Protein synthesis and memory: a review

The mechanism regulating the production of steroids in response to trophic hormone stimulation has been the subject of investigation for over three decades. When considering the effects of trophic hormones on the steroidogenic process it is necessary to first distinguish between acute effects and chronic effects. Acute effects are those which result in the very rapid (within minutes) synthesis and secretion of steroids in response to hormone stimulation and involve the rapid translocation of intracellular cholesterol to the site of its cleavage, as will be discussed later. Chronic effects are those which occur on the order of hours to tens of hours and involve increased gene transcription and translation of the proteins involved in the biosynthesis of steroids. This chapter will focus on studies designed to elucidate the mechanisms involved in the acute regulation of steroid production in response to hormone stimulation. Overviews of the effects of chronic stimulation on steroidogenic enzymes have appeared in several excellent review articles (Simpson and Waterman 1983; Miller 1988; Hanukoglu 1992).

Regulation of the acute production of steroids in steroidogenic cells.

Cyclic AMP (adenosine 3',5'-monophosphate or cyclic adenylate) has now been established as a second messenger mediating many of the effects of a variety of hormones. Several of the metabolic effects mediated by cyclic AMP are discussed, and it is suggested that certain other ("functional" or "mechanical") hormonal effects may be similarly mediated. In particular, the evidence presented supports the hypothesis that the positive inotropic response to the catecholamines is mediated by cyclic AMP. Although knowledge of the biological role of cyclic AMP has not been widely applied clinically, sufficient knowledge has now accumulated to make research in this area desirable.

Some Aspects of the Biological Role of Adenosine 3',5'-monophosphate (Cyclic AMP)

Steroid hormone biosynthesis is acutely regulated by pituitary trophic hormones and other steroidogenic stimuli. This regulation requires the synthesis of a protein whose function is to translocate cholesterol from the outer to the inner mitochondrial membrane in steroidogenic cells, the rate-limiting step in steroid hormone formation. The steroidogenic acute regulatory (StAR) protein is an indispensable component in this process and is the best candidate to fill the role of the putative regulator. StAR is expressed in steroidogenic tissues in response to agents that stimulate steroid production, and mutations in the StAR gene result in the disease congenital lipoid adrenal hyperplasia, in which steroid hormone biosynthesis is severely compromised. The StAR null mouse has a phenotype that is essentially identical to the human disease. The positive and negative expression of StAR is sensitive to agents that increase and inhibit steroid biosynthesis respectively. The mechanism by which StAR mediates cholesterol transfer in the mitochondria has not been fully characterized. However, the tertiary structure of the START domain of a StAR homolog has been solved, and identification of a cholesterol-binding hydrophobic tunnel within this domain raises the possibility that StAR acts as a cholesterol-shuttling protein.

StAR Protein and the Regulation of Steroid Hormone Biosynthesis

Publisher Summary This chapter discusses the regulation of function in the adrenocortical system. There are three major characteristics that describe most changes in activity of the system: (1) the circadian rhythm in basal activity, (2) stress-induced activation, and (3) corticosteroid feedback regulation. The first two may occur on very different timescales, and it is probably a consequence of the differing temporal demands that the third, corticosteroid feedback inhibition, is exerted by a variety of mechanisms over time. At any time of the day, the adrenocortical system can be activated by application of stressors. These include alteration of the value of a regulated variable or may be invoked by subjecting an animal to sudden disturbances of its environment, for example, noise, flashing lights, handling, strange environment, mild heat or cold. The adrenocortical system may be activated by traumatic stimuli or by psychological stimuli—in man, examinations, or mental arithmetic, or medical school admissions exams; in rats, unexpected decreases in food rewards.

Regulation of ACTH secretion: variations on a theme of B.

** Recipient of a Career Scientist Award of the Health Research Council of the City of New York under contract no. 1-336. 1 Marks, P. A., E. R. Burka, and D. Schlessinger, these PROCEEDINGS, 48, 2163 (1962). 2Warner, J. R., P. M. Knopf, and A. Rich, these PROCEEDINGS, 49, 122 (1963). 3 Gierer, A., J. Mol. Biol., 6, 148 (1963). 4 Mathias, A. P., R. Williamson, H. E. Huxley, and S. Page, J. Mol. Biol., 9, 154 (1964). 5 Wettstein, F. O., T. Staehelin, and H. Noll, Nature, 197, 430 (1963). 6Penman, S., K. Scherrer, Y. Becker, and J. E. Darnell, these PROCEEDINGS, 49, 654 (1963). 7Korner, A., and A. J. Munro, Biochem. Biophys. Res. Commun., 11, 235 (1963). 8Clark, M. F., R. E. F. Matthews, and R. K. Ralph, Biochem. Biophys. Res. Commun., 13, 505 (1963). 9 Gilbert, W., J. Mol. Biol., 6, 374 (1963). 10 Schlessinger, D., J. Mol. Biol., 7, 569 (1963). 11 Rifkind, R. A., L. Luzatto, and P. A. Marks, these PROCEEDINGS, 52, 1227 (1964). 12 Warner, J. R., A. Rich, and C. E. Hall, Science, 138, 1309 (1962). 13 Slayter, H. S., J. R. Warner, A. Rich, and C. E. Hall, J. Mol. Biol., 7, 652 (1963). 14 Monroy, A., and A. Tyler, Arch. Biochem. Biophys., 103, 431 (1963). 15 Hultin, T., Develop. Biol., 10, 305 (1964). 16 Marks, P. A., R. A. Rifkind, and D. Danon, these PROCEEDINGS, 56, 336 (1963). 17 Rifkind, R. A., D. Danon, and P. A. Marks, J. Cell Biol., 22, 599 (1964). 18 Glowacki, E. R., and R. L. Millette, J. Mol. Biol., 11, 116 (1965). '9 Marks, P. A., E. R. Burka, R. A. Rifkind, and D. Danon, in Synthesis and Structure of Macromolecules, Cold Spring Harbor Symposia on Quantitative Biology, vol. 22 (1963), p. 599. 20Borsook, H., C. L. Deasy, A. J. Haagen-Smit, G. Keighley, and P. H. Lowy, J. Biol. Chem., 196, 699 (1952). 21 Szeinberg, A., and P. A. Marks, J. Clin. Invest., 40, 914 (1961). 22 Kornberg, A., in Methods in Enzymology (New York: Academic Press, 1955), vol. 2, p. 497. 23Lohrmann, K., and 0. Meyerhoff, Biochem. Z., 273, 60 (1934). 24 Goodman, H., and A. Rich, Nature, 199, 318 (1963). 25 Hardesty, B., J. J. Hutton, R. Arlinghaus, and R. Schweet, these PROCEEDINGS, 50, 1078 (1963). 26Burka, E. R., and P. A. Marks, Nature, 204, 659 (1964). 27 Gross, P., J. Exptl. Zool., 157, 21 (1964). 28 Maggio, R., A. NIonroy, A. M. Rinaldi, and Al. L. Vittorelli, Compt. Rend., 260, 1293 (1965). 29 Spirin, A. S., and M. Nemer, in preparation.

