Regulation of Hormone Production

Regulation of Hormone Production tài liệu, giáo án, bài giảng , luận văn, luận án, đồ án, bài tập lớn về tất cả các lĩnh...

Concerted regulation of free arachidonic acid and hormone-induced steroid synthesis by acyl-CoA thioesterases and acyl-CoA synthetases in adrenal cells Paula Maloberti, Rocı ´ o Castilla Lozano, Pablo G. Mele, Florencia Cano, Cecilia Colonna, Carlos F. Mendez, Cristina Paz and Ernesto J. Podesta ´ Department of Biochemistry, School of Medicine, University of Buenos Aires Although the role of arachidonic acid (AA) in the regulation of steroidogenesis is well documented, the mechanism for AA releaseis notclear. Therefore,the aim ofthis studywas to characterize the role of an acyl-CoA thioesterase (ARTISt) and an acyl-CoA synthetase as members of an alternative pathway in the regulation of the intracellular levels of AA in steroidogenesis. Purified recombinant ARTISt releases AA from arachidonoyl-CoA (AA-CoA) with a K m of 2 l M . Antibodies raised against recombinant acyl-CoA thioest- erase recognize the endogenous protein in both adrenal tissue and Y1 adrenal tumor cells by immunohistochemistry and immunocytochemistry and Western blot. Stimulation of Y1 cells with ACTH significantly stimulated endogenous mitochondrial thioesterases activity (1.8-fold). Nordihydro- guaiaretic acid (NDGA), an inhibitor of AA release known to affect steroidogenesis, affects the in vitro activity of recombinant ARTISt and also the endogenous mitochond- rial acyl-CoA thioesterases. ACTH-stimulated steroid syn- thesis in Y1 cells was significantly inhibited by a synergistic effect of NDGA and triacsin C an inhibitor of the AA-CoA synthetase. The apparent IC 50 for NDGA was reduced from 50 l M to 25, 7.5 and 4.5 l M in the presence of 0.1, 0.5 and 2 l M triacsin C, respectively. Our results strongly support the existence of a new pathway of AA release that operates in the regulation of steroid synthesis in adrenal cells. Keywords: arachidonic acid; steroidogenesis; acyl-CoA thio- esterases; acyl-CoA synthetase; arachidonoyl-CoA. The rate-limiting step, which initiates the synthesis of all steroids, depends on the availability of cholesterol to cytochrome P450scc [1,2]. The involvement of a cAMP- dependent protein kinase (PKA) phosphorylation event is accepted as an intermediate step in the cAMP-mediated stimulation of cholesterol availability [3–9] and particularly in the transport of cholesterol from the outer to the inner mitochondrial membrane [1,2,10,11]. The latter event is, in turn, controlled by the steroidogenic acute regulatory protein (StAR protein) [12–16]. Several reports have shown that arachidonic acid (AA) and its metabolites play an essential role in the regulation of steroidogenesis and both the expression and function of StAR [17–26]. Adrenal cholesterol metabolism is inhibited by nordihydroguaiaretic acid (NDGA) [19–25], a lipoxy- genase inhibitor that also acts as phospholipase A 2 inhibitor [27]. NDGA blocks the acute response of bovine cells to ACTH particularly when cAMP release is low [24], and it also decreases the expression of StAR mRNA in rodent steroidogenic cells [23,25,26]. Those effects can be reversed by AA hydroperoxides, a fact that suggests the involvement of lipoxygenases [23,25]. Although the role of AA in trophic hormone-stimulated steroid production in various steroidogenic cells is well documented [17–26], the mechanism responsible for the release of AA remains unknown. Previous Regulation of Hormone Production Regulation of Hormone Production Bởi: OpenStaxCollege Hormone production and release are primarily controlled by negative feedback In negative feedback systems, a stimulus elicits the release of a substance; once the substance reaches a certain level, it sends a signal that stops further release of the substance In this way, the concentration of hormones in blood is maintained within a narrow range For example, the anterior pituitary signals the thyroid to release thyroid hormones Increasing levels of these hormones in the blood then give feedback to the hypothalamus and anterior pituitary to inhibit further signaling to the thyroid gland, as illustrated in [link] There are three mechanisms by which endocrine glands are stimulated to synthesize and release hormones: humoral stimuli, hormonal stimuli, and neural stimuli Art Connection 1/4 Regulation of Hormone Production The anterior pituitary stimulates the thyroid gland to release thyroid hormones T3 and T4 Increasing levels of these hormones in