CDC42EP5/BORG3 modulates SEPT9 to promote actomyosin function, migration, and invasion.

Fast amoeboid migration is critical for developmental processes and can be hijacked by cancer cells to enhance metastatic dissemination. This migratory behavior is tightly controlled by high levels of actomyosin contractility, but how it is coupled to other cytoskeletal components is poorly understood. Septins are increasingly recognized as novel cytoskeletal components, but details on their regulation and contribution to migration are lacking. Here, we show that the septin regulator Cdc42EP5 is consistently required for amoeboid melanoma cells to invade and migrate into collagen-rich matrices and locally invade and disseminate in vivo. Cdc42EP5 associates with actin structures, leading to increased actomyosin contractility and amoeboid migration. Cdc42EP5 affects these functions through SEPT9-dependent F-actin cross-linking, which enables the generation of F-actin bundles required for the sustained stabilization of highly contractile actomyosin structures. This study provides evidence that Cdc42EP5 is a regulator of cancer cell motility that coordinates actin and septin networks and describes a unique role for SEPT9 in melanoma invasion and metastasis

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

The GATA Transcription Factor Gaf1 Represses tRNAs, Inhibits Growth, and Extends Chronological Lifespan Downstream of Fission Yeast TORC1

Target of Rapamycin Complex 1 (TORC1) signaling promotes growth and aging. Inhibition of TORC1 leads to reduced protein translation, which promotes longevity. TORC1-dependent post-transcriptional regulation of protein translation has been well studied, while analogous transcriptional regulation is less understood. Here we screen fission yeast mutants for resistance to Torin1, which inhibits TORC1 and cell growth. Cells lacking the GATA factor Gaf1 (gaf1Δ) grow normally even in high doses of Torin1. The gaf1Δ mutation shortens the chronological lifespan of non-dividing cells and diminishes Torin1-mediated longevity. Expression profiling and genome-wide binding experiments show that upon TORC1 inhibition, Gaf1 directly upregulates genes for small-molecule metabolic pathways and indirectly represses genes for protein translation. Surprisingly, Gaf1 binds to and downregulates the tRNA genes, so it also functions as a transcription factor for RNA polymerase III. Thus, Gaf1 controls the transcription of both protein-coding and tRNA genes to inhibit translation and growth downstream of TORC1

The GATA transcription factor Gaf1 represses tRNA genes, inhibits growth, and extends chronological lifespan downstream of fission yeast TORC1

Target of Rapamycin Complex 1 (TORC1) signaling promotes growth and ageing. Inhibition of TORC1 leads to a down-regulation of factors that stimulate protein translation, including RNA polymerase III, which in turn contributes to longevity. TORC1-mediated post-transcriptional regulation of protein translation has been well studied, while analogous transcriptional regulation is less well understood. Here we screened fission yeast deletion mutants for resistance to Torin1, which inhibits TORC1 and cell growth. Mutants lacking the GATA transcription factor Gaf1 (gaf1Δ) grew normally even in high doses of Torin1. The gaf1Δ mutants shortened the chronological lifespan of non-dividing cells and diminished the lifespan extension triggered by Torin1 treatment. Expression profiling and genome-wide binding experiments showed that, after TORC1 inhibition, Gaf1 directly up-regulated genes for small-molecule metabolic pathways and indirectly repressed genes for protein translation. Surprisingly, Gaf1 bound to, and down-regulated the tRNA genes, so also functions as a transcription factor for genes transcribed by RNA polymerase III. We conclude that Gaf1 controls the transcription of both coding and tRNA genes to inhibit translation and growth downstream of TORC1

Rôle des microtubules et de la kinésine-1 dans l'autophagie de survie

Dans cette étude, nous montrons que les autophagosomes matures peuvent se déplacer le long des microtubules stables et que la formation des autophagosomes requiert les microtubules dynamiques. Dans des conditions de carence nutritionnelle, les microtubules dynamiques recrutent spécifiquement les marqueurs de la formation des autophagosomes. De plus dans ces conditions, la tubuline est hyperacétylée, ce qui permet le recrutement sur le microtubule de la kinésine-1 et de JIP-1. Ce recrutement permet l'activation de JNK qui provoque la libération de Bécline 1 et de l'initiation de la formation de l'autophagosome. Finalement, la kinésine-1 participe à la formation des autophagosomes en carence nutritionnelle tandis qu'en conditions basales, elle participe uniquement à leur mobilité. Nos résultats montrent que la dynamique microtubulaire et les modifications post-traductionnelles de la tubuline jouent un rôle majeur dans la régulation de l'autophagie.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Cancer-related functions and subcellular localizations of septins

Since the initial discovery of septin family GTPases, the understanding of their molecular organization and cellular roles keeps being refined. Septins have been involved in many physiological processes and the misregulation of specific septin gene expression has been implicated in diverse human pathologies, including neurological disorders and cancer. In this minireview, we focus on the importance of the subunit composition and subcellular localization of septins relevant to tumor initiation, progression and metastasis. We especially underline the importance of septin polymer composition and of their association with the plasma membrane, actin or microtubules in cell functions involved in cancer and in resistance to cancer therapies. Through their scaffolding role, their function in membrane compartmentalization or through their protective function against protein degradation, septins also emerge as critical organizers of membrane-associated proteins and of signaling pathways implicated in cancer-associated angiogenesis, apoptosis, polarity, migration, proliferation and in metastasis. Also, the question as to which of the free monomers, hetero-oligomers or filaments is the functional form of mammalian septins is raised and the control over their spatial and temporal localization is discussed. The increasing amount of crosstalks identified between septins and cellular signaling mediators reinforces the exciting possibility that septins could be new targets in anti-cancer therapies or in therapeutic strategies to limit drug resistance

Compartimentation et plasticité du réseau microtubulaire

La structuration du cytoplasme repose en grande partie sur le cytosquelette au sein duquel le réseau de microtubules joue de multiples rôles, notamment dans le trafic intracellulaire et la signalisation. Certaines fonctions cellulaires nécessitent des microtubules hautement dynamiques, alors que d’autres utilisent des microtubules stables où la tubuline peut être fortement modifiée. Des données récentes sur les mécanismes de contrôle de la dynamique des microtubules et de leurs modifications post-traductionnelles, notamment de l’acétylation de la tubuline, révèlent la grande plasticité des microtubules et mettent en lumière l’importance de leur compartimentation structurale et fonctionnelle

Rôle de la glutamate déshydrogénase dans la régulation de l'autophagie par la leucine

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF