Human P-450 genes: evolution, regulation and possible role in carcinogenesis.

sequences probably mediate their effect by binding, in a sequence-specific manner, a protein which activates transcription. The recognition of elevated concentrations of heavy metals (for example, zinc) probably occurs by binding of the zinc ions to this hypothetical metal regulatory protein (MRP), such that normally only a low porportion of MRP has bound zinc. It is proposed that zinc (or other heavy metal ions) increases the affinity of MRP for the MREs. At normal concentrations of zinc most of MRP would not have zinc bound, and would therefore bind only weakly to MREs. Thus the MREs would be occupied by MRP only a small fraction of the time. Increased levels of zinc in the cell would lead to an increase in the concentration of the MRP-Zn complex. This would bind more tightly to the M REs, resulting in a higher occupancy. MRP bound in the promoter region of the gene is proposed to increase the rate of transcription initiation either by helping RNA polymerase I1 or some other essential transcription factor to bind, or by some other direct interaction with components of the transcriptional machinery leading to an increased rate of transcription initiation. Either apo-MRP or MRP-Zn might be equally effective at stimulating transcription when they are bound in the promoter region, in which case a low but significant occupancy of MREs by apo-MRP in the absence of elevated heavy metal concentrations could contribute to the basal level of expression of the gene. The multiple MREs present in MT gene promoters probably all contribute to the magnitude of the response; in at least some situations they can function co-operatively with each other as well as with other promoter elements that are not themselves responsive to heavy metals.