METALLOTHIONEIN INDUCTION IN RESPONSE TO RESTRAINT STRESS - TRANSCRIPTIONAL CONTROL, ADAPTATION TO STRESS, AND ROLE OF GLUCOCORTICOID

Metallothioneins (MT) have been implicated in the protection of cells from oxidative stress. We studied the molecular mechanism of induction of MT-I and MT-II in response to restraint stress using a mouse model system in which the animals were restrained in well ventilated polypr opylene tubes for 12 h each day (one cycle). Here, we show that MT-I a nd MT-II mRNA levels were elevated as much as 10-20-fold after just on e cycle of this simple stress. Stress-mediated MT induction occurred a t the transcriptional level. The level of MT mRNA correlated with the stress-induced increase, and not with the diurnal variation, in the le vel of serum glucocorticoid. Treatment of the mice with RU 486, a gluc ocorticoid receptor antagonist, prior to restraint stress inhibited MT induction by at least 50%. Furthermore, the glucocorticoid responsive element-binding activity in the liver nuclear extracts from the stres sed mice was significantly higher than that in the control mice. The c omplex formations between the transcription factor Sp1, MTF1, or MLTF/ ARE and the respective specific oligonucleotides were not altered in t he liver from the stressed mouse. The MT mRNA levels returned to the b asal level at the end of nine cycles of stress, indicating habituation of the animals to restraint stress. At this stage, exposure of the an imals to another type of stress, treatment with heavy metals, resulted in further induction of MT. These data indicate that glucocorticoid i s the primary physiological factor responsible for MT induction follow ing restraint stress, and the glucocorticoid receptor is the major tra nscription factor involved in this process.