Activation of the cAMP pathway by TSH stimulates both cell proliferation and differentiation of thyrocytes. TSH is known to bind to a seven transmembrane receptor, coupled to heterotrimeric G proteins. Adenylate cyclase activity is increased by TSH through activation of Gs. But the human TSH receptor also activates the phospholipase C-diacylglycerol-inositol phosphate cascade. Hyperfunctioning thyroid adenomas are monoclonal and their growth and functional activity are TSH-independent. Therefore, somatic activating mutations in genes encoding proteins of the TSH signaling pathway (mainly the cAMP-regulatory cascade) were expected in these tumors. GaS activating mutations leading to TSH-independent constitutive adenylate cyclase activity were the first to be described. More recently, activating point mutations of TSH receptor were reported. The mutations studied initially cause constitutive activation of the cAMP-regulatory cascade only, without stimulation of the inositol phosphate-diacylglycerol one. The effect of TSH receptor and Gas mutations is dominant. TSH receptor activating mutations have been found
The von Hippel-Lindau disease is an autosomal dominant genetic syndrome characterized by the development of multiple tumors, including hemangioblastoma of the central nervous system and retina, renal cyst or carcinoma, and pheochromocytoma. Pheochromocytomas are frequently bilateral in VHL patients and are observed in 10 to 19% of cases. The von Hippel-Lindau susceptibility gene (VHL) is located on the short arm of chromosome 3 (3p25–26). Mutations of VHL are found in most affected kindred. Loss of heterozygosity at the VHL locus affecting selectively the wild-type VHL allele is associated with tumor formation, as commonly observed with tumor suppressor genes. Interestingly, in most cases of sporadic renal carcinoma or hemangioblastoma, the VHL gene is also altered by mutation or hypermethylation. Furthermore, transfection of the wild-type VHL cDNA into renal carcinoma cells inhibits tumor development, whereas transfection of the mutant does not.
Cloning of the human VHL gene was first reported in 1993.
The insulin-like growth factors (IGFs) have been known for a long time to play an important stimulatory role in cell growth. Their bioavailability is regulated by at least six IGF binding proteins. More recently, an inhibition of cell proliferation by one of these IGF binding proteins (IGFBP-3) has been observed. The growth inhibitory effect of IGFBP-3 could be mediated by inhibition of IGF-I. Nevertheless, experiments performed using fibroblasts devoid of IGF-I receptor (derived from IGF-I receptor knockout embryos) suggest that growth inhibition by IGFBP-3 could be independent of the IGF-I receptor (1). The human tumor suppressor protein p53 is critical for the regulation of the cell cycle in response to genotoxic stress. Deleterious mutations or loss of the p53 gene are observed in over half of all human tumors. It is also speculated that the upstream or downstream component of the p53 pathway could be altered in some of the
Resistance to hormone action is often explained by alterations in hormone receptors, transduction mechanisms or enzymes. Two recent reports suggest that, in the case of insulin resistance, alterations in gene expression control at the nuclear level (in particular, transcriptional regulation) might also represent a potential mechanism for resistance to hormone action in human disease. The transcriptional regulation of gene expression is controlled by regulatory proteins known as transcription factors (or trans-acting factors). They bind to defined DNA sequences in the regulatory regions of specific genes (cis-elements). It was tempting to speculate that alteration in trans-acting factors or ciselements implicated in insulin action could result in insulin resistance.
Apolipoprotein C-III (apo C-III) is present in triglyceride-rich lipoproteins. In diabetic mice, a clear increase in apo C-III is observed. Transcription of the apo C-III gene is inhibited by insulin. Several observations suggest that apo C-III overexpression might be
Synthesis and secretion of growth hormone by the anterior pituitary gland is mainly controlled by two antagonist hypothalamic neuropeptides: the stimulatory hormone GHRH and the inhibitory hormone somatostatin. The GHRH receptor (GHRH-R) is a member of the seven-transmembrane G-proteincoupled receptor superfamily. It interacts with Gs protein to stimulate adenylate cyclase activity and cyclic AMP (cAMP) production. Both GHRH and cAMP are known to be involved in somatotroph proliferation and differentiation. Growth hormone-releasing hormone was purified for the first time in 1982 from a pancreatic tumor responsible for acromegaly and pituitary hyperplasia. In transgenic mice, overexpression of GHRH causes also gigantism and somatotroph hyperplasia or tumor.
