Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to study the mechanism of GH secretion from somatotroph adenoma cells, we have compared the effect of 12-O-tetradecanoyl phorbol-13-acetate (TPA) with that of growth hormone releasing factor (GRF) on GH secretion from human somatotroph adenoma cells cultured in monolayer. Pituitary adenoma cells were obtained from 13 patients with acromegaly undergoing surgery. On the 7th day of culture, the cells were exposed for 2 h to secretagogues. All 13 adenoma cell cultures (100%) responded to TPA (1.6-16.0 nmol/l) with a two- to six-fold increase in GH release (240 +/- 37% increase of control: mean +/- SE). The response was detectable within 10 min, and was maximal at 2 h. Phospholipase C (7.7 mmol/l) also stimulated a two- to ten-fold increase in GH release in all four adenomas examined (100%). GH release was stimulated by GRF (2.0 nmol/l) in eight out of 12 adenoma cells (67%), but the magnitude of the responses to GRF (60 +/- 18% increase of control: mean +/- SE) were much smaller than that of TPA. Five out of 13 adenomas secreted detectable amount of PRL into the medium and these five adenomas (100%) responded to TPA (16.0 nmol/l) with a two- to six-fold increase. These observations indicate that the activation of protein kinase C is the consistent stimulator in GH and PRL secretion in human somatotroph adenoma cells. However, it is not determined whether the protein kinase C is involved in the in-vivo production of GH in patients with acromegaly.
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PMID:Phorbol ester, not growth hormone releasing factor, consistently stimulates growth hormone release from somatotroph adenomas in culture. 206 Jan 47

L-692,429 is a non-peptidyl GH secretagogue. We examined the effects of L-692,429 on cultured human pituitary tumors removed from patients with acromegaly. Dose-dependent stimulation of GH secretion was observed, with 1 mumol/L leading to 2 or 3-fold increases. Prolactin (PRL) secretion by a mixed somatotrophic-lactotrophic tumor was also stimulated. The effects of L-692,429 were abolished by phloretin and W7 but not Rp-cAMPS. Rate of phosphatidylinositol turnover was markedly increased up to 3-fold by L-692,429. These results show that L-692,429 increases hormone secretion by human pituitary cells via a protein kinase C and Ca2+ dependent mechanism.
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PMID:The growth hormone secretagogue, L-692,429, induces phosphatidylinositol hydrolysis and hormone secretion by human pituitary tumors. 769 7

Immunohistochemical expression of the three major isozymes of protein kinase C--Types I, II, and III--was studied in 32 cases of human pituitary adenomas, and the results were compared in detail with their clinical data. Immunoreactivity for the Type I and Type II isozymes was negative in tumor cells of all pituitary adenomas. Moderate to strong cytoplasmic immunoreactivity for the Type III isozyme was constantly seen in acromegaly, Cushing's disease, and nonfunctioning adenomas, which indicated overexpression of the isozyme, since only slight cytoplasmic immunoreactivity was observed in the normal human anterior pituitary cells. Among 13 prolactinomas, 5 cases showed positive immunoreactivity for Type III in all tumor cells, whereas 8 cases showed negative immunoreactivity for the isozyme in all or more than 85% of tumor cells. The sizes of the tumors in this protein kinase C Type III negative group of prolactinomas tended to be smaller than those of the Type III positive prolactinomas. Also, the negative immunoreactivity for Type III was predominantly observed in those cases where prolactinomas were relatively well controlled by continuous oral dosage of dopamine agonists before operation. These results suggest that protein kinase C Type III is closely involved in human pituitary adenomas. The exceptional negativity for the isozyme in prolactinomas may be relevant to the suppression of tumor growth by dopamine agonists.
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PMID:Immunohistochemical expression of protein kinase C type III in human pituitary adenomas. 809 3

We examined the effect of phorbol ester on growth hormone (GH)-releasing hormone (GRH)-induced GH secretion and cyclic adenosine monophosphate (cAMP) production in three pituitary adenomas and thyrotropin-releasing hormone (TRH)- and corticotropin-releasing hormone (CRH)-induced redistribution of protein kinase C (PKC) from cytosol to membrane in a pituitary adenoma resected from patients with acromegaly. GRH stimulated GH secretion in accordance with cAMP production in three cases, whereas 12-O-tetradecanoyl phorbol-13 acetate (TPA) stimulated GH secretion with cAMP production in one case. Simultaneous addition of GRH and TPA enhanced cAMP production in three pituitary adenomas. Moreover, addition of TPA with GRH resulted in additive secretion of GH in vitro. In one case, we were able to measure PKC activity and prove translocation of PKC stimulated by TRH and CRH in accordance with GH secretion in vitro and in vivo. These results suggest that TPA, an activator of PKC, has a stimulatory effect on GRH-induced cAMP production and that, finally, TRH- and CRH-induced PKC activation may cause greater secretion of GH by enhancement of cAMP production in human GH-hypersecreting adenoma cells.
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PMID:Growth hormone secretion in human acromegalic pituitary adenomas: cyclic adenosine monophosphate and protein kinase C responses. 859 91

