Shlomo Melmed

Somatostatin (SRIF), a hypothalamic inhibitor of pituitary growth hormone (GH) and thyroid-stimulating hormone (TSH) secretion, binds to five distinct receptor (SSTR) subtypes. We therefore tested SSTR subtype-specific SRIF analogs in primary human fetal pituitary cultures (23-25-wk gestation) to elucidate their role in regulating human pituitary function. Using reverse transcription-PCR, mRNA expression of SSTR2 and SSTR5 were detected in fetal pituitary by 25 wk. SRIF analog affinities ...

We recently described the expression of leukemia inhibitory factor (LIF) in human fetal and murine corticotrophs. LIF and the related cytokine oncostatin M induced basal, and corticotropin-releasing hormone (CRH) induced proopiomelanocortin (POMC) mRNA and ACTH secretion in AtT20 cells. LIF signaling and regulation of POMC gene transcription were therefore tested. Dexamethasone inhibited both basal- and LIF-induced ACTH secretion (P<0.05) and LIF induction of ACTH was also attenuated by ...

Previously, we have shown somatostatin receptor (SSTR) subtype-specific regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SSTR subtype-selective analogues in primary human GH- and PRL-secreting pituitary adenoma cultures. Analogue affinities determined by membrane ...

Cushing disease is a condition in which the pituitary gland releases excessive adrenocorticotropic hormone (ACTH) as a result of an adenoma arising from the ACTH-secreting cells in the anterior pituitary. ACTH-secreting pituitary adenomas lead to hypercortisolemia and cause significant morbidity and mortality. Pituitary-directed medications are mostly ineffective, and new treatment options are needed. As these tumors express EGFR, we tested whether EGFR might provide a therapeutic target ...

Neuroendocrine ACTH secretion responds to peripheral inflammatory and stress signals. We previously demonstrated that the proinflammatory cytokine, leukemia inhibitory factor (LIF), affects the hypothalamo-pituitary-adrenal axis (HPA) by stimulating in vitro and in vivo pituitary proopiomelanocortin (POMC) gene expression and ACTH secretion and by potentiating the action of hypothalamic corticotropin releasing hormone (CRH). Whereas pathways shown thus far to regulate POMC expression ...

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that stimulates the hypothalamo-pituitary-adrenal (HPA) axis through JAK-STAT activation. We show here that LIF-induced JAK2 and STAT3 tyrosine phosphorylation is transient, disappearing within 20 and 40 minutes, respectively. LIF activates the SH2 domain-containing tyrosine phosphatase, SHP-1, with maximal stimulation observed at 30 minutes. SHP-1 is constitutively associated with JAK2, and LIF induces recruitment of ...

CONTEXT: Pasireotide (SOM230) is a novel multireceptor ligand somatostatin analog with affinity for somatostatin receptor subtypes sst(1-3) and sst(5). Because most GH-secreting pituitary adenomas express sst(2) and sst(5), pasireotide has the potential to be more effective than the sst(2)-preferential somatostatin analogs octreotide and lanreotide.

OBJECTIVE: Our objective was to evaluate the efficacy and safety of three different doses of pasireotide in patients with ...

Pituitary somatotroph adenomas result in dysregulated growth hormone (GH) hypersecretion and acromegaly; however, regulatory mechanisms that promote GH hypersecretion remain elusive. Here, we provide evidence that STAT3 directly induces somatotroph tumor cell GH. Evaluation of pituitary tumors revealed that STAT3 expression was enhanced in human GH-secreting adenomas compared with that in nonsecreting pituitary tumors. Moreover, STAT3 and GH expression were concordant in a somatotroph ...

Leukemia inhibitory factor (LIF) is a pleiotropic neuroimmune cytokine that promotes corticotroph cell differentiation and induces proopiomelanocortin (POMC) mRNA expression and adrenocorticotropin hormone (ACTH) secretion. However, molecular mechanisms for this induction remain elusive. We therefore developed ACTH-secreting AtT20 transformants for wild-type or mutated STAT3, a cytokine signaling molecule, to address whether STAT3 is a determinant of LIF-mediated ACTH regulation. We show ...

Pituitary tumor-transforming gene (PTTG), the index mammalian securin, is abundantly expressed in several tumors and regulates tumor growth and progression. Molecular mechanisms elucidating PTTG regulation and actions remain elusive. Here, we provide evidence that PTTG acts as a signal transducer and activator of transcription factor 3 (STAT3) target gene. Total STAT3 and Tyr705 phosphorylated STAT3 were concordantly expressed with PTTG in human colorectal tumors (n=97 and n=95, ...