Cel The binding of TGF-b to its receptors induces phosphorylation of Smad2 and Smad3, their subsequent association to Smad4 and their nuclear translocation. In the nucleus, the Smad3/Smad4 and Smad2/Smad4 heterodimers act as transcription factors and induce specific target genes. TGF-b pathway has a tumor suppressor function characterized by its ability to inhibit cell growth. Many cancer cell lines have acquired resistance to the antiproliferative effect of TGF-b. This is mainly achieved through loss of function mutations or deletions that affect TGF-b receptors or Smad4, particularly in colon cancer and pancreatic cancer. During my Postdoctoral training in Caroline Hill’s laboratory, I have shown that the E3 Ub-ligase Arkadia is involved in the degradation of the transcriptional repressor SnoN and is therefore absolutely required for the activation of Smad3/Smad4 target genes such as PAI-1. The laboratory of Azeddine Atfi has recently performed a two-hybrid screen using another repressor of the pathway, TGIF, as a bait. This study has led to the identification of a new partner of TGIF, TIP11 (TGIF interacting protein 11), which is a new potential E3 Ub-ligase. Preliminary results indicate that TIP11 also contributes to TGF-b responses. Recently, we both have independently identified that Arkadia and TIP11 can be altered in tumor cell lines. Our study aimed to determine whether these two E3 Ub-ligases, essential for the TGF-b pathway, are novel tumor suppressor genes. Our objectives are: (1) to identify Alterations of Arkadia and TIP11 in human carcinoma cell lines and tumor samples. (2) to study the function of Arkadia and TIP11 by reintroducing Arkadia or TIP11 in deficient cell lines, in order to better understand their role in TGF-b signaling and tumorigenesis. (3) to unravel the mechanism of action of these two E3 Ub-ligases by a biochemistry approach. (4) to identify novel binding partners of Arkadia and TIP11 by performing a two-hybrid screen. Dziedzina nauki natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesclinical medicineoncologycolorectal cancernatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologypancreatic cancer Słowa kluczowe Cell biology Genomics Human biology Molecular biology Oncology Program(-y) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Temat(-y) PEOPLE-2007-2-2.ERG - Marie Curie Action: "European Reintegration Grants" Zaproszenie do składania wniosków FP7-PEOPLE-2007-2-2-ERG Zobacz inne projekty w ramach tego zaproszenia System finansowania MC-ERG - European Re-integration Grants (ERG) Koordynator INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE Wkład UE € 45 000,00 Adres RUE DE TOLBIAC 101 75654 Paris Francja Zobacz na mapie Region Ile-de-France Ile-de-France Paris Rodzaj działalności Research Organisations Kontakt administracyjny Eric Blanqui (Mr.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych
