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Green tea polyphenol (–)‐epigallocatechin‐3‐gallate promotes the rapid protein kinase C‐ and proteasome‐mediated degradation of Bad: implications for neuroprotection
Author(s) -
Kalfon Limor,
Youdim Moussa B. H.,
Mandel Silvia A.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04265.x
Subject(s) - lactacystin , neuroprotection , cycloheximide , protein kinase c , proteasome , proteasome inhibitor , protein degradation , protein kinase a , epigallocatechin gallate , catechin , microbiology and biotechnology , programmed cell death , biology , kinase , viability assay , biochemistry , pharmacology , cell , polyphenol , protein biosynthesis , apoptosis , antioxidant
The aim of the present study was to gain a deeper insight into the cell signaling pathways involved in the neuroprotection/neurorescue activity of the major green tea polyphenol (–)‐epigallocatechin‐3‐gallate (EGCG). EGCG (1 μ m ) caused an immediate (30 min) down‐regulation (∼40%) of Bad protein levels, and a more pronounced reduction after 24 h (55%) in the human neuroblastoma cell line SH‐SY5Y. Co‐treatment with EGCG and the protein synthesis inhibitor cycloheximide prominently shortened Bad half‐life, with as little as 30% of the Bad protein content remaining after 2 h, suggesting an effect of EGCG on Bad protein degradation. Accordingly, the proteasome inhibitors MG‐132 and lactacystin damped Bad down‐regulation by EGCG. The general protein kinase C (PKC) inhibitor GF109203X, or the down‐regulation of conventional and novel PKC isoforms, abolished EGCG‐induced Bad decline. However, no inhibition was seen with the cell‐permeable myristoylated pseudosubstrate inhibitor of the atypical PKCζ isoform. The enforced expression of Bad for up to 72 h rendered the cells more susceptible to serum deprivation‐induced cell death, whereas EGCG treatment significantly improved cell viability (up to 1.6‐fold). The present study reveals a novel pathway in the neuroprotective mechanism of the action of EGCG, which involves a rapid PKC‐mediated degradation of Bad by the proteasome.