui pour intervenir dans cette voie de biogenèse, le plus récemment décrit étant la protéine Arf qui contrôle négativement le cycle cellulaire par la voie classique Arf-Mdm2-p53. L’étude des fonctions suppresseurs de tumeurs de la protéine Arf, dans un contexte déficient en p53, a permis de montrer qu’elle exerce un contrôle négatif de la voie de biogenèse des ribosomes à deux niveaux. Au niveau transcriptionnel, en se liant directement au promoteur des ARNr, Arf réduit de 50 à 70 % la production du transcrit primaire ARNr 47S. Au niveau post-transcriptionnel, la maturation de cet ARNr 47S en ARNr matures 18S, 28S et 5,8S requiert l’endonucléase NPM/B23, régulée négativement par la protéine Arf. Cette nouvelle voie de contrôle de la prolifération est vraisemblablement mise en jeu lorsque la voie principale Arf-Mdm2-p53 est inopérante, mais rien n’empêche d’imaginer que les deux mécanismes coopèrent pour atteindre une meilleure efficacité du processus de suppression tumorale.The nucleolar Arf protein has initially been shown to regulate cell cycle through the so-called Arf-mdm2-p53 pathway. In addition to this well characterized pathway, convergent data published since 2000 indicate that Arf can inhibit cell proliferation in absence of p53, suggesting the existence of a p53-independent pathway. Several partners have recently been described that could participate in an alternative regulatory process. Recent results show that : (1) Arf binds the rDNA promoter to inhibit the transcription of the 47S rRNA precursor and (2) Arf interacts with the nucleophosmin/B23 protein to negatively regulate rRNA maturation, it is assumed that the tumour suppressor may downregulate the cell cycle progression through the control of ribosome biogenesis, thus resulting in completion of cell cycle arrest

Front Physiol

Glioblastoma is among the most common tumor of the central nervous system in adults. Overall survival has not significantly improved over the last decade, even with optimizing standard therapeutic care including extent of resection and radio- and chemotherapy. In this article, we review features of the brain vasculature found in healthy cerebral tissue and in glioblastoma. Brain vessels are of various sizes and composed of several vascular cell types. Non-vascular cells such as astrocytes or microglia also interact with the vasculature and play important roles. We also discuss engineered artificial blood vessels which may represent useful models for better understanding the tumor-vessel interaction. Finally, we summarize results from clinical trials with anti-angiogenic therapy alone or in combination, and discuss the value of these approaches for targeting glioblastoma

UMA EXPERIÊNCIA EDUCATIVA DE ROBÓTICA EM BAIRROS DE VULNERABILIDADE SOCIAL DE VITÓRIA DA CONQUISTA – BAHIA1

O presente artigo procura descrever a primeira experiência do curso de robótica educacional, planejada para ser desenvolvida com algumas crianças e adolescentes residentes nos bairros das Pedrinhas e do Alto Maron – Vitória da Conquista – BA. O curso é uma ação do projeto de extensão da UESB Alfabetização científica: Uma Perspectiva de Reconstrução Social para a Diversidade Étnicorracial. Esse projeto se propõe tanto a contribuir para a formação de professores na diversidade étnicorracial e étnico-cultural presente nas salas de aulas, quanto possibilitar uma alfabetização científica inclusiva ao se dirigir às crianças e adolescentes pertencentes a escolas localizadas nos bairros de vulnerabilidade social. Nessa perspectiva, procuramos fazer a inserção da física e da robótica nas séries iniciais do ensino fundamental, em um processo de aprendizagem que prima pela construção do conhecimento em concomitância com as (re)construções de identidade e auto-estima. A estratégia metodológica para tal objetivo é fazer uso da robótica educacional e da narrativa poética da ciência

UMA EXPERIÊNCIA EDUCATIVA DE ROBÓTICA EM BAIRROS DE VULNERABILIDADE SOCIAL DE VITÓRIA DA CONQUISTA – BAHIA1

O presente artigo procura descrever a primeira experiência do curso de robótica educacional, planejada para ser desenvolvida com algumas crianças e adolescentes residentes nos bairros das Pedrinhas e do Alto Maron – Vitória da Conquista – BA. O curso é uma ação do projeto de extensão da UESB Alfabetização científica: Uma Perspectiva de Reconstrução Social para a Diversidade Étnicorracial. Esse projeto se propõe tanto a contribuir para a formação de professores na diversidade étnicorracial e étnico-cultural presente nas salas de aulas, quanto possibilitar uma alfabetização científica inclusiva ao se dirigir às crianças e adolescentes pertencentes a escolas localizadas nos bairros de vulnerabilidade social. Nessa perspectiva, procuramos fazer a inserção da física e da robótica nas séries iniciais do ensino fundamental, em um processo de aprendizagem que prima pela construção do conhecimento em concomitância com as (re)construções de identidade e auto-estima. A estratégia metodológica para tal objetivo é fazer uso da robótica educacional e da narrativa poética da ciência

