Metallothionein-I and -II knock-out mice are sensitive to cadmium-induced liver mRNA expression of c-jun and p53.
Zinc pretreatment has been shown in vitro (rat myoblasts) to induce metallothionein (MT) and inhibit cadmium (Cd)-induced protooncogenes c-myc and c-jun mRNA levels. therefore, the purpose of this study was to determine whether the mRNA expression of the protooncogene c-jun as well as the tumor suppressor gene p53 is increased by Cd in the intact animal and, more specifically, in the target organ for Cd toxicity, the liver. Additionally, modulation of the expression of these genes was investigated in the absence of MT. The effect of CdCl2 on the mRNA levels of c-jun and p53 was studied in livers of C57BL/6J (control) and MT-null mice by Northern- and slot-blot analyses. The mRNA for c-jun and p53 were increased by Cd in a dose-dependent fashion. In the control mice, Cd induced c-jun mRNA (5-fold) at 3 and 12 hr and p53 mRNA (1.8- to 2-fold) at 6 and 12 hr. Compared to controls, the MT-null mice were more sensitive to the Cd-induced gene expression. The magnitude of the inductions was more pronounced and the elevated mRNA levels of c-jun and p53 were seen at lower doses of Cd (10mumol/kg in MT-null mice vs 40 mmol/kg in control mice). In conclusion, these data demonstrate that Cd induces mRNA expression of the protooncogene c-jun and tumor suppressor gene p53 in liver, and that MT modulates this effect.
Zheng
H
H
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Liu
J
J
Choo
K H
KH
Michalska
A E
AE
Klaassen
C D
CD
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D015152:Blotting, Northern; D002104:Cadmium / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D016758:Genes, jun / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics*; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; C004203:cadmium-binding protein; D002104:Cadmium; D008668:Metallothionein; D000410:Alanine Transaminase