Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Suramin is a polysulfonated naphthylurea with demonstrated antineoplastic activity. Toxicity includes adrenal insufficiency and peripheral neuropathy. Although the mechanism of antitumor activity is unknown, inhibition of binding of growth factors to their receptors has been suggested. Growth factors inhibited by suramin include platelet-derived growth factor, fibroblast growth factor, transforming growth factor, epidermal growth factor, insulin-like growth factor, and nerve growth factor (NGF). In these studies, suramin was shown to be cytotoxic to PC12 cells in a dose-dependent manner. At lower doses and in surviving cells, we observed the induction of neurite outgrowth. To determine the mechanism of suramin-induced neurite outgrowth, PC12 cells were exposed to suramin and/or NGF for various time periods and treated cells were analyzed, by western blot analysis, for expression of tyrosine phosphoproteins. There was a similarity in the pattern of tyrosine-phosphorylated proteins in PC12 cells stimulated with suramin or NGF. Of particular interest was the rapid phosphorylation (by 1 min) of the high-affinity NGF (TrkA) receptor. Activation of other members of the signal-transduction cascade (Shc, p21ras, Raf-1, ERK-1) revealed similar phosphorylation levels induced by suramin and NGF. Parallel studies were performed in rat dorsal root ganglion cultures; suramin potentiated neurite outgrowth and activated the NGF receptor on these cells. This finding of specific patterns of tyrosine phosphorylation of cellular proteins in response to suramin treatment demonstrated that suramin is a partial agonist for the NGF receptor in both PC12 cells and dorsal root ganglion neurons.
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PMID:Suramin induces phosphorylation of the high-affinity nerve growth factor receptor in PC12 cells and dorsal root ganglion neurons. 876 55

We have cloned a bovine adrenal cortical (bKv1.4) K(+) channel cDNA whose expression is rapidly inhibited by adrenocorticotropic hormone (ACTH). The 4386-nucleotide cDNA is homologous to other voltage-gated, rapidly inactivating Kv1.4 channels, and includes a 1986-nucleotide coding region and large 5'- and 3'-untranslated regions. Bovine Kv1.4-specific mRNA from adrenal zona fasciculata (AZF) cells was rapidly and potently reduced by ACTH, with a t(12) of approximately 1 h and an IC(50) of 1.2 pm. The membrane-permeable cAMP analog 8-pcpt-cAMP also reduced bKv1.4 mRNA expression with kinetics similar to that observed with ACTH. Reduction of bKv1.4 mRNA expression by ACTH and 8-pcpt-cAMP was only partially inhibited by the selective protein kinase A antagonist H-89. Consistent with their effect on bKv1.4 mRNA, ACTH and 8-pcpt-cAMP both dramatically reduced the expression of bKv1.4-associated A-type current measured over 72 h. These results demonstrate that bovine AZF cells synthesize a Kv1.4-type channel whose expression is inhibited at the pretranslational level by ACTH and 8-pcpt-cAMP by a mechanism that is partially dependent on the activation of protein kinase A. The rapid, potent reduction of bKv1.4 mRNA produced by ACTH and 8-pcpt-cAMP indicates that the expression of this K(+) channel is under tonic inhibitory control of the hypothalamic-pituitary-adrenal axis. The basic electrical properties of AZF cells might be tightly regulated at the transcriptional level by the normal diurnal pattern of ACTH secretion, and altered during bouts of stress by the enhanced release of this pituitary peptide. Under conditions of prolonged stress or adrenal insufficiency, persistent ACTH-induced changes in the electrical properties of AZF cells could be coupled to parallel changes in cortisol secretion.
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PMID:A bovine adrenocortical Kv1.4 K(+) channel whose expression is potently inhibited by ACTH. 1091 43

The molecular basis of pituitary tumorigenesis remains controversial, but there are two major theories which have been subject to most investigation: hormonal (usually hypothalamic factors) and/or growth factor overstimulation, or a molecular defect within the pituitary itself. It has been shown, for example, that excessive regulatory hormone stimulation can lead to an increased number of cells in the pituitary in various physiological or pathological states such as pregnancy (lactotrophs), untreated primary hypothyroidism (thyrotrophs and lactotrophs),primary hypoadrenalism (corticotrophs) and ectopic GHRH-secreting tumours (somatotrophs). Animal models also provide data that in the presence of excessive hypothalamic hormone stimulation, adenoma formation can occur. However, evidence in favour of the monoclonal nature of pituitary tumours argues for an intrinsic molecular defect as the primary initiating event in tumour formation. We review the various hormonal factors and their receptors effecting the different types of pituitary cells, such as CRH, AVP and cortisol feedback on corticotrophs; GHRH, Galpha PKA, somatostatin and GH and IGF feedback on somatotrophs; GnRH, LH/FSH, activin and oestrogen feedback on gonadotrophs; dopamine, oestrogen and prolactin feedback on lactotrophs; and TRH, TSH and thyroid hormone feedback on thyrotrophs. The monoclonal origin of adenomas makes it unlikely that hypothalamic factors could initiate pituitary transformation, but they could still create an environment where there is a higher chance that a possible causative tumorigenic mutation may occur in one (or several) of the overstimulated pituitary cells, or enhance the proliferation of an already-mutated cell.
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PMID:Role of regulatory factors in pituitary tumour formation. 1528 40

Adrenal insufficiency is managed by hormone replacement therapy, which is far from optimal; the ability to generate functional steroidogenic cells would offer a unique opportunity for a curative approach to restoring the complex feedback regulation of the hypothalamic-pituitary-adrenal axis. Here, we generated human induced steroidogenic cells (hiSCs) from fibroblasts, blood-, and urine-derived cells through forced expression of steroidogenic factor-1 and activation of the PKA and LHRH pathways. hiSCs had ultrastructural features resembling steroid-secreting cells, expressed steroidogenic enzymes, and secreted steroid hormones in response to stimuli. hiSCs were viable when transplanted into the mouse kidney capsule and intra-adrenal. Importantly, the hypocortisolism of hiSCs derived from patients with adrenal insufficiency due to congenital adrenal hyperplasia was rescued by expressing the wild-type version of the defective disease-causing enzymes. Our study provides an effective tool with many potential applications for studying adrenal pathobiology in a personalized manner and opens venues for the development of precision therapies.
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PMID:Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells. 2938 11

Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.
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PMID:Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex. 3054 88