the blood results in feedback to the hypothalamus and anterior pituitary to inhibit further signaling to the thyroid gland (credit: modification of work by Mikael Häggström) Hyperthyroidism is a condition in which the thyroid gland is overactive Hypothyroidism is a condition in which the thyroid gland is underactive Which of the conditions are the following two patients most likely to have? Patient A has symptoms including weight gain, cold sensitivity, low heart rate and fatigue Patient B has symptoms including weight loss, profuse sweating, increased heart rate and difficulty sleeping Humoral Stimuli The term “humoral” is derived from the term “humor,” which refers to bodily fluids such as blood A humoral stimulus refers to the control of hormone release in response to changes in extracellular fluids such as blood or the ion concentration in the blood For example, a rise in blood glucose levels triggers the pancreatic release of insulin Insulin causes blood glucose levels to drop, which signals the pancreas to stop producing insulin in a negative feedback loop Hormonal Stimuli Hormonal stimuli refers to the release of a hormone in response to another hormone A number of endocrine glands release hormones when stimulated by hormones released by other endocrine glands For example, the hypothalamus produces hormones that stimulate the anterior portion of the pituitary gland The anterior pituitary in turn releases hormones that regulate hormone production by other endocrine glands The anterior pituitary releases the thyroid-stimulating hormone, which then stimulates the thyroid gland to produce the hormones T3 and T4 As blood concentrations of T3 and T4 rise, they inhibit both the pituitary and the hypothalamus in a negative feedback loop Neural Stimuli In some cases, the nervous system directly stimulates endocrine glands to release hormones, which is referred to as neural stimuli Recall that in a short-term stress response, the hormones epinephrine and norepinephrine are important for providing the bursts of energy required for the body to respond Here, neuronal signaling from the sympathetic nervous system directly stimulates the adrenal medulla to release the hormones epinephrine and norepinephrine in response to stress 2/4 Regulation of Hormone Production Section Summary Hormone levels are primarily controlled through negative feedback, in which rising levels of a hormone inhibit its further release The three mechanisms of hormonal release are humoral stimuli, hormonal stimuli, and neural stimuli Humoral stimuli refers to the control of hormonal release in response to changes in extracellular fluid levels or ion levels Hormonal stimuli refers to the release of hormones in response to hormones released by other endocrine glands Neural stimuli refers to the release of hormones in response to neural stimulation Art Connections [link] Hyperthyroidism is a condition in which the thyroid gland is overactive Hypothyroidism is a condition in which the thyroid gland is underactive Which of the conditions are the following two patients most likely to have? Patient A has symptoms including weight gain, cold sensitivity, low heart rate and fatigue Patient B has symptoms including weight loss, profuse sweating, increased heart rate and difficulty sleeping [link] Patient A has symptoms associated with decreased metabolism, and may be suffering from hypothyroidism Patient B has symptoms associated with increased metabolism, and may be suffering from hyperthyroidism Review Questions A rise in blood glucose levels triggers release of insulin from the pancreas This mechanism of hormone production is stimulated by: humoral stimuli hormonal stimuli neural stimuli negative stimuli A Which mechanism of hormonal stimulation would be affected if signaling and hormone release from the hypothalamus was blocked? humoral and hormonal stimuli hormonal and neural stimuli 3/4 Regulation of Hormone Production ...MINIREVIEW Gonadotropin-releasing hormone: regulation of the GnRH gene Vien H. Y. Lee, Leo T. O. Lee and Billy K. C. Chow School of Biological Sciences, The University of Hong Kong, China Introduction Gonadotropin-releasing hormone (GnRH) is a central regulator in the hypothalamic–pituitary–gonadal axis of the reproductive hormonal cascade. It is expressed in a discrete population of neurosecretory cells located throughout the basal hypothalamus of the brain, and is released into the hypothalamo-hypophyseal portal circulation in a pulsatile manner and in surges during the female preovulatory period [1]. The released GnRH is transported to the anterior pituitary gland, where the hormone binds to its receptor on the gonadotropes. This triggers the synthesis and release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are respon- sible for gonadal steroidogenesis and gametogenesis. Keywords estrogen; follicle-stimulating hormone; GnRH; gonadotropin; luteinizing hormone; PKC signalling; progesterone; promoter; steroid hormone; transcriptional regulation Correspondence B. K. C. Chow, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong, China Fax: +852 2559 9114 Tel: +852 2299 0850 E-mail: bkcc@hkusua.hku.hk (Received 18 April 2008, revised 4 August 2008, accepted 29 August 2008) doi:10.1111/j.1742-4658.2008.06676.x As the key regulator of reproduction, gonadotropin-releasing hormone (GnRH) is released by neurons in the hypothalamus, and transported via the hypothalamo-hypophyseal portal circulation to the anterior pituitary to trigger gonadotropin release for gonadal steroidogenesis and gametogene- sis. To achieve appropriate reproductive function, mammals have precise regulatory mechanisms; one of these is the control of GnRH synthesis and release. In the past, the scarcity of GnRH neurons and their widespread distribution in the brain hindered the study of GnRH gene expression. Until recently, the development of GnRH-expressing cell lines with proper- ties similar to those of in vivo GnRH neurons and also transgenic mice facilitated GnRH gene regulation research. This minireview provides a sum- mary of the molecular mechanisms for the control of GnRH-I and GnRH-II gene expression. These include basal transcription regulation, which involves essential cis-acting elements in the GnRH-I and GnRH-II promoters and interacting transcription factors, and also feedback control by gonadotropins and gonadal sex steroids. Other physiological stimuli, e.g. insulin and melatonin, will also be discussed. Abbreviations AP-1, activator protein-1; AR, androgen receptor; atRA, all-trans-retinoic acid; C ⁄ EBP, CCAAT ⁄ enhancer-binding protein; CREB, cAMP response element-binding protein; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; Dlx2, distal-less homeobox 2; DREAM, downstream regulatory element antagonist modulator; E 2 ,17b-estradiol; EMSA, electrophoretic mobility shift assay; ER, estrogen receptor; FSH, follicle-stimulating hormone; GABA, c-aminobutyric acid; GnRH, gonadotropin-releasing hormone; GRG, Groucho-related gene; hCG, human chorionic gonadotropin; hGLC, human granulosa-luteal cell; hGnRH-I, human gonadotropin-releasing hormone type I; IGF-I, insulin-like growth factor-I; LH, luteinizing hormone; mGnRH-I, mouse gonadotropin-releasing hormone type I; Msx, muscle segment homeobox; NIRKO, neuron-specific insulin receptor knockout; NMDA, N-methyl- D-aspartic acid; NO, nitric oxide; nPRE, negative progesterone response element; Oct-1, octamer-binding transcription factor-1; Regulation of luteinizing hormone receptor mRNA expression by mevalonate kinase – role of the catalytic center in mRNA recognition Anil K. Nair 1,2 , Matthew A. Young 2,3 and K. M. J. Menon 1,2 1 Department of Obstetrics ⁄ Gynecology, University of Michigan Medical Center, Ann Arbor, MI, USA 2 Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI, USA 3 Bioinformatics Program, University of Michigan Medical Center, Ann Arbor, MI, USA The luteinizing hormone receptor (LHR) present on cell membranes of gonadal tissues belongs to the family of leucine-rich repeat-containing G-protein-cou- pled receptors (LGRs) [1,2]. Interaction of luteinizing hormone (LH) or its placental counterpart, human chorionic gonadotropin (hCG), with LHR induces Gs-protein-mediated adenylate cyclase activation, which leads to an increase in cellular cAMP levels [1,3,4]. The expression of LHRs varies during the ovarian cycle, and some of these changes in receptor Keywords LH receptor; mevalonate kinase; mRNA stability; ovary; post-transcriptional regulation Correspondence K. M. J. Menon, 6428 Medical Science 1, 1301 E. Catherine Street, Ann Arbor, MI 48109-0617, USA Fax: +1 734 936 8617 Tel: +1 734 764 8142 E-mail: kmjmenon@umich.edu (Received 24 January 2008, revised 2 April 2008, accepted 30 April 2008) doi:10.1111/j.1742-4658.2008.06490.x We have shown that hormone-induced downregulation of luteinizing hor- mone receptor (LHR) in the ovary is post-transcriptionally regulated by an mRNA binding protein. This protein, later identified as mevalonate kinase (MVK), binds to the coding region of LHR mRNA, suppresses its