Cadmium and cellular signaling cascades: to be or not to be?
The cellular effects of the toxic metal cadmium (Cd) are manifold. A large proportion of the cellular reactions affected by ionic Cd(2+) are mediated by cellular signaling cascades. The aim of this review is to provide a principal understanding of the known physiological signaling cascades, which are recruited by Cd(2+), and to highlight the fact that Cd(2+), similarly to other toxic metals, disrupts physiological signal transduction. In principle, second messengers are generated at the time of receptor activation, are short-lived, and act specifically in space and time through non-covalent binding on effectors to transiently alter their activity. Signaling dysregulation induced by Cd(2+) is reflected by a permanent disruption of transducing modules, resulting in low and/or elevated and constant levels of second messengers, which overwhelm the control mechanisms of signaling. This disturbs physiological cellular functions, gene transcription and regulation and may result in cell death and/or stress-induced adaptation and survival as well as carcinogenesis. The impact of Cd(2+) on Ca(2+)-, cAMP-, NO-, ROS-, MAP-kinase-, PKB/Akt-, nuclear factor-kappa B-, and developmental signaling is critically discussed. The hierarchical as well as cooperative and integrative character of signaling cascades activated by Cd(2+) is illustrated in the kidney proximal tubule, a major target of Cd(2+) toxicity. This review also aspires to pinpoint new avenues of research that may contribute to a more differentiated view of the complex mechanisms underlying Cd(2+) toxicity in target tissues and eventually lead to rationales and strategies for prevention and therapy of Cd(2+) toxicity.
Thévenod
Frank
F
Department of Physiology and Pathophysiology, University of Witten/Herdecke, Witten, Germany. frank.thevenod@uni-wh.de
D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D020013:Calcium Signaling / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D004785:Environmental Pollutants; D053823:Hedgehog Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D051153:Wnt Proteins; D051176:beta Catenin; D002104:Cadmium; D009569:Nitric Oxide; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases