Induction of C/EBPP and GADD153 expression by dopamine in human neuroblastoma cells relationship with α-synuclein increase and cell damage

Expression of CCAAT/enhancer-binding protein beta (C/EBPbeta) and growth-arrest DNA damage-inducible t53/C/EBPbeta homology protein (GADD153/CHOP) increased after incubation of human neuroblastoma SH-SY5Y cells with a range of dopamine concentrations. Dopamine (100 muM) caused an increase in C/EBPbeta expression between 2 and 12 h of treatment, with no evident intracellular morphological changes. Dopamine (500 muM) led to the appearance of autophagic-like vacuoles and a marked increase in GADD153/CHOP between 6 and 24 h of treatment. The expression of a-synuclein, the main protein of Lewy bodies in Parkinson's disease and other neurological disorders, increased with a profile similar to C/EBPbeta. In addition, overexpression of C/EBPbeta caused a concomitant increase in the expression of alpha-synuclein but not of GADD153. In contrast, the overexpression of GADD153 did not alter the expression of alpha-synuclein. Inhibition of JNK by SP600125 reduced increases in C/EBPbeta and alpha-synuclein expression, whereas inhibition of both JNK and p38MAPK (with SB203580) blocked the increase in GADD153 expression. We conclude that dopamine, through a mechanism driven by stress-activated MAPKs, triggers C/EBPbeta and GADD153 expression in a dose-dependent way. Given that the promoter region of the alpha-synuclein gene contains distinct zones that are susceptible to regulation by C/EBPbeta, this factor could be involved in the increased expression of a-synuclein after dopamine-induced cell stress. GADD153 increase seems to be related with the endoplasmic reticulum stress, autophagy and cell death observed at high dopamine concentrations. (C) 2004 Elsevier Inc. All rights reserved.