title: The Transcription Factor p8 Regulates Autophagy in Response to Palmitic Acid Stress via a Mammalian Target of Rapamycin (mTOR)-independent Signaling Pathway.
abstract: Autophagy is an evolutionarily conserved degradative process that allows cells to maintain homoeostasis in numerous physiological situations. This process also functions as an essential protective response to endoplasmic reticulum (ER) stress, which promotes the removal and degradation of unfolded proteins. However, little is known regarding the mechanism by which autophagy is initiated and regulated in response to ER stress. In this study, different types of autophagy were identified in human gastric cancer MKN45 cells in response to the stress induced by nutrient starvation or lipotoxicity in which the regulation of these pathways is mammalian target of rapamycin (mTOR)-dependent or -independent, respectively. Interestingly, we found that p8, a stress-inducible transcription factor, was enhanced in MKN45 cells treated with palmitic acid to induce lipotoxicity. Furthermore, an increase in autophagy was observed in MKN45 cells stably overexpressing p8 using a lentivirus system, and autophagy induced by palmitic acid was blocked by p8 RNAi compared with the control. Western blotting analyses showed that autophagy was regulated by p8 or mTOR in response to the protein kinase-like endoplasmic reticulum kinase/activating transcription factor 6-mediated ER stress of lipotoxicity or the parkin-mediated mitochondrial stress of nutrient starvation, respectively. Furthermore, our results indicated that autophagy induced by palmitic acid is mTOR-independent, but this autophagy pathway was regulated by p8 via p53- and PKCα-mediated signaling in MKN45 cells. Our findings provide insights into the role of p8 in regulating autophagy induced by the lipotoxic effects of excess fat accumulation in cells.
authors.affiliation: From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Jia
authors.affiliation: From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Lin
authors.affiliation: From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Dian-Fu
authors.initials: DF
authors.lastname: Chen
authors.affiliation: From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: An-Qi
authors.initials: AQ
authors.lastname: Li
authors.affiliation: From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Li
authors.initials: L
authors.lastname: Dai
authors.affiliation: From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Zhao
authors.affiliation: From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jin-Shu
authors.initials: JS
authors.lastname: Yang
authors.affiliation: From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: From the College of Life Sciences, Zhejiang University, Hangzhou 310058, China w_jyang@zju.edu.cn.
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Yang
mesh_terms: D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000009:adverse effects*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008856:Microscopy, Fluorescence; D019308:Palmitic Acid / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D005230:Fatty Acids, Nonesterified; D049452:Green Fluorescent Proteins; D019308:Palmitic Acid; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C501901:SP8 protein, human; C485184:enhanced green fluorescent protein; C546842:MTOR protein, human
keywords: autophagy; lipotoxicity; mammalian target of rapamycin (mTOR); p53; p8; protein kinase C (PKC)