transla- tion, and the resulting ribonucleoprotein complex is targeted for degrada- tion. Mutagenesis and crystallographic studies of rat MVK have established Ser146, Glu193, Asp204 and Lys13 as being crucial for its cata- lytic function. The present study examined the structural aspects of MVK required for LHR mRNA recognition and translational suppression. Single MVK mutants (S146A, E193Q, D204N and K13A) were overexpressed in 293T cells. Cytosolic fractions were examined for LHR mRNA binding activities by RNA electrophoretic mobility shift analysis. All the single MVK mutants showed decreased LHR mRNA binding activity compared with the wild-type MVK. Double mutants (S146A & E193Q, E193Q & D204N and E193Q & K13A) of MVK also showed a significant decrease in binding to LHR mRNA, suggesting that the residues required for cata- lytic function are also involved in LHR mRNA recognition. Mutation of the residues outside the catalytic site (D316A and S314A) did not cause any change in LHR mRNA binding activity of MVK when compared with wild-type MVK. To examine the biological effects of these mutants on LHR mRNA expression, a full-length capped rat LHR mRNA was synthe- sized and translated using a rabbit reticulocyte lysate system in the pres- ence or absence of the MVK mutant proteins. The results showed that mutations of the active site residues of MVK abrogated the inhibitory effect on LHR mRNA translation. Therefore, these data indicate that an intact active site of MVK is required for its binding to rat LHR mRNA and for its translational suppressor function. Abbreviations GHMP, galactokinase homoserine kinase mevalonate kinase phosphomevalonate kinase; hCG, human chorionic gonadotropin; IRE, iron regulatory element; IRP1, iron regulatory protein 1; Regulation of glypican-1, syndecan-1 and syndecan-4 mRNAs expression by follicle-stimulating hormone, cAMP increase and calcium influx during rat Sertoli cell development Sylvie Brucato, Jean Bocquet and Corinne Villers Laboratoire de Biochimie IRBA, UPRES, Universite ´ de Caen, France In seminiferous tubules, Sertoli cells provide structural and nutritional support for the developing germinal cells. Cell- to-cell signaling and cell adhesion require proteoglycans expressed at the cell membrane. A preliminary biochemical and structural approach indicated that cell surface proteo- glycans are mostly heparan sulfate proteoglycans (HSPG). Glypican-1, syndecans-1 and -4 were identified using a molecular approach. Their differential regulation was dem- onstrated in immature rat Sertoli cells. Follicle-stimulating hormone (FSH) is the main regulator of Sertoli cell function. Signal transduction triggered by FSH involves both an increased intracellular cAMP synthesis and a calcium influx. This study demonstrates that FSH, through its second messengers (increase in intracellular cAMP and intracellular calcium), downregulated the glypican-1 mRNA expression in Sertoli cells from 20-day-old rats. On the other hand, syndecan-1 mRNA expression is not modulated by FSH as it would result from the antagonistic effects of increased intracellular cAMP and intracellular calcium levels. Finally, syndecan-4 mRNA expression is not regulated by this pathway. The present study was extended during Sertoli cell devel- opment. Indeed, Sertoli cells undergo extensive changes during the postnatal period both in structure and function. These important transformations are critical for the esta- blishment of spermatogenesis and development of the adult pattern of testicular function. Our data indicated that the regulation of HSPG mRNA expression is HSPG-specific and depends on the Sertoli cell developmental stage. Keywords: 1 FSH; calcium; heparan sulfate proteoglycan; Sertoli cell development. Syndecans and glypicans are cell surface receptors bearing heparan sulfate (HS) chains and comprising four (syndecan-1 to -4) [1,2] and six members (glypican-1 to -6) [3], respectively. Syndecans are characterized by a specific extracellular domain displaying low sequence homology, and highly conserved transmembrane and cytoplasmic domains. How- ever, the cytoplasmic domain of all four syndecans contains a central region unique to each syndecan, which would confer specific biological activity [4,5]. Glypicans are attached to the plasma membrane via glycosylphophatidylinositol (GPI) anchors [1,2]. Although the primary structure of the glypi- cans is only marginally conserved (about 30% identity), there is a strict conservation of 14 cysteine residues within the core protein