Deciphering the complex role of thrombospondin-1 in glioblastoma development

We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFβ canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process

Overexpression of CD44 accompanies acquired tamoxifen resistance in MCF7 cells and augments their sensitivity to the stromal factors, heregulin and hyaluronan

Background: Acquired resistance to endocrine therapy in breast cancer is a significant problem with relapse being associated with local and/or regional recurrence and frequent distant metastases. Breast cancer cell models reveal that endocrine resistance is accompanied by a gain in aggressive behaviour driven in part through altered growth factor receptor signalling, particularly involving erbB family receptors. Recently we identified that CD44, a transmembrane cell adhesion receptor known to interact with growth factor receptors, is upregulated in tamoxifen-resistant (TamR) MCF7 breast cancer cells. The purpose of this study was to explore the consequences of CD44 upregulation in an MCF7 cell model of acquired tamoxifen resistance, specifically with respect to the hypothesis that CD44 may influence erbB activity to promote an adverse phenotype. Methods: CD44 expression in MCF7 and TamR cells was assessed by RT-PCR, Western blotting and immunocytochemistry. Immunofluorescence and immunoprecipitation studies revealed CD44-erbB associations. TamR cells (± siRNA-mediated CD44 suppression) or MCF7 cells (± transfection with the CD44 gene) were treated with the CD44 ligand, hyaluronon (HA), or heregulin and their in vitro growth (MTT), migration (Boyden chamber and wound healing) and invasion (Matrigel transwell migration) determined. erbB signalling was assessed using Western blotting. The effect of HA on erbB family dimerisation in TamR cells was determined by immunoprecipitation in the presence or absence of CD44 siRNA. Results: TamR cells overexpressed CD44 where it was seen to associate with erbB2 at the cell surface. siRNA-mediated suppression of CD44 in TamR cells significantly attenuated their response to heregulin, inhibiting heregulin-induced cell migration and invasion. Furthermore, TamR cells exhibited enhanced sensitivity to HA, with HA treatment resulting in modulation of erbB dimerisation, ligand-independent activation of erbB2 and EGFR and induction of cell migration. Overexpression of CD44 in MCF7 cells, which lack endogenous CD44, generated an HA-sensitive phenotype, with HA-stimulation promoting erbB/EGFR activation and migration. Conclusions: These data suggest an important role for CD44 in the context of tamoxifen-resistance where it may augment cellular response to erbB ligands and HA, factors that are reported to be present within the tumour microenvironment in vivo. Thus CD44 may present an important determinant of breast cancer progression in the setting of endocrine resistance

La calpaine- 6 identifie et maintient la population de cellules souches des necones osseux en contrôlant les processus d'autophagie et de sénescence.

Cancer stem cells contribute to sarcoma development, but lack of specific markers prevents their characterization and the possibility of targeting. We used the regulatory sequence of calpain-6 in reporter constructions to identify calpain-6–expressing cells. These cells were tumor-initiating cells and behaved like stem cells at the apex of the cellular hierarchy. Calpain-6 expression depended on the stem-cell transcription network that involves Oct4, Nanog, and Sox2 and was activated by hypoxia. Calpain-6 knockdown blocked tumor development and induced depletion of sarcoma stem cells. Calpain-6 was inversely associated with expression of senescence markers but was associated with a dynamic autophagy flux. Calpain-6 knockdown induced cell entry into senescence and suppressed autophagy flux. Our results reveal that calpain-6 identifies sarcoma stem-cell and plays an important role as a regulator of cancer cell fate driving a switch between autophagy and senescence. Calpain-6 may be a promising therapeutic target to eradicate sarcoma stem cells.Les cellules souche cancéreuses contribuent au développement des sarcomes, mais le manque de marqueurs spécifiques empêche leur caractérisation et la possibilité de cibler ce type de cellules. Nous avons utilisé la séquence régulatrice de la calpaïne-6 dans des systèmes rapporteurs pour identifier les cellules exprimant la calpaïne-6. Ces cellules étaient des cellules initiatrices de tumeurs et se comportaient comme des cellules souche, au sommet de la hiérarchie cellulaire. L'expression de la calpaïne-6 dépend d’un programme génique de cellules souche qui implique Oct4, Nanog et Sox2 et est activée par l'hypoxie. L’inhibition de la calpaïne-6 a bloqué le développement tumoral et a induit la diminution du nombre de cellules souche cancéreuses dans les sarcomes osseux. L’expression de la calpaïne-6 était inversement corrélée à l'expression de marqueurs de sénescence mais était associé à un flux autophagique dynamique. L’inhibition de la calpaïne-6 a induit l'entrée des cellules en sénescence et a supprimé le flux autophagique. Nos résultats révèlent que le calpaïne-6 identifie les cellules souche des sarcomes et joue un rôle important dans le maintien des cellules souche cancéreuses en contrôlant les processus d’autophagie et de sénescence. La calpaïne-6 semble être une cible thérapeutique prometteuse pour éradiquer les cellules souche dans les sarcome

