REGULATION of AUTOPHAGY through miRNAs
Biological Sciences and Bioengineering, Ph.D Dissertation, 2012
Assoc. Prof. Devrim Gözüaçık (Thesis Supervisor), Assoc. Prof Ugur Sezerman, Asst. Prof. Elif Erson Bensan, Asst. Prof. Ibrahim Yaman,Assoc. Prof. Ali Koşar, Assoc. Prof. Işın Doğan Ekici
Place: FENS 2019
Key Words: Autophagy, miRNA, chemotherapy, cell death, cancer
Autophagy is a cellular catabolic mechanism conserved from yeast to mammals. Recycling and degradation of long-lived proteins and organelles by autophagy maintain cellular homeostasis. Furthermore, activation of autophagy can lead to cell death or survival depending on cellular context. Moreover, autophagy abnormalities play a role in various diseases including cancer. Hence, it is essential to understand molecular pathways regulating autophagy.
In this study, we demonstrated the role of a microRNA family, miR-376, in the regulation of autophagic activity. miR-376 family blocked starvation- and rapamycin-induced autophagy and led to a decrease in the cellular levels of two key autophagy mRNA and proteins, namely Atg4C and Beclin 1. Additionally, autophagic activity was recovered in rescue experiments where miR-376 family member and target genes were co-expressed. Using luciferase assays, we showed that potential miRNA binding regions in the 3’UTR regions of target genes were functional and their mutations blocked the miRNA effect. We also demonstrated that endogenous miR-376 levels were upregulated in response to various stress and death-inducing stimuli. Therefore, we introduce miR-376 family as a novel regulator of autophagy and Atg4C and Beclin 1 as its cellular effectors. miRNA, autophagy, and cancer relationship will be discussed from a basic scientific and clinical point of view.