Contribution à l'étude du rôle et de la régulation de Fra-1 dans le cancer

Fra-1 appartient à la famille des facteurs de transcription AP-1. Son expression est particulièrement élevée dans les cellules de cancer du sein qui n'expriment pas le récepteur aux œstrogènes (RE-), c'est-à-dire les cellules les plus agressives. L'inhibition de Fra-1 dans ces cellules entraîne une diminution de la motilité, de l'invasion et de la prolifération, mais elle entraîne aussi de profonds changements de morphologie. Les cellules RE-, qui présentent un phénotype mésenchymateux s'arrondissent et établissent un plus grand nombre de contacts cellule-cellule après l'inhibition de Fra-1. Dans les cellules RE-, la b-caténine est localisée au noyau ou dans le cytoplasme, ce qui est un marqueur de mauvais pronostic. Au cours de cette thèse, j'ai montré que Fra-1 régule la localisation nucléaire de la b-caténine et ainsi régule son activité transcriptionelle en agissant très tardivement sur la voie Wnt. J'ai également mis en évidence une interaction physique directe entre Fra-1 et la b-caténine qui pourrait être responsable de cet effet. De plus, l'analyse de microarrays par RT-QPCR a révélé la régulation d'autres gènes comme la mœsine, la fibronectine et l'extracellular matrix protein 1, qui pourraient également jouer un rôle dans la régulation de l'agressivité tumorale par Fra-1. Par ailleurs, Fra-1 est une protéine instable et nous avons montré qu'elle est phosphorylée et stabilisée par PKC . Fra-1 est d'ailleurs nécessaire à l'effet de la kinase sur la motilité cellulaire.Fra-1 is a member of the AP-1 transcription factor family. It is aberrantly expressed in breast cancer cells lacking Estrogen Receptor (ER-) expression, which are the most aggressive ones. Fra-1 inhibition in these cells leads to a decreased in motility, invasion and proliferation, but also to deep morphologic changes. ER- cells, which present a mesenchymal phenotype, become rounder and establish a greater number of cell-cell contacts after Fra-1 inhibition. In ER- cells, b-catenin is nuclear or cytoplasmic, which is considering as a poor prognosis marker. During this PhD, I demonstrate that Fra-1, which acts very downstream in the Wnt/b-catenin signaling pathway, regulates the nuclear localization of b-catenin leading to up-regulation transcriptional activity of b-catenin. I also found that Fra-1 directly interacts with b-catenin. In addition, RT-QPCR microarrays analysis has revealed the regulation of other genes such as mœsin, fibronectin and extracellular matrix protein 1, which might also take part in the tumoral aggressiveness regulated by Fra-1. Moreover, we show that Fra-1, which is an unstable protein, is phosphorylated and stabilized by PKC . Furthermore, Fra-1 is necessary to mediate the kinase effect on cell motility.MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Mécanisme de l'interférence transcriptionnelle entre le récepteur des oestrogènes et les facteurs AP-1

MONTPELLIER-BU Médecine (341722104) / SudocMONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Fra-1 et cancer du sein (analyse de son rôle dans le contrôle de la progression tumorale et mécanismes responsables de sa surexpression dans les cancers du sein les plus invasifs)

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUP (751062107) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Facteurs AP-1 et cancer du sein (interférence transcriptionnelle avec le récepteur a des oestrogènes et contrôle de l'agressivité tumorale)

MONTPELLIER-BU Médecine UPM (341722108) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

PTPN13/PTPL1: an important regulator of tumor aggressiveness.

International audienceProtein tyrosine phosphorylation plays a major role in many cellular functions implicated in cancer development and progression, but only a few of the known protein tyrosine phosphatases have yet been clearly classified as oncogenes or tumor suppressors. PTPL1 interacts with tumor-associated proteins, suggesting a link between PTPL1, the PTPN13 gene product, and tumorigenesis or cancer progression. However, the impact of PTPL1 on cancer is divided between its capacity to counteract the activity of oncogenic tyrosine kinases and its inhibitory interaction with the death receptor, Fas. In this manuscript, we review the PTPL1-interacting proteins implicated in cancer. In addition, we examine the phenotypic arguments concerning both the PTPL1/Fas interaction and the ability of PTPL1 to inhibit signaling from growth factor receptors or oncogenes with tyrosine kinase activity. Finally, we compare the alterations in expression and the genetic and epigenetic arguments supporting an oncogenic or an anti-oncogenic impact of PTPL1

Ubiquitin-Independent Proteasomal Degradation of Fra-1 Is Antagonized by Erk1/2 Pathway-Mediated Phosphorylation of a Unique C-Terminal Destabilizer▿

Fra-1, a transcription factor that is phylogenetically and functionally related to the proto-oncoprotein c-Fos, controls many essential cell functions. It is expressed in many cell types, albeit with differing kinetics and abundances. In cells reentering the cell cycle, Fra-1 expression is transiently stimulated albeit later than that of c-Fos and for a longer time. Moreover, Fra-1 overexpression is found in cancer cells displaying high Erk1/2 activity and has been linked to tumorigenesis. One crucial point of regulation of Fra-1 levels is controlled protein degradation, the mechanism of which remains poorly characterized. Here, we have combined genetic, pharmacological, and signaling studies to investigate this process in nontransformed cells and to elucidate how it is altered in cancer cells. We report that the intrinsic instability of Fra-1 depends on a single destabilizer contained within the C-terminal 30 to 40 amino acids. Two serines therein, S252 and S265, are phosphorylated by kinases of the Erk1/2 pathway, which compromises protein destruction upon both normal physiological induction and tumorigenic constitutive activation of this cascade. Our data also indicate that Fra-1, like c-Fos, belongs to a small group of proteins that may, under certain circumstances, undergo ubiquitin-independent degradation by the proteasome. Our work reveals both similitudes and differences between Fra-1 and c-Fos degradation mechanisms. In particular, the presence of a single destabilizer within Fra-1, instead of two that are differentially regulated in c-Fos, explains the much faster turnover of the latter when cells traverse the G0/G1-to-S-phase transition. Finally, our study offers further insights into the signaling-regulated expression of the other Fos family proteins