6533b86efe1ef96bd12cb00a

RESEARCH PRODUCT

Analysis of cIAP1 oncogenic properties : importance of cIAP1-TRAF2 interplay

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Analysis of cIAP1 oncogenic properties: cIAP1 and TRAF2 ubiquitin ligases duo in tumor growth.cIAP1 (cellular Inhibitor of APoptosis-1) is a signaling intermediate belonging to the IAP (Inhibitor of APoptosis) family. This E3 ubiquitin ligase protein shows oncogenic properties. cIAP1 expression is frequently altered in various human tumor samples and represents a marker of bad prognosis and resistance to chemotherapies. Some IAP antagonists have been synthesized. They showed promising results in preclinical study and some of them are now being tested in clinical study. Unfortunately, these molecules are poorly specific as they can neutralize several IAP family members. Moreover, the mechanisms of the cIAP1 oncogenic activity are still unclear. The protein is involved in various cellular functions such as proliferation, differentiation, cell cycle regulation, inflammation, and cell migration. My work confirmed the oncogenic properties of cIAP1 in a mouse embryonic fibroblast lacking cIAP1 and transformed by HRas-V12. cIAP1 deletion reduces tumor growth and lung foci formation. Using several mutants of cIAP1 showed that its interaction with the protein TRAF2 was necessary for its oncogenic properties. The cIAP1-TRAF2 complex increases NF-κB, ERK1/2 and interleukin 6 / JAK/STAT3 signalization pathways. We observed a correlation between IL-6 and cIAP1 expression, but not with cIAP1 mutants unable to bind TRAF2. Deletion of cIAP1 or TRAF2 decreases STAT3 phosphorylatio in our MEF model and in the A549 cell line of human lung cancer. The expression of a construct coding for the isolated BIR1 domain of cIAP1 in our cIAP1-depleted cells showed a role of TRAF2 in cIAP1 oncogenic properties. The analysis of TRAF2 interactome by mass spectrometry revealed that cIAP1 deletion greatly reduces the number of TRAF2 partners. These results on cIAP1 function suggest that its interaction with TRAF2 could be a key point for its oncogenic properties by activating various signaling pathways involved in cancer.Keywords: cIAP1, BIR1 domain, TRAF2, NF-κB, ERK1/2, IL-6, tumor growth, oncogenic properties.