A reappraisal of the role of zinc in life and death decisions of cells.
There is a great deal of interest in chemicals and biochemicals that can modulate apoptosis. As will be discussed, zinc, an essential trace element, can induce as well as block apoptosis. High concentrations of extracellular zinc (500-1000 microM) have frequently been used to block apoptosis or programmed cell death in a variety of systems. Early investigators provided evidence that this concentration of zinc could block DNA fragmentation that is often associated with apoptosis. Since zinc plays a role in many aspects of cell function, there are probably many sites in a death pathway that zinc could potentially modulate. In the case of glucocorticoid-mediated apoptotic death, new evidence presented herein indicates that high zinc can also block the binding of steroids to the glucocorticoid receptor thereby inhibiting the death signal itself. In this case, zinc probably binds to the vicinal cysteines in the receptor ligand binding site thereby blocking binding of glucocorticoid. Indeed, glucocorticoid-induced apoptosis in thymocytes has become one of the most frequently studied systems and is a focal point of this review. Studies herein will show that unlike zinc other trace-like metals such as nickel, copper, cadmium, and gold do not afford thymocytes protection against the DNA fragmentation induced by glucocorticoid-mediated cell death. Interestingly, in attempting to determine if lower or more physiological concentrations of zinc could provide protection against apoptosis, it was found that 80-200 microM zinc could actually induce death in 40% of CD4+ CD8+ alpha beta TCR10CD3(10) thymocytes. From these experiments one might have been optimistic that zinc could, indeed, be a modulator of cell death. However, this thought has been overshadowed by growing evidence that zinc does not provide long-term protection to so-called surviving cells.
Fraker
P J
PJ
Department of Biochemistry, Michigan State University, East Lansing 48824, USA.
Telford
W G
WG
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D002614:Chelating Agents; D005110:Extracellular Space; D006801:Humans; D009474:Neurons / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology; D015032:Zinc / Q000502:physiology*
D002614:Chelating Agents; D015032:Zinc