Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The tetramerization domain for wild-type p53 (p53tet-wt) and a p53 mutant, R337H (p53tet-R337H), associated with adrenocortical carcinoma (ACC) in children, can be converted from the soluble native state to amyloid-like fibrils under certain conditions. Circular dichroism, Fourier transform infrared spectroscopy and staining with Congo red and thioflavin T showed that p53tet-wt and p53tet-R337H adopt an alternative beta-sheet conformation (p53tet-wt-beta and p53tet-R337H-beta, respectively), characteristic of amyloid-like fibrils, when incubated at pH 4.0 and elevated temperatures. Electron micrographs showed that the alternative conformations for p53tet-wt (p53tet-wt-beta) and p53tet-R337H (p53tet-R337H-beta) were supramolecular structures best described as "molecular ribbons". FT-IR analysis demonstrated that the mechanism of amyloid-like fibril formation involved unfolding of the p53tet-wt beta-strands, followed by unfolding of the alpha-helices, followed finally by formation of beta-strand-containing structures that other methods showed were amyloid-like ribbons. The mutant, p53tet-R337H, had a significantly higher propensity to form amyloid-like fibrils. Both p53tet-wt (pH 4.0) and p53tet-R337H (pH 4.0 and 5.0), when incubated at room temperature (22 degrees C) for one month, were converted to molecular ribbons. In addition, p53tet-R337H, and not p53tet-wt, readily formed ribbons at pH 4.0 and 37 degrees C over 20 hours. Interestingly, unlike other amyloid-forming proteins, p53tet-wt-beta and p53tet-R337H-beta disassembled and refolded to the native tetramer conformation when the solution pH was raised from 4.0 to 8.5. Although fibril formation at pH 4.0 was concentration and temperature-dependent, fibril disassembly at pH 8.5 was independent of both. Finally, we propose that the significantly higher propensity of the mutant to form ribbons, compared to the wild-type, may provide a possible mechanism for the observed nuclear accumulation of p53 in ACC cells and other cancerous cells.
J Mol Biol 2003 Mar 28
PMID:Reversible amyloid formation by the p53 tetramerization domain and a cancer-associated mutant. 1263 62

Inhibin and activin are members of the transforming growth factor beta (TGF-beta) family of ligands produced and secreted primarily by the gonads and adrenals. Inhibin-null (INH(-/-)) mice develop gonadal tumors and-when gonadectomized-adrenocortical carcinoma. The mechanisms leading to adrenal tumorigenesis have been proposed to involve the lack of a gonadal factor and/or a compensatory increase in gonadotropins. In order to achieve elevation of gonadotropins without the concomitant loss of a gonadal hormone, we crossed INH(-/-) mice with a transgenic mouse strain that has chronically elevated luteinizing hormone (LH) levels (LH-CTP). Compound INH(-/-)-LH-CTP mice die within 6 weeks of age from severe cancer cachexia induced by large, activin-secreting ovarian tumors. Unexpectedly, INH(-/-)-LH-CTP mice not only fail to develop adrenal tumors but have smaller adrenals, with a regressed x zone, indicating that elevated LH levels are not sufficient to induