Ubiquitin ligases in ER stress and cancer - implications for ischemia, metabolism and chemotherapy

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講演要旨

The ubiquitin ligase Siah2 has been implicated in the regulation of prolyl hydroxylases (PHD1 and PHD3), key players in the VHL-dependent regulation of HIF1a stability (Cell 2004). Siah1/2 control of PHD3 was found to be relevant for the regulation of ATF4, one of the three major sensors/transducers of the unfolded protein response (UPR). Siah1/2 control of PHD3 enables increased ATF4 levels, as well as UPR-directed cell death. Notably, ATF4 directly induces Siah1/2 transcription, pointing to a feed-forward mechanism underlying Siah1/2 control of the UPR (PLoS Genetics 2014). The importance of Siah1/2 for melanoma, prostate cancer and ischemic conditions will be discussed.

The ubiquitin ligase RNF5 (AKA as RMA1) was previously shown to be associated with ERAD, as part of the ER stress response. RNF5 was also found to limit basal autophagy, when it is not needed, through its regulation of ATG4B, a key component in LC3 maturation. RNF5 was also recently found to control glutamine metabolism via its ubiquitination-dependent degradation of two glutamine carrier proteins, under ER stress induced by select chemotherapies. As a result, reduced intracellular glutamine, affected mTOR signaling resulting in autophagy and cell death. The significance of this pathway for breast cancer response to therapy and the possible stratification of breast cancer to select therapies will be discussed. One of the critical unmet needs today pertain to the resistance of tumor to leading therapies. For example, melanoma treated with BRAF inhibitor often develops resistance to which there are no effective solutions. We will discuss the discovery and characterization of ubiquitin ligase, which contributes to the control of resistance mechanisms in these melanoma tumors, allowing to offer potential new ways for their treatment.