The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR).

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.

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

Molecular cloning of a novel melanocortin receptor.

Steroid hormone biosynthesis in steroidogenic cells is regulated through trophic hormone activation of protein kinase A (PKA) signaling pathways. However, many examples of the regulation of steroid synthesis via pathways other than the PKA pathway have been documented. In some cases these pathways act independently of PKA activation whereas in other cases, they act synergistically with it. The current understanding of additional signaling pathways and factors, such as the protein kinase C pathway, arachidonic acid metabolites, growth factors, chloride ion, the calcium messenger system, and others capable of regulating/modulating steroid hormone biosynthesis, and in many cases steroidogenic acute regulatory protein expression, are discussed in this review.

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Multiple Signaling Pathways Regulating Steroidogenesis and Steroidogenic Acute Regulatory Protein Expression: More Complicated than We Thought

As determined by electron-microscope autoradiography of adrenal glands containing tritiated cholesterol and by modified differential centrifugation techniques, 70 to 80 percent of adrenal cholesterol is contained within lipid droplets of rat adrenal cortical cells.

http://science.sciencemag.org/content/sci/163/3872/1203.full.pdf

Adrenal Cholesterol: Localization by Electron-Microscope Autoradiography

On the Mechanism of Action of Adrenocorticotropic Hormone THE INHIBITORY SITE OF CYCLOHEXIMIDE IN THE PATHWAY OF STEROID BIOSYNTHESIS

Publisher Summary This chapter discusses the relationship of the structure of adrenocorticotropic hormone (ACTH) to its function and the pathway of adrenal cortical biosynthesis. A series of remarkable achievements in protein chemistry have led to the isolation and purification of ACTH, the determination of its primary structure, and its synthesis. The biochemical synthesis of adrenal corticosteroids with its many complexities is explained in the chapter. The influence of ACTH on the adrenal cortex is not limited to the stimulation of corticosteroid production; the maintenance of the structure of the adrenal cortex is also dependent upon this hormone. The removal of the pituitary gland from rats resulted in the atrophy of the adrenal cortex and that the transplantation of the pituitary to hypophysectomized animals caused a return of adrenal cortical weight toward normal. The synthesis of glucocorticoids in the adrenal cortex is accomplished by a series of enzymes situated in different organelles. The evidence indicates that the first substrate, cholesterol, enters the mitochondrion where it is transformed into pregnenolone. Pregnenolone leaves the mitochondrion and is converted into progesterone in the cytoplasm. Progesterone, in turn, is transformed into deoxycorticosterone by an enzyme system in the microsomal fraction of the cell. Corticosterone is produced finally from deoxycorticosterone that has reentered the mitochondrion.

The Mechanism of Action of Adrenocorticotropic Hormone

Template RNA in adrenal glands appears to be heterogeneous in stability. The RNA that regulates synthesis of a large fraction of adrenal protein has a turnover time of 4 hours or less. The remainder of adrenal-protein synthesis, including synthesis of protein that mediates the rapid steroidogenic response to ACTH, depends on RNA with considerably greater stability.

http://science.sciencemag.org/content/sci/153/3738/896.full.pdf

Leonard D. Garren

Papers

Adrenal Cholesterol: Localization by Electron-Microscope Autoradiography

On the Mechanism of Action of Adrenocorticotropic Hormone THE INHIBITORY SITE OF CYCLOHEXIMIDE IN THE PATHWAY OF STEROID BIOSYNTHESIS

The Mechanism of Action of Adrenocorticotropic Hormone

Heterogeneity of Template RNA in Adrenal Glands

Amino acid incorporation by mitochondria of the adrenal cortex: the effect of chloramphenicol.