Linking gene expression to mechanisms of toxicity.

Activation of gene expression is one of the earliest cellular responses to toxicity. However, our understanding of the biological and biochemical signals that activate these toxicant-responsive genes as well as the consequences of gene activation to survival of the organism remains sketchy. In this article, strategies that can be used to link changes in gene expression to biochemical mechanisms of toxicity are addressed using the hsp70 and grp78 genes as examples. The data indicate that activation of hsp70 is linked to changes in thiol-disulfide redox perturbations while grp78 activation may be caused by loss of calcium from the endoplasmic reticulum. Each gene is part of a discrete feedback regulated signaling pathway designed to protect cells against the toxic signals that activate gene expression.