Calpain-6 controls the fate of sarcoma stem cells by promoting autophagy and preventing senescence

Les cellules souche cancéreuses contribuent au développement des sarcomes, mais le manque de marqueurs spécifiques empêche leur caractérisation et la possibilité de cibler ce type de cellules. Nous avons utilisé la séquence régulatrice de la calpaïne-6 dans des systèmes rapporteurs pour identifier les cellules exprimant la calpaïne-6. Ces cellules étaient des cellules initiatrices de tumeurs et se comportaient comme des cellules souche, au sommet de la hiérarchie cellulaire. L'expression de la calpaïne-6 dépend d’un programme génique de cellules souche qui implique Oct4, Nanog et Sox2 et est activée par l'hypoxie. L’inhibition de la calpaïne-6 a bloqué le développement tumoral et a induit la diminution du nombre de cellules souche cancéreuses dans les sarcomes osseux. L’expression de la calpaïne-6 était inversement corrélée à l'expression de marqueurs de sénescence mais était associé à un flux autophagique dynamique. L’inhibition de la calpaïne-6 a induit l'entrée des cellules en sénescence et a supprimé le flux autophagique. Nos résultats révèlent que le calpaïne-6 identifie les cellules souche des sarcomes et joue un rôle important dans le maintien des cellules souche cancéreuses en contrôlant les processus d’autophagie et de sénescence. La calpaïne-6 semble être une cible thérapeutique prometteuse pour éradiquer les cellules souche dans les sarcomesCancer stem cells contribute to sarcoma development, but lack of specific markers prevents their characterization and the possibility of targeting. We used the regulatory sequence of calpain-6 in reporter constructions to identify calpain-6–expressing cells. These cells were tumor-initiating cells and behaved like stem cells at the apex of the cellular hierarchy. Calpain-6 expression depended on the stem-cell transcription network that involves Oct4, Nanog, and Sox2 and was activated by hypoxia. Calpain-6 knockdown blocked tumor development and induced depletion of sarcoma stem cells. Calpain-6 was inversely associated with expression of senescence markers but was associated with a dynamic autophagy flux. Calpain-6 knockdown induced cell entry into senescence and suppressed autophagy flux. Our results reveal that calpain-6 identifies sarcoma stem-cell and plays an important role as a regulator of cancer cell fate driving a switch between autophagy and senescence. Calpain-6 may be a promising therapeutic target to eradicate sarcoma stem cells

La régulation négative de la biogenèse des ribosomes

La prolifération cellulaire est intimement liée à la biogenèse des ribosomes dont dépendent les mécanismes fondamentaux de réplication, transcription, traduction. Toutefois, les arguments expérimentaux démontrant un lien direct entre la voie de biogenèse des ribosomes et le contrôle de la prolifération sont rares. Est-ce la prolifération anarchique des cellules qui induit l’activation de la synthèse des ribosomes ou, au contraire, est-ce qu’une synthèse accrue de ribosomes a pour conséquence une perte de contrôle de la prolifération ? Plusieurs suppresseurs de tumeurs sont connus aujourd’hui pour intervenir dans cette voie de biogenèse, le plus récemment décrit étant la protéine Arf qui contrôle négativement le cycle cellulaire par la voie classique Arf-Mdm2-p53. L’étude des fonctions suppresseurs de tumeurs de la protéine Arf, dans un contexte déficient en p53, a permis de montrer qu’elle exerce un contrôle négatif de la voie de biogenèse des ribosomes à deux niveaux. Au niveau transcriptionnel, en se liant directement au promoteur des ARNr, Arf réduit de 50 à 70 % la production du transcrit primaire ARNr 47S. Au niveau post-transcriptionnel, la maturation de cet ARNr 47S en ARNr matures 18S, 28S et 5,8S requiert l’endonucléase NPM/B23, régulée négativement par la protéine Arf. Cette nouvelle voie de contrôle de la prolifération est vraisemblablement mise en jeu lorsque la voie principale Arf- Mdm2-p53 est inopérante, mais rien n’empêche d’imaginer que les deux mécanismes coopèrent pour atteindre une meilleure effica cité du processus de suppression tumorale