RT Journal Article
ID 1c90e7cf60957fe9
A1 Hait-Darshan, Ravit
A1 Babushkin, Tania
A1 Malik, Zvi
T1 Regulation of Heme Synthesis and Proteasomal Activity by Copper: Possible Implications for Wilson's Disease
JF Journal of Environmental Pathology, Toxicology and Oncology
JO JEP(T)
YR 2009
FD 2009-11-04
VO 28
IS 3
SP 209
OP 221
K1 ALAD
K1 ATP7B
K1 PBGD
K1 proteasome
K1 protoporphyrin IX
K1 ubiquitin
AB Wilson's disease (Wd) is a genetic disorder resulting in Cu2+ accumulation, and is caused by mutations in the ATP7B gene, the copper transporter. In vivo studies show a correlation between Cu2+ accumulation and malfunction of the heme biosynthesis pathway. In this study, we describe multiple effects of Cu2+ accumulation on heme synthesis, which, in turn, affect proteasomal activity. Cu2+ toxicity was examined in two hepatocellular carcinoma cell lines, HepG2 and Hep3B, with Hep3B cells containing an integrated hepatitis B virus genome. Exposure of HepG2 and Hep3B cells to Cu2+ inhibited the enzymes PBGD and ALAD of the heme synthesis pathway and, in parallel, upregulated heme oxygenase-1 (HO-1). Proto-porphyrin IX (PpIX) and the heme pool were reduced as a result of these processes. PpIX synthesis was found to be lower in cells expressing the mutant ATP7B (P1134P), compared to those expressing the WT enzyme. Proteasomal activity was inhibited under Cu2+ treatment in HepG2 cells; however, Cu2+ induced marked proteosomal acceleration in Hep3B cells. Under these conditions, Ub-conjugated proteins were gradually accumulated, whereas treatment with bathocuproine disulfonic acid (BCS), a Cu2+ chelator, reversed this effect. In conclusion, our data suggest that copper downregulates the heme synthesis pathway in hepatocellular cells and further reduces it in the presence of mutated ATP7B.
PB Begell House
LK https://www.dl.begellhouse.com/journals/0ff459a57a4c08d0,019e22cb279c7547,1c90e7cf60957fe9.html