leading to compact conformation but also of HS-attachment consensus sequences at the C-termini of proteins. Syndecans and glypicans are individually expressed in distinct cell-, tissue-, and development-specific patterns [6–10]. Modifications in glypican and syndecan expression may be induced by activation of signaling processes. It was shown that glypican-1 is downregulated by the presence of both bFGF and TGF-b1 in fibroblasts [11] and by bFGF in mature oligodendrocytes [12], but the mechanisms that account for the regulated expression of the glypican are almost completely unknown. In contrast, syndecan expres- sion is modulated by growth factors MINIREVIEW Tec family kinases Itk and Rlk ⁄ Txk in T lymphocytes: cross-regulation of cytokine production and T-cell fates Julio Gomez-Rodriguez, Zachary J. Kraus and Pamela L. Schwartzberg National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA Introduction Among the key players in intracellular signaling in lym- phocytes are the Tec family kinases (TFKs), which include Tec, Bruton’s tyrosine kinase (Btk), IL-2 induc- ible T-cell kinase (Itk, also known as EMT or TSK), resting lymphocyte kinase (Rlk, also known as Txk) and Bmx (Etk). These kinases are activated by a wide variety of surface receptors including antigen, cytokine, chemokine, G-protein coupled and Toll-like receptors, as well as integrins [1]. Three TFKs are expressed in the T-cell lineage, Itk, Rlk ⁄ Txk and Tec, which are found in both thymocytes and mature T cells. Itk is expressed at the highest levels, followed by Rlk ⁄ Txk and then Tec. Consistent with these levels of expression, Itk has the greatest effects on T-cell function, where it plays a major role in T-cell receptor (TCR) signaling. Although BTK was the first tyrosine kinase associated with a primary immunodeficiency, X-linked agamma- globulinemia in humans and X-linked immunodefi- ciency in mice [1], IL-2 inducible T-cell kinase has only recently been implicated in a human primary genetic immune disorder. A homozygous missense mutation in ITK was found in two patients with a fatal Epstein- Barr Virus-associated lymphoproliferative disorder [2]. Nonetheless, mice deficient in the TFKs Itk or Itk and Rlk ⁄ Txk show altered T-cell development and impaired mature T-cell effector function, highlighting the importance of this family in T cells [1]. In addition, altered expression of Tec kinases has been found in pathological states. Patients with atopic dermatitis, a Th2-mediated disease, exhibit increased Itk expression Keywords cytokines; innate lymphocytes; Itk; PLZF; Rlk ⁄ Txk; T-helper cells; Th1; Th2; Th17; thymus Correspondence P. L. Schwartzberg, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA Fax: +1 301 402-2170 Tel: +1 301 435-1906 E-mail: pams@nhgri.nih.gov (Received 1 September 2010, revised 2 December 2010, accepted 25 February 2011) doi:10.1111/j.1742-4658.2011.08072.x Developing thymocytes and T cells express the Tec kinases Itk, Rlk ⁄ Txk and Tec, which are critical modulators of T-cell receptor signaling, required for full activation of phospholipase Cc, and downstream Ca 2+ and ERK- mediated signaling pathways. Over the last 10 years, data have implicated the Tec family kinases Itk and Rlk ⁄ Txk as important regulators of cyto- kine production by CD4 + effector T-cell populations. Emerging data now suggest that the Tec family kinases not only influence cytokine-producing T-cell populations in the periphery, but also regulate the development of distinct innate-type cytokine-producing T-cell populations in the thymus. Together, these results suggest that the Tec family kinases play critical roles in helping shape immune responses via their effects on the differentiation and function of distinct cytokine-producing, effector T-cell populations. Abbreviations BTK, Bruton’s tyrosine kinase; IFN, interferon; IL, interleukin; iNKT, invariant natural killer T cell; MHC, major histocompatibility complex; NFAT, nuclear .. .Regulation of Hormone Production The anterior pituitary stimulates the thyroid gland to release thyroid hormones T3 and T4 Increasing levels of these hormones in the blood... Stimuli Hormonal stimuli refers to the release of a hormone in response to another hormone A number of endocrine glands release hormones when stimulated by hormones released by other endocrine glands... stimulates the adrenal medulla to release the hormones epinephrine and norepinephrine in response to stress 2/4 Regulation of Hormone Production Section Summary Hormone levels are primarily controlled