Cadmium and calcium-dependent c-fos expression in mesangial cells.

Abstract:

:Cadmium is a carcinogenic metal known to increase the expression of several protooncogenes in a variety of cells. although the underlying mechanisms are unknown. Renal mesangial cells are smooth muscle cells in which Ca2+ signaling pathways regulate the induction of c-fos through both cAMP-dependent and mitogen-activated protein kinase- (MAPK-) dependent pathways. We report that c-fos is induced in these cells by both protein kinase C- (PKC-) dependent (phorbol ester, platelet-derived growth factor), and independent (serum, ionomycin) mechanisms. In all cases, prevention of an increase in cytosolic [Ca2+] with the chelator BAPTA prevented this induction. CdCl2 (10 microM) caused an accumulation of c-fos mRNA over 30 min that was sustained for at least 8 h. Cycloheximide inhibits turnover of c-fos mRNA and shows a synergistic effect with Cd2+ on transcript levels. Together with a similar half life of the transcript whether accumulated in response Cd2+ or induced by phorbol ester, this suggests induction of c-fos by Cd2+ rather than an effect of Cd2+ on transcript stability. Cadmium increased MAPK activity by 5 min; this was sustained for at least 8 h, consistent with the time course of c-fos mRNA accumulation. The MAPK kinase inhibitor PD98059 caused a marked decrease in the induction of c-fos by Cd2+, but did not eliminate the phenomenon completely. Although Cd2+ has been reported to activate PKC in vitro, no effect was found on PKC activity in Cd2+ -treated cells, indicating the activation of MAPK by Cd2+ is through an unidentified PKC-independent pathway. We conclude that Cd2+ can cause a sustained induction of c-fos in part through sustained activation of MAPK, that contrasts with the transient activation of these species in response to physiological mitogenic stimuli.

journal_name

Toxicol Lett

journal_title

Toxicology letters

authors

Templeton DM,Wang Z,Miralem T

doi

10.1016/s0378-4274(98)00015-0

subject

Has Abstract

pub_date

1998-03-16 00:00:00

pages

1-8

issue

1

eissn

0378-4274

issn

1879-3169

pii

S0378427498000150

journal_volume

95

pub_type

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