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A Role for Guanyl Nucleotide-Binding Regulatory Protein ß- and -Subunits in the Expression of the Adrenocorticotropin Receptor

Banting and Best Department of Medical Research and Department of Pharmacology University of Toronto Toronto, Ontario, Canada M5G 1L6

Mutant Y1 mouse adrenocortical tumor cells, isolated on the basis of their resistance to the growth-inhibitory effects of forskolin, arise from single mutational events. These mutants present complex phenotypes in which the activity of Gß/ is impaired, ACTH receptor gene expression is markedly diminished, and ACTH-responsive adenylyl cyclase activity is lost. In this study, we have tested the hypothesis that the impairment in Gß/ activity is responsible for the loss of ACTH receptor gene expression and ACTH-responsive adenylyl cyclase activity. Transfection of one of the mutant clones with expression vectors encoding either Gß1 or Gß2 together with G2 increased ACTH receptor expression and restored ACTH-responsive adenylyl cyclase activity. Interestingly, either Gß2 or G2 alone was effective. These results thus support the hypothesis that the impairment in Gß/ activity is responsible for the loss of ACTH receptor expression. A luciferase reporter plasmid driven by the proximal promoter region of the mouse ACTH receptor gene was expressed poorly in the mutants compared with parental Y1 cells, suggesting that the Gß/ defect compromised transcriptional activity at the proximal promoter region of the ACTH receptor gene.

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