The 1994 Upjohn Award Lecture. Molecular and genetic approaches to the study of signal transduction in the adrenal cortex

Abstract

This review highlights contributions from my laboratory in which the sites and mechanisms of action of the adrenocorticotropic hormone (ACTH) in the adrenal cortex have been explored. Early studies showing that ACTH stimulates adrenal steroidogenesis by interacting with specific receptors at the cell surface are summarized. Next, the development of a strategy of genetic analysis to define the signalling events that follow ACTH interaction with its receptor is described. This strategy involved the isolation and characterization of mutant adrenal cell lines harboring specific defects in the ACTH-responsive steroidogenic pathway. I describe the isolation and characterization of several of these mutants and demonstrate how these mutants have helped to establish obligatory roles for adenylyl cyclase, cyclic AMP (cAMP), and cAMP-dependent protein kinase in the steroidogenic actions of ACTH. Finally, some of our studies on the regulated expression of the steroidogenic cytochrome P450 enzymes in Y1 adrenal cells are reviewed. These latter studies have led to the discovery of a novel promoter element and transcription factor (designated steroidogenic factor 1) that participates in the coordinate expression of these cytochrome P450 enzymes and that is required for their regulated expression by ACTH and cAMP.Key words: adrenocorticotropic hormone, cyclic AMP, cytochrome P450 genes, steroidogenesis, Y1 adrenocortical tumor cells.