Cadmium interferes with the degradation of ATF5 via a post-ubiquitination step of the proteasome degradation pathway.
ATF5 is a member of the CREB/ATF family of transcription factors. In the current study, using a transient transfection system to express FLAG epitope fusion proteins of ATF5, we have shown that CdCl(2) or NaAsO(3) increases the protein levels of ATF5 in cells, and that cadmium stabilizes the ATF5 protein. Proteasome inhibitors had a similar effect to cadmium on the cellular accumulation of ATF5. Proteasome inhibition led to an increase in ubiquitinated ATF5, while cadmium did not appear to reduce the extent of ATF5 ubiquitination. ATF5 contains a putative nuclear export signal within its N-terminus. We demonstrated that whereas deletion of N-terminal region resulted in a increase of ATF5 levels, this region does not appear to be involved in the ubiquitination of ATF5. These results indicate that ATF5 is targeted for degradation by the ubiquitin-proteasome pathway, and that cadmium slows the rate of ATF5 degradation via a post-ubiquitination mechanism.
Uekusa
Hiroyuki
H
Laboratory of Environmental Molecular Physiology, School of Life Science, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Namimatsu
Mihoko
M
Hiwatashi
Yusuke
Y
Akimoto
Takuya
T
Nishida
Tamotsu
T
Takahashi
Shigeru
S
Takahashi
Yuji
Y
D051696:Activating Transcription Factors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D019556:COS Cells; D019256:Cadmium Chloride / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D054875:Ubiquitination
C507532:ATF5 protein, human; D051696:Activating Transcription Factors; D018053:Arsenites; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; D019256:Cadmium Chloride; C015001:arsenite