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Corticotropin-releasing hormone (CRH) coordinates hormonal and behavioral responses to stress. The mitogen-activated protein kinase extracellular signal-related kinase ½ (ERK½) mediates several functions in different forebrain structures and recently has been implicated in CRH signaling in cultured cells. To study in vivo CRH-mediated activation of central ERK½, we investigated the expression pattern of the phosphorylated ERK½ (p-ERK½) in the mouse brain after intracerebroventricular CRH injections. As shown by immunohistochemistry and confocal microscopy analysis, CRH administration increased p-ERK½ levels specifically in the CA3 and CA1 hippocampal subfields and basolateral complex of the amygdala, both structures related to external environmental information processing and behavioral aspects of stress. Other regions such as hypothalamic nuclei and the central nucleus of the amygdala, also related to central CRH system but involved in the processing of the ascending visceral information and neuroendocrine-autonomic response to stress, did not show CRH-mediated ERK½ activation. To dissect the involvement of CRH receptor 1 (CRHR1) and CRHR2, we used conditional knockout mice in which Crhr1 is inactivated in the anterior forebrain and limbic structures. The conditional genetic ablation of Crhr1 inhibited the p-ERK½ increase, underlining the involvement of CRHR1 in the CRH-mediated activation. These findings underscore the fact that CRH activates p-ERK½ through CRHR1 only in selected brain regions, pointing to a specific role of this pathway in mediating behavioral adaptation to stress. [ABSTRACT FROM AUTHOR]

Presents a study which investigated the expression and function of sonic hedgehog (Shh) in the adult pituitary gland. Expression of Shh pathway components by corticotroph cells; Stimulation of corticotropin secretion by Shh; Additive effects of Shh and corticotropin-releasing hormone in corticotropin secretion.

Purpose: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST 2 and SST 5 . Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST 2 . However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST 3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST 3 -agonists and characterize their effects on experimental NFPT models., Experimental Design: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST 3 -agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST 3 -agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST 3 -agonist., Results: We successfully identified the first SST 3 -agonist peptides. SST 3 -agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro , and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST 3 -agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST 3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST 3 -agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs., Conclusions: This study demonstrates that SST 3 -agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST 3 , suggesting that targeting this receptor could be an efficacious treatment for NFPTs., (©2019 American Association for Cancer Research.)

Interferon-gamma (IFNG) is a cytokine that exerts potent antiproliferative and tumoricidal effects in a variety of cancers. Moreover, IFNG modulates normal pituitary hormone secretion, and was shown to inhibit the expression of the ACTH precursor POMC in murine ACTH-secreting AtT-2010/21/2008 tumor cells. We have studied the functional role of IFNG on pituitary tumor cells, focusing on the involvement of IFNG in the molecular events leading to the control of POMC transcriptional repression. Herein, it is shown that IFNG inhibits AtT-20 tumor cell proliferation without inducing apoptosis. Unexpectedly, an activated janus kinases-signal transducer and activator of transcription (JAK-STAT1) cascade is required for IFNG inhibitory action on POMC promoter activity. Factor-kappa B (NF-kappaB) is necessary for the inhibitory action of IFNG on Pomc transcription, since loss of NF-kappaB activity with IkappaB super-repressor abolishes this effect. In addition, 1 and 2 IFNG receptor immunoreactivity was detected in human corticotropinoma cells. Interestingly, IFNG inhibits ACTH production from these cells in primary cell culture, without affecting basal ACTH biosynthesis in normal non-tumoral pituitary cells. In conclusion, our data show for the first time that POMC transcription can be negatively regulated by a JAK-STAT1 and NF-kappaB-dependent pathway.

Pituitary adenomas are neuroendocrine tumors that produce different endocrine and metabolic alterations, including hyperprolactinemia, acromegaly and Cushing's disease. These different clinical features of pituitary tumors are the result of the overproduction of hormones produced by the different pituitary cell types. Recent advances in the understanding of the signaling pathways that control hormone production in pituitary cells provide a source of potential therapeutic targets. In ACTH-secreting cells, the mechanisms that control hormone biosynthesis have been clarified to a great extent, indicating a number of protein kinases and ligand-activated nuclear receptors as targets for experimental drugs. ACTH production requires the activation of signal transduction through the PKA, the MAPK and the CamK pathways. These pathways activate nuclear receptors, including Nur and PPAR gamma. The inhibition of these kinases and nuclear receptors has been shown to produce therapeutic effects in mouse models of Cushing's syndrome. On the other hand, the signaling pathways that control prolactin and growth hormone production also have potential targets. It has been recently shown that SMAD proteins activated by growth factors of the TGF beta and BMP family interact with estrogen receptors to stimulate the proliferation of prolactin and growth hormone-secreting cells. Cytokines that bind to the membrane protein gp130 also stimulate the proliferation of these cells. The inhibition of both of these pathways results in the decrease of tumor growth in animal models of prolactinoma. Therefore, the study of signaling pathways that control hormone production and proliferation is a good source of candidate targets in pituitary tumors.

The growth and functions of the anterior pituitary cells are regulated by hypothalamic factors, peripheral hormones and growth factors. However, the expression of numerous growth factors and cytokines, as well as their receptors, within the anterior pituitary suggests that these factors could be locally involved in the control of pituitary development, function and proliferation by auto-/paracrine mechanisms. In the normal pituitary, intrapituitary factors probably play a role in modifying endocrine signals in the pituitary cells. However, since alterations in growth factor production and receptor expression have been found in pituitary adenomas, these factors may also contribute to the pathophysiology and progression of pituitary tumours. The potential roles of the most important growth factors and cytokines in pituitary adenoma pathogenesis are reviewed.

An essential event in immune activation is the increase of cytokines in both plasma and immune tissues. Steroid hormones influence several adaptive responses in both health and disease. Cytokines and steroids have an intimate cross-communication in many systems, making possible a satisfactory adaptive response to environmental changes. The ultimate level of integration of the cytokine-steroids cross-talk is the molecular level. We have demonstrated this in four types of cross-talk mechanisms on different cells in which steroids have major roles: (1) The tumor necrosis factor (TNF)-glucocorticoid receptor (GR) transcriptional interaction in cellular targets of TNF-induced cytotoxicity. TNF potentiates the transactivation activity of GR and the priming with TNF increases the protective action of GR on TNF-induced cytotoxicity. (2) The GR-T cell receptor (TCR) antagonism in GR-TCR-induced T cell apoptosis and its modulation by cAMP. cAMP inhibits the TCR-induced apoptosis through a PKA-CREB-dependent mechanism and potentiates glucocorticoid-induced apoptosis by means of a CREB-independent mechanism. (3) The GR influence on Th1-Th2 cytokine expression and differentiation. Glucocorticoids inhibit the induction of GATA-3 and T-bet transcription factors. (4) The influence of ER/Smad-4 signaling cross-communication on prolactinoma pathogenesis. Physical and functional interactions between Smad-4 and estrogen receptors take place in prolactinoma cells, providing a molecular explanation to link the tumorigenic action of these two important players of prolactinoma pathogenesis. The molecular cross-talk between steroids and transcription factors is the mechanism that provides the basis for the outcome of adaptive responses integrating the systemic information provided by hormones and cytokines.