The GH secretory mechanism of GH-releasing hexapeptide (GHRP-6), GHRH, and TRH were studied in vivo and in vitro in seven patients with acromegaly. In an in vivo study, these patients showed clear GH responses to single administration of GHRP (four of four patients), GHRH (seven of seven patients), and TRH (seven of seven patients) and enhanced responses to GHRP plus GHRH (two of four patients) or TRH plus GHRH (six of six patients). In an in vitro dispersed cell study, the majority of patients examined also showed clear GH responses to GHRP (four of four patients), GHRH (six of six patients), and TRH (four of four patients) and an enhanced response to GHRP plus GHRH (three of three patients) or TRH plus GHRH (three of four patients). In one patient (no. 3), GHRP plus forskolin (adenylate cyclase activator), but not GHRP plus phorbol 12-myristate 13-acetate (protein kinase C activator), additively enhanced the GH response. Nordihydroguaiaretic acid (NDGA; inhibitor of arachidonic cascade) inhibited GH release induced by GHRP, TRH, GHRH, TRH plus GHRH, or GHRP plus GHRH, but did not inhibit basal GH secretion. In contrast, NDGA distinctly elevated intracellular cAMP levels in another patient (no. 7) when coadministered with GHRP, GHRH, or GHRP plus GHRH, whereas cAMP levels were not modified by single administration of GHRP and NDGA. The GH response to the combined administration of GHRP and GHRH was synergistic in this patient, but was additive in the other two patients. It is concluded that GHRP, TRH, and GHRH directly stimulate in vivo and in vitro GH release from human somatotropinomas, and GHRP and TRH mainly exert their action through activation of the phosphatidylinositol-protein kinase C pathway, whereas GHRH exerts its action through the adenylate cyclase-protein kinase A pathway. These three agents seem to release GH via the arachidonic cascade.
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PMID:Secretory mechanisms of growth hormone (GH)-releasing peptide-, GH-releasing hormone-, and thyrotropin-releasing hormone-induced GH release in patients with acromegaly. 976 68

Previous observations raised the possibility that circulating GH-binding protein (GHBP) may serve as a useful index for tissue GH receptor (GHR) responsiveness in humans. Indeed, there are many examples to indicate that across a wide scope of comparative studies, ontogenic data, experimental systems, physiological conditions, nutritional states, and diseases there is a close relationship between the concentration of GHR and the level of serum GHBP. In the present review, we discuss various aspects that might affect differentially cellular GHR and circulating GHBP, based on species and tissue divergence, regulation of cell-surface GHR turnover, GHR cleavage mechanism, GHR mRNA splicing, and GH insensitivity (GHI) syndrome patients with normal or high serum GHBP levels. Most previous experimental data were collected through comparative analysis of human GHBP against GHR and GHBP determinations in animal models. Yet, GHBPs possess species-specific properties, and the mechanism for their generation and regulation display evolutionary divergence. Another important aspect is tissue divergence, in terms of GHR regulation and its cleavage to GHBP. Although GHBP is generated mainly from the liver GHR, many other tissues express GHRs and probably also contribute to the total GHBP level. Human GHBP is generated by proteolytic cleavage of GHR at the cell-surface and, thus, occupancy or modulation of GHR turnover/internalization would impact the level of cell-surface GHR that are available for proteolysis. An additional degree of complexity arises from recent reports, implicating a protein kinase C-regulated metalloprotease activity in GHBP generation. This suggests that the proteolytic system, which controls the specific cleavage mechanism and switch between GHR proteolysis and GHBP shedding, is a regulated process. Finally, differential splicing regulation to the full-length, active human GHR (hGHR) and the inactive truncated hGHRtr isoform messenger RNA transcripts might regulate both the production of GHBP and GHR bioactivity, as hGHRtr generates large amounts of GHBP but has a dominant negative effect on GH signaling. Several clinical GH-resistant conditions, such as liver cirrhosis, renal insufficiency, insulin-dependent diabetes mellitus, hypothyroidism, malnutrition, or critical illness are associated with reduced GHBP levels. However, this is not universally true, as in other conditions (e.g. early childhood, acromegaly) decreased GHBP levels are not associated with GHI. Divergence between serum GHBP and insulin-like growth factor I, such as which occur during puberty or obesity, also questions whether GHBP levels reflect GHR function. Even in patients with GHI syndrome, serum GHBP cannot be relied on to detect all GHR mutations. The correct assessment of GHR expression and GH functionality in an individual patient will require, in parallel to measurements of serum GHBP, additional detailed diagnostic screening of the entire GH-insulin-like growth factor I axis.
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PMID:Clinical review 112: Does serum growth hormone (GH) binding protein reflect human GH receptor function? 1072 17

Abnormal GH responses to GnRH test, observed in about 15% of patients with acromegaly, have been reported exclusively in patients bearing tumors without gsp mutation. The absence of responsiveness to GnRH in gsp+ tumors was not predicted on the basis of the mechanism of GnRH action that mainly involves the activation of calcium and protein kinase C dependent pathways. The aim of the present study was to investigate in detail the transduction of GnRH signaling in these tumors. GH-secreting adenomas removed from patients in vivo responsive to GnRH test were studied. Tumor DNA was screened for Gsalpha and GnRH receptor gene sequences. Intracellular calcium ([Ca2+]i) and cAMP levels were measured in dispersed cells and adenylyl cyclase (AC) activity in membrane preparations. DNA analysis showed wild sequence of both Gsalpha and GnRH receptor genes. GnRH caused a significant increase in intracellular Ca2+ that was associated with a significant stimulation of cAMP accumulation. In these cells neither TRH nor GHRP-6 were effective in causing significant modifications of cAMP levels, despite their ability to increase [Ca2+]i. Finally, GnRH was able to directly stimulate AC from 11.1 +/- 3.3 pmol/mg prot/min to 26.9 +/- 5.4 (p<0.005). We report that GnRH was effective in increasing both [Ca2+]i and AC in GH-secreting adenomas removed from responsive patients. The ability of GnRH to signal through Gsalpha protein may account for the lack of GH responses to GnRH observed in acromegalic patients with tumors carrying gsp mutation.
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PMID:Gonadotropin-releasing hormone initiates multiple signaling pathways in human GH-secreting adenomas. 1523 51