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The somatotropic axis is one of the major hormonal systems regulating growth, development, and metabolism. Growth hormone (GH) can act directly on target tissues or indirectly by stimulating insulin-like growth factor (IGF-I) through the JAK2-Stat5 pathway. The first objective of this dissertation was to test whether exogenous GH could stimulate growth, development, and insulin resistance in the absence of functional Stat5 proteins. Wild type (WT) and Stat5 mutant (Stat5DN) mice were treated with exogenous GH for 4 weeks. Stat5DN mice grew at a slower rate and had lower hepatic IGF-I expression and plasma IGF-I than WT animals. GH stimulated growth in WT animals but had absolutely no effect in Stat5DN mice. GH increased hepatic IGF-I expression and plasma IGF-I in WT mice but failed to do so in Stat5DN mice. GH-stimulated IGF-I expression also occurred in the muscle and adipose of WT mice only. GH-treated Stat5DN mice were protected from GH-induced insulin resistance. This protection was associated with lack of GH-stimulated expression of p85a mRNA in insulin sensitive tissues. GH plays a critical role in mammary development through its modulation of mammary production of IGF-I and IGF binding proteins (IGFBPs). One component of the IGF system that has not been studied in mammary development is the acid labile subunit (ALS). ALS is thought to function exclusively by forming ternary complexes with IGF-I and IGFBP-3 or -5 to build a reservoir of circulating IGF-I. The second objective was to evaluate the role of ALS in mammary gland development using null ALS mice. Null ALS mice had three specific mammary defects, namely delayed ductal elongation, impaired ductal branching in early pregnancy, and delayed involution following lactation. In contrast, mammary development during late ALS mRNA was pregnancy and lactation appeared normal in null ALS mice. detected in the mouse mammary gland, and levels of expression were comparable to liver during pregnancy, lactation, and involution. Therefore, mammary defects seen in null ALS mice cannot be attributed solely to disruption of the circulating IGF system and could relate partly to local ALS expression.
This revised new edition reviews the substantial advances in our understanding of the vital role of growth hormone (GH) in maintaining adult health, and the resulting disorders from GH deficiency. The first edition, published in 1996, provided a pioneering overview of the subject; this new edition provides an even more comprehensive account, fully updated with the latest research, clinical applications, and references. The therapeutic benefits of GH treatment in GH deficiency are thoroughly evaluated, including effects on metabolism, cardiac function, exercise performance, psychosocial aspects, and aging and gender-specific effects. This compilation by the world's leading experts covers clinical investigation, diagnosis and treatment issues, and encompasses new knowledge of the control and action of GH secretion. This volume is the most authoritative, comprehensive, and detailed account available and will be an essential source of reference for all endocrinologists.
Insulin-like growth factor (IGF)-I is a widely expressed growth factor with diverse effects on many tissues throughout development and in adult life. The purpose of this work is to provide detailed and updated information on the role of the growth hormone (GH)-IGF axis in fetal and postnatal development, as well as its physiological functions and implications in pathology.
Insulin-like growth factors are ubiquitously expressed and are crucial for growth and function of almost all cells. Together with their binding proteins and receptors, they form a widely studied biological system involving many proteins and characterized by complex interactions. In addition to its significance in growth and development, the insulin-like growth factor system also has important roles in a wide variety of pathological states. This has led to interest in the therapeutic potential of insulin-like growth factors and their binding proteins as candidate drug targets. This comprehensive book contains current information on both basic science and clinical aspects of IGFs and their regulatory proteins, with emphasis on their relevance to cancer.
