TGF alpha in normal physiology.

This paper reviews our work on the localization of transforming growth factor-alpha (TGF alpha) in normal adult tissues and the regulation of its synthesis and that of its receptor. We detected TGF alpha immunohistochemically in brain neurons and showed the TGF alpha mRNA derived from the human brain stem is virtually identical to the mRNA derived from human renal tumour cells. In cells derived from anterior pituitary glands, another site of TGF alpha expression, TGF alpha secretion and mRNA levels can be regulated by phorbol esters. The expression of the epidermal growth factor (EGF) receptor, which is also the TGF alpha receptor, is also stimulated by phorbol esters. Similar stimulation of receptor and ligand expression in human breast cancer cells was shown in response to phorbol esters and EGF. The ability of ligand to stimulate its own synthesis and that of its receptor suggests the presence of an autocrine positive feedback loop, however we were unable to break this loop in the breast cancer cells by antibodies that blocked the interaction of TGF alpha with the EGF receptor. The ability of EGF to stimulate EGF receptor and TGF alpha expression appears to require protein kinase C, since inhibition of this enzyme blocked the ability of EGF to stimulate these genes. These studies raise the possibility that hormones capable of activating protein kinase C could stimulate EGF receptor and TGF alpha expression.