The essential role of calcium in induction of the DSCR1 (ADAPT78) gene.

Abstract

Stress responses have been of great interest to biologists for many years, both as interesting phenomena in their own right, and as tools to study gene expression. Stresses such as heat shock, cold shock, oxidative stress, glucose deprivation, heavy metals, and anoxia have all been studied. We have been studying transient adaptive responses to oxidative stress, in both prokaryotes and dividing eukaryotic cells, for over 10 years [1–5]. Oxidative stress involves responses to oxidants, or to agents that cause oxidation via intracellular redox reactions. Severe oxidative stress can result in compromise of vital cell or organismal functions, or even loss of viability. The transient adaptive response model to stress involves first finding a “challenge” level of stress that will either kill a large proportion of cells, or significantly inhibit cell growth or division. Having established the degree of stress required for this cytotoxicity, new cell cultures are “pre-treated” with various low stress exposures, for various time periods, in an attempt to induce an adaptive response. The pre-treated cells are then exposed to the challenge stress level and their resistance is measured. Through much trial and error (and not a little luck) an effective pre-treatment stress level can usually be found that will induce significant short-term protection against a subsequent stress challenge: this is a transient adaptive response. Importantly, such transient adaptation must be further tested to ensure that the cells become sensitive to stress again over time (de-adaptation), to insure that mutation has not caused a permanent change in stress phenotype. In the last few years we have discovered several new oxidant stress-inducible genes, all of which provide partial protection against acute oxidative stress. These include: Adapt15, Adapt33, Adapt66, Adapt73, Adapt78, and Adapt116. All of these genes contain a calcium response element, all can be induced by calcium ionophores such as A23187 in the presence of calcium; and by other agents, such as thapsigargin and cyclopiazonic acid, that increase intracellular calcium concentrations. In contrast, cell-permeant calcium chelators, such as BAPTA-AM, can completely block the induction of all the ‘adapt’ genes. Of all the adapt genes, Adapt78 is the most responsive to calcium signaling. Adapt78 was simultaneously discovered by Fuentes et al. and called Down Syndrome Critical Region 1 gene, or DSCR1 (subsequently called Down Syndrome Candidate Region 1) [6,7]. Recently we have discovered