First published in 1943, Vitamins and Hormones is the longest-running serial published by Academic Press. The Editorial Board now reflects expertise in the field of hormone action, vitamin action, X-ray crystal structure, physiology, and enzyme mechanisms. Under the capable and qualified editorial leadership of Dr. Gerald Litwack, Vitamins and Hormones continues to publish cutting-edge reviews of interest to endocrinologists, biochemists, nutritionists, pharmacologists, cell biologists, and molecular biologists. Others interested in the structure and function of biologically active molecules like hormones and vitamins will, as always, turn to this series for comprehensive reviews by leading contributors to this and related disciplines.This volume focuses on insulin and IGFs. - Longest running series published by Academic Press - Contributions by leading international authorities
Insulin-like growth factor I (IGF-I) gene expression is under developmental control, however, molecular mechanisms governing its regulation remain poorly defined. Growth hormone (GH), whose action is mediated by the GH receptor (GHR), is a major regulator of IGF-I gene expression. The expression of IGF-I and GHR mRNA is widely distributed, with the liver being the primary site of expression of both genes. Mechanisms of GH action are known, however signal transduction pathways that mediate GH activation of the IGF-I gene are undefined. In this series of studies, we investigated what factors determine IGF-I gene expression during development. RNase protection assays and Western blot analysis demonstrated that the expression of the IGF-I gene correlates with GHR expression in all the rat tissues we examined such as liver, testis, skeletal muscle, heart, kidney, lung and brain. Further, with the exception of insulin receptor substrate 1 (IRS-1), GH signaling molecules were expressed at all stages of development. In addition, levels of hepatic and brain nuclear protein binding to IGF-I foot print I (IGFI-FPI), a protein binding site in the major promoter of the rat IGF-I gene that is important for basal promoter activity in vitro, were similar throughout development, demonstrating that the IGFI-FPI is likely not involved in the developmental regulation of IGF-I gene expression. These data indicated a critical role of GHR in determining levels of IGF-I gene expression during development. However, increasing the level of GHR expression in fetal rat hepatocytes did not induce GH-dependent IGF-I gene expression, despite inducing GH-dependent activation of genes with defined GH responsive elements such as c-fos and spi 2.1 in these cells. This indicated that in addition to GHR expression, regulation of factors operating at a post-receptor level is likely to be important for inducing GH-mediated IGF-I gene expression. This led us to begin to define the signal transduction pathways that are utilized by GH to mediate IGF-I gene expression. We show that PI3-kinase and the ERKs are important for GH dependent regulation of IGF-I gene expression in rat hepatocytes, with PI3-kinase having a more robust effect.
The various congresses on growth hormone (GH) which have been held in Milan since 1967, the Milan Congresses, have witnessed over 25 years the tremendous expansion of a research field that was based initially upon the scarce knowledge of the biological properties of a protein. GH, whose chemical structure had just been identified and a radioimmunoassay developed for its measurement in blood, became in the following years a major area of biological research. The boundaries have since become blurred, as the research area has extended to the physiology and pathology of growth, puberty and reproduction, and the control of metabolism during the whole lifespan. Since the last GH Congress held in 1987, GH studies using the molecular biological approach have resulted in the puri fication, cloning and expression of the human GH (hGH) recep tor and binding protein, in new and exciting information on the insulin-like growth factors (IGF) and their paracrine and autocrine roles, and in the awareness that a panoply of binding proteins are present in the extracellular fluids and can, possibly, modulate IGF-receptor interactions and, thus, IGF actions. Finally, the availability of large amounts of biosynthetic hGH, besides allow ing more extensive clinical use in states of GH deficiency and extrasomatotrophic pathologies, has permitted disclosure of im portant metabolic effects of hGH during adulthood and, perhaps, aging and in many protein catabolic states.
Biotechnology in Growth Regulation focuses on mechanisms of action of growth hormones and how immunological and transgenic procedures can affect growth response. The book first examines species specificity and structure-function relationship of growth hormones. Microheterogeneity of growth hormones; variations in amino acid sequence and biological properties of growth hormones; and structure-function relationship are discussed. The text also looks at growth hormone receptors and binding proteins; regulation of growth hormone receptors; modulations of growth hormone release; and neuroregulation of growth hormone secretion. The book then discusses the role of growth hormones in the regulation of adipocyte growth and function. Chronic effects of growth hormones on insulin action and lipid synthesis; effects of growth hormones on lipolysis; and adipogenesis are also described. The text looks at growth-promoting properties of recombinant growth hormones and mechanisms by which porcine growth hormone enhances growth in pigs. The book also highlights the direct effects of growth hormones on osteogenesis and chondrogenesis; action of IGF-I on mammary function; antigen-antibody complexes that enhance growth; and transgenics. The text also presents experiments that show the effects of growth hormones on animals. The book is a good source of information for readers wanting to study growth hormones.
During the past decade, the continued interest in insulin-related growth factors has been documented by a plethora of research programs and publications focused on these growth factors. Both molecular and cellular biological techniques have improved and enabled investigators to study the properties of the growth factors in depth. This volume covers the molecular (genetic) aspects of the growth factors, their binding proteins and receptors, as well as those factors affecting their gene transcription and translation. In addition, aspects of the cellular action of these growth factors through their receptors and how this impacts normal cellular function are discussed. The book will provide valuable information for researchers in physiology, biology, endocrinology, and metabolism.
Readers of this book can update their knowledge in the fast-moving field of endocrinology and neurobiology. Topics concerning growth and development are extensively reviewed from both basic science and clinical viewpoints. Aspects related to growth development and to the control of cellular differentiation and multiplication are discussed. Further new information is provided on: synthetic recombinant human growth hormone (rHGH); potential diagnostic and therapeutic applications of the neuropeptide, growth hormone releasing hormone (GHRH); the physiology and physiopathology of the neural control of growth hormone secretion; the diagnosis and therapy of growth hormone deficiency or excess states; and the biology, function and possible utilization of growth factors. These important new findings are relevant to progress in pediatrics, pediatric and clinical endocrinology, neuroendocrinology and physiology.