DJ-1 activates SIRT1 through its direct binding to SIRT1.
The DJ-1 gene is a ras-dependent oncogene and also a causative gene for a familial form of Parkinson's disease park7. DJ-1 is a multi-functional protein and plays roles in regulation of cell growth, cells death, metabolism and mitochondrial homeostasis against oxidative stress. To explore various functions, DJ-1 associates with a number of proteins localized in the nucleus, cytoplasm and mitochondria. The oxidative status of a cysteine residue at an amino acid number 106 (C106) of DJ-1 determines the active level of DJ-1. Precise molecular mechanism of exploration of DJ-1 function is, however, not resolved. In this study, we identified Sirtuin family proteins (SIRT1, 2, and 4-6) as DJ-1-binding proteins, and DJ-1 associated with SIRT1 in cells. Sirtuins like DJ-1 also regulates growth, death and metabolism of cells and mitochondrial homeostasis. We found that DJ-1 stimulated deacetylase activity of SIRT1 and that SIRT1-suppressed transcriptional activity of SIRT1-target p53 was further decreased by DJ-1. Furthermore, SIRT1 activity was reduced in DJ-1-knockout cells, and this reduced activity was restored by re-introduction of wild-type DJ-1 but not of C106-mutant DJ-1 into DJ-1-knockout cells. It is first report showing direct connection of DJ-1 with SIRT1.
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
Kazuko
K
Takahashi-Niki
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
Yoko
Y
Ganaha
Faculty of Agriculture, Hokkaido University, Kita 9 Nishi 9, Kita-ku, Sapporo 060-8589, Japan.
Takeshi
T
Niki
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
Shota
S
Nakagawa
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
Izumi
I
Kato-Ose
Faculty of Agriculture, Hokkaido University, Kita 9 Nishi 9, Kita-ku, Sapporo 060-8589, Japan.
Sanae M M
SMM
Iguchi-Ariga
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: hiro@pharm.hokudai.ac.jp.
Hiroyoshi
H
Ariga
D000072283:A549 Cells; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding; D000071617:Protein Deglycase DJ-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D056564:Sirtuin 1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; C447939:SIRT1 protein, human; D056564:Sirtuin 1
DJ-1; Deacetylase; SIRT1; p53