Growth hormone (GH) deficiency leading to growth failure might result from alterations of the hypothalamic control of the anterior pituitary, abnormal development of the somatotroph cell or GH synthesis and alterations of secretion. Some familial cases of GH deficiency have been explained by mutations of
Transcriptional regulation by cyclic AMP (cAMP) of numerous eukaryotic genes is mediated through a consensus sequence present in the proximal part of their promoter (cis-elements) and termed cAMP-response element (CRE). Three transcription factors (transacting factors) that bind the CRE and are phosphorylated by protein kinase A (PKA) after activation of the cAMP signal transduction pathway have been identified: CRE binding protein (CREB), CRE modulator (CREM) and activating transcription factor 1 (ATF-1). They belong to the bZIP protein superfamily of transcription factors. Both CREB and ATF-1 are considered as transcriptional activators. The CREM gene generates numerous proteins by alternative splicing, promoter usage and translational initiation. Some of the products of the CREM gene are activators, while others are transcriptional repressors. A differential regulation of expression of the CREM gene has been observed in the testis during spermiogenesis. Premeiotic germ cells express the repressor isoforms of CREM at low level,
Specific pituitary vasopressin receptors involved in stress-induced ACTH secretion have been postulated for a long time. This hypothesis was recently confirmed by the cloning of a cDNA coding for a new subtype of vasopressin receptor, termed V3 or V1b (1, 2). This receptor belongs to the superfamily of seven transmembrane domain receptors coupled to G proteins. It is coupled to a Gq-like protein and activates phospholipase C. The pharmacological characteristics of the V3 receptor are different from the characteristics of the Via and V2 receptors. In humans, this receptor seems mainly expressed in the pituitary corticotrophs.
Various neuroendocrine tumors expressing the proopiomelanocortin (POMC) gene, such as bronchial carcinoids, small cell carcinomas of the lung (SCCL), pheochromocytomas, pancreatic carcinoids, medullary thyroid cancer and others are known to secrete ectopic ACTH and induce Cushing's syndrome. The bronchial carcinoids are usually highly differentiated and have a rather benign course. On the other hand,
Postnatal growth is dependent on growth hormone (GH). Patients presenting with GH deficiency exhibit growth failure. The molecular defects identified so far as responsible for postnatal growth retardation are alterations in the GH, GH receptor and GH-releasing hormone receptor genes and in the gene of the pituitary transcription factor Pit-1. Even when severe GH deficiency is observed in patients harboring such molecular defects, only mild growth delay is observed at birth. The growth effects of GH in humans are therefore more important after birth, and GH seems to play a minor role during intrauterine development. Insulin-like growth factor-I (IGF-I) mediates most of the effects of GH during the postnatal period. IGF-I acts both as a mitogen and a differentiation factor. Transgenic mice with a targeted disruption of the IGF-I gene exhibit severe intrauterine as well as postnatal growth deficiency (1–3). Furthermore, this mouse has a higher perinatal death rate, delayed
The pulsatile secretion of growth hormone (GH) by the somatotrophs is controlled by at least two antagonistic hypothalamic peptides: somatostatin (SRIH) which inhibits GH release and growth hormone releasing hormone (GHRH) which stimulates GH release. Both peptides have been purified and well characterized. The mechanisms of action of these hypothalamic peptides has also been extensively studied and their receptors have been cloned. Both GHRH and SRIH receptors belong to the family of seven transmembrane receptors coupled to a heterotrimeric GTP-binding protein. The SRIH receptor is coupled to a Gi protein and its activation inhibits adenylate cyclase. On the other hand, the GHRH receptor is coupled to a Gs protein and its activation stimulates adenylate cyclase activity leading to increased cyclic AMP (cAMP) intracellular levels.
Recently, the discovery of new stimulators of GH secretion has led to the postulation of a third endocrine pathway controlling GH secretion. A synthetic hexapetide, termed
Laurence Guignat and Jérôme Bertherat
Cushing's syndrome is considered a rare disease and its diagnosis can be challenging. Establishment of evidence-based recommendations is difficult. In 2008, several national and international consensus recommendations for the diagnosis or management of Cushing's syndrome were reported. The Endocrine Society, with the participation of the European Society of Endocrinology, has developed a task force to update recommendations for the diagnosis of Cushing's syndrome. The main aspects of these recommendations are presented in this article and discussed in the context of current research efforts in Europe focusing on the improvement of diagnosis and management of rare diseases including adrenal disorders such as Cushing's syndrome.