¹Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Yongbong-dong, Buk-ku, Gwangju 500-757, Republic of Korea

Correspondence: H-S Park, School of Biological Sciences and Technology, Chonnam National University, 300, Yongbong-dong, Buk-ku, Gwangju 500-757, Republic of Korea. Tel: +82 62 530 0021; Fax: +82 62 530 2199; E-mail: proteome@jnu.ac.kr

Received 29 August 2007; Revised 31 January 2008; Accepted 1 February 2008; Published online 29 February 2008.

Abstract

DJ-1 is a multifunctional protein that performs functions in transcriptional regulation and oxidative stress, and the loss of its function is believed to result in the onset of Parkinson's disease (PD). In this study, we report that DJ-1 protects against UV-induced cell death through the suppression of the JNK1 signaling pathway. The results of both binding and kinase studies have revealed that MEKK1 is the direct target of DJ-1. The C-terminus of DJ-1 was crucial to the inhibition of the MEKK1 kinase activity. Wild-type DJ-1 sequesters MEKK1 within the cytoplasm and the L166P mutant facilitates the translocation of MEKK1 toward the nucleus without physical association. Both DJ-1 knockdown and pathogenic L166P mutant were determined to be highly susceptible to the UV-induced activation of the MEKK1-SEK1-JNK1 signaling cascade and cell death. Taken together, our findings show that missense mutation in DJ-1 sensitizes cells to stress-induced cell death through the MEKK1-SEK1-JNK1 signaling pathway, a process, which may trigger the early onset of PD.