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  • Title: The role of protein kinase C alpha in tri-ortho-cresyl phosphate-induced autophagy in human neuroblastoma SK-N-SH cells.
    Author: Deng Q, Jiang L, Mao L, Song XH, He CQ, Li XL, Zhang ZH, Zeng HC, Chen JX, Long DX.
    Journal: J Appl Toxicol; 2020 Nov; 40(11):1480-1490. PubMed ID: 33020912.
    Abstract:
    As an organophosphorus ester, tri-ortho-cresyl phosphate (TOCP) has been widely used in agriculture and industry. It is reported that TOCP can induce organophosphate-induced delayed neuropathy (OPIDN) in sensitive animal and human species. However, the exact molecular mechanisms underlying TOCP-induced neurotoxicity are still unknown. In this study, we found that TOCP could induce autophagy by activating protein kinase C alpha (PKCα) signaling in neuroblastoma SK-N-SH cells. PKCα activators could positively regulate TOCP-induced autophagy by increasing the expression levels of neighbor BRCA1 gene protein 1 (NBR1), LC3 and P62 autophagic receptor protein. Furthermore, PKCα activation impaired the ubiquitin-proteasome system (UPS), resulting in inhibition of proteasome activity and accumulation of ubiquitinated proteins. UPS dysfunction could stimulate autophagy to serve as a compensatory pathway, which contributed to the accumulation of the abnormally hyperphosphorylated tau proteins and degradation of impaired proteins of the MAP 2 and NF-H families in neurodegenerative disorders.
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