Candidates send the completed application form with all the requested documents by February 20, 2015 to the PhD project supervisor.
2015 PhD Studentship in Cancer and Reticulum Endoplasmic stress at University of Bordeaux
Project Title: the Cancer Relevant AGR2 Interactome: dynamics and functions in cholangiocarcinoma and lung cancers.
Anterior Gradient 2 (AGR2) is an Endoplasmic Reticulum (ER) resident protein that belongs to the Protein Disulfide Isomerase (PDI) family. In normal cells, AGR2 forms mixed disulfide bonds with protein substrates and controls their correct folding and export throughout the secretory pathway. In cancer cells, AGR2 is overexpressed and has been described to promote cell adhesion and tumor metastasis through the interactions and regulations of cell surface protein targets. Although AGR2 has been clearly identified as a pro-oncogenic protein, its exact biological function(s) and its role in cancer remain to be characterized. One way to address such question is to identify AGR2 interacting partners and from this, deduce putative molecular functions associated with this protein. Thus far this problematic was nailed down using either yeast two-hybrid- or tandem affinity purification/ mass spectrometry sequencing-based approaches. Unfortunately those strategies mainly led to the identification of false positive hits comprising almost exclusively cytosolic proteins, a compartment to which AGR2 never localizes. As ER-occurring protein-protein interactions depend on the specific ER environment (oxidative, calcium-rich), the proposed research project will use a recently developed mammalian interaction trap to investigate at the proteome scale the AGR2 interactome in a sub-cellular compartment relevant fashion. Indeed the ER Mammalian protein-protein Interaction Trap (ERMIT) is a two-hybrid system based on the restoration of the Inositol Requiring Enzyme 1 (IRE1) signaling. IRE1 is a key sensor of the Unfolded Protein Response (UPR) that senses accumulation of misfolded proteins in the ER lumen, dimerizes and transduces a signal to the cell through its cytosolic kinase and RNase activities. The activation of IRE1 RNase activity leads to the unconventional splicing of XBP1 mRNA thereby leading to the translation of an active transcription factor. ERMIT relies on these signaling properties. The bait AGR2 and the preys from the ORFeome library V8.1 are fused to the transmembrane and cytosolic domains of IRE1 and when the bait AGR2 interacts with a prey the RNase activity is induced and an XBP1 splicing reporter gene is activated. The identification of cancer relevant AGR2 interactors will then be established by mining the literature and publicly available databases and the functional relevance of the positive hits evaluated using in vitro models as well as patient-derived samples focusing on two types of cancers: cholangiocarcinoma and lung cancers in which AGR2 has been shown to be overexpressed and functionally involved in cancer aggressiveness. This project will establish the Cancer AGR2 Interactome and provide novel research avenues to understand and control carcinogenesis.
The candidate must have a master's degree or equivalent in cell biology and biochemistry or a related field. Knowledge of functional analysis and screening approaches is clearly a plus, as are programming skills, and a motivation to understand cancer biology. The international nature of the project requires a high level of English.
Type/Duration: 36-48 months PhD position (financed)
Eligibility: Chinese students
Applicants should send a letter of motivation, their CV, together copies of relevant certificates, and contact details of no more than three references. Send your application as a single PDF to Saïd Taouji (firstname.lastname@example.org). A link to your bachelor/master thesis would also be appreciated. Applications will be considered until the position is filled - those received before 01/15/15 will receive full consideration.
Keywords: Cancer, functional genomics, proteomics, ER stress
Supervisor: Dr Said Taouji
INSERM UMR916, CRLC-Institut Bergonié
University of Bordeaux.