PubMed · 7370677
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
1980-03-22. Corticosteroids and hypothalamic-pituitary-adrenocortical function.. https://doi.org/10.1136/bmj.280.6217.813
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
Steroidogenic factor-1/adrenal 4-binding protein (SF-1/Ad4BP) is an orphan nuclear receptor/transcription factor known to regulate the P450 steroid hydroxylases; however, mechanisms that regulate the activity of SF-1/Ad4BP are not well defined. In addition, little is known about the mechanisms that regulate the human steroidogenic enzyme, type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD II), the major gonadal and adrenal isoform. Regulation of the 3beta-HSD II promoter was examined using human adrenal cortical (H295R; steroidogenic) and cervical (HeLa; non-steroidogenic) carcinoma cells. H295R cells were transfected with a series of 5' deletions of 1251 base pairs (bp) of the 3beta-HSD II 5'-flanking region fused to a chloramphenicol acetyltransferase (CAT) reporter gene followed by treatment with or without phorbol ester (phorbol 12-myristate 13-acetate; PMA). CAT assay data indicated that the region from -101 to -52 bp of the promoter was required for PMA-induced expression. A putative SF-1/Ad4BP regulatory element, TCAAGGTAA, was identified by sequence homology at -64 to -56 bp of the promoter. Cotransfection of HeLa cells with the -101 3beta-HSD-CAT construct and an expression vector for SF-1/Ad4BP increased CAT activity 49-fold. Subsequent treatment with PMA induced an unexpected synergistic increase in transcriptional activity 540-fold over basal. Mutation of the putative response element (TCAAGGTAA to TCAATTTAA) abolished SF-1-induced CAT activity and the synergistic response to PMA. Gel mobility shift assays confirmed that SF-1/Ad4BP interacts with the putative element and transcripts for SF-1/Ad4BP were detected in H295R cells by Northern analysis. These data are the first to demonstrate 1) regulation of a non-cytochrome P450 steroidogenic enzyme promoter by SF-1/Ad4BP, 2) a powerful synergistic effect of PMA on SF-1/Ad4BP-induced transcription, and 3) the importance of the SF-1/Ad4BP regulatory element in the regulation of the 3beta-HSD II promoter.
Stressful experience during early brain development has been shown to produce profound alterations in several mechanisms of adaptation, while several signs of behavioral and neuroendocrine impairment resulting from neonatal exposure to stress resemble symptoms of dysregulation associated with major depression. This study demonstrates that when applied concomitantly with the stressful challenge, the steroid GABA(A) receptor agonist 3,21-dihydropregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) can attenuate the behavioral and neuroendocrine consequences of repeated maternal separation during early life, e.g., increased anxiety, an exaggerated adrenocortical secretory response to stress, impaired responsiveness to glucocorticoid feedback, and altered transcription of the genes encoding corticotropin-releasing hormone (CRH) in the hypothalamus and glucocorticoid receptors in the hippocampus. These data indicate that neuroactive steroid derivatives with GABA-agonistic properties may exert persisting stress-protective effects in the developing brain, and may form the basis for therapeutic agents which have the potential to prevent mental disorders resulting from adverse experience during neonatal life.
The ras-transformed newborn rat adrenocortical (RTAC) cells were obtained by transfection with the mutated c-Ha-rasEJ oncogene. They are proliferative and tumorigenic cells characterized by expression of the c-Ha-rasEJ oncogene and overexpression of a wild-type ras oncogene. The overproduced Ras p21 was identified here as Ki-Ras p21 by western blotting using a specific anti-Ki-Ras monoclonal antibody. Radioactivity derived from [14C]mevalonolactone was strongly incorporated into Ras p21 overproduced in RTAC cells. RTAC cells pretreated with lovastatin and labeled with either [3H]geranylgeranyl-pyrophosphate or [3H]farnesyl-pyrophosphate incorporated also radioactivity into Ras p21. These results showed that overproduced Ras proteins were geranylgeranylated as well as farnesylated in RTAC cells. These findings suggest that the strategy for inhibiting proliferation of Ki-ras-dependent tumorigenic cells should be directed against not only farnesylation but also geranylgeranylation of Ras p21.