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Studies on the role of protein synthesis in the regulation of corticosterone production by adrenocorticotropic hormone in vivo

Plasma ACTH and 17-hydroxycorticosteroid concentrations were measured at various intervals in patients recovering from prolonged pituitary suppression. Pituitary-adrenal recovery was found to follow a definite pattern requiring several months for completion. Initially, both ACTH and corticosteroid levels were relatively low, a situation similar to that seen in patients with hypopituitarism. Thereafter, plasma ACTH levels gradually increased until they were supernormal, but there was a lag of several months in the recovery of normal adrenal responsiveness. Despite the fact that the pituitary gland could secrete large quantities of ACTH and despite the fact that corticosteroid levels were subnormal, a diurnal rhythm was observed in ACTH levels with a decrease to low values during the latter portion of each day. After several months, corticosteroid levels rose to normal, and soon thereafter plasma ACTH concentrations fell again to normal.

Natural history of pituitary-adrenal recovery following long-term suppression with corticosteroids.

Amino-glutethimide inhibits corticosterone synthesis by the rat adrenal cortex both in vivo and in vitro. In intact rats the decrease in corticosterone production is accompanied by an increase in plasma ACTH. In the presence of endogenous or exogenous ACTH, amino-glutethimide causes marked accumulation of adrenal cholesterol. These observations, plus the fact that amino-glutethimide does not impair the conversion of pregnenolone to corticosterone, indicate that the drug inhibits the conversion of cholesterol to pregnenolone. Aminoglutethimide administration results in adrenal enlargement, an effect that appears to be partly due to cholesterol accumulation and partly due to the adrenal growth-promoting effect of increased endogenous ACTH.

Inhibition of adrenal corticosteroid synthesis by aminoglutethimide: studies of the mechanism of action.

Introduction A recent paper 1 published jointly from this laboratory and that of Dr. John A. Luetscher developed the concept that certain tumors of "nonendocrine" tissues can give rise to Cushing's syndrome through the mechanism of secreting an adrenocorticotropic substance which promotes growth of the adrenal cortices and stimulates the secretion of adrenal steroids. It was demonstrated that patients harboring such tumors had excessive concentrations of adrenocorticotropic material in their plasma and that they secreted excessive quantities of cortisol (hydrocortisone), resulting in high levels of plasma and urinary 17-hydroxycorticosteroids (17-OHCS). The hypersecretion of cortisol could not be suppressed by the administration of exogenous steroids such as dexamethasone. Clinical manifestations varied from patient to patient depending upon such factors as the severity of the endocrinologic disturbance, the duration of the disorder, and the sex of the patient. A sine qua non in the diagnosis of this clinicopathological entity is the demonstration

Nonpituitary Neoplasms and Cushing's Syndrome: Ectopic Adrenocorticotropin Produced by Nonpituitary Neoplasms as a Cause of Cushing's Syndrome

Properties of adenyl cyclase of normal adrenals and of a corticosterone-producing adrenal cancer of the rat have been compared. Enzyme activity was found in all particulate fractions of both tissues. The cyclase of the tumor as well as of the adrenals was stimulated by adrenocorticotropic hormone (ACTH) over similar concentration ranges. Unexpectedly, the tumor enzyme was also stimulated by epinephrine, norepinephrine, and thyroid-stimulating hormone (TSH). These hormones produced a dose-related effect over a concentration span that was comparable with that for ACTH. The tumor cyclase was not responsive to angiotensin Il, vasopressin, glucagon, insulin, growth hormone, parathyroid hormone, and thyrocalcitonin. ACTH was the only hormonal preparation that stimulated normal adrenal cyclase. These findings are compatible either with the possibility that the adenyl cyclase receptor of the tumor has undergone structural alteration with a consequent loss of specificity for ACTH or with the possibility that the tumor possesses several cyclase regulatory receptors.

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Robert L. Ney

Papers

Studies on the role of protein synthesis in the regulation of corticosterone production by adrenocorticotropic hormone in vivo

Natural history of pituitary-adrenal recovery following long-term suppression with corticosteroids.

Inhibition of adrenal corticosteroid synthesis by aminoglutethimide: studies of the mechanism of action.

Nonpituitary Neoplasms and Cushing's Syndrome: Ectopic Adrenocorticotropin Produced by Nonpituitary Neoplasms as a Cause of Cushing's Syndrome

Abnormal hormone responses of an adrenocortical cancer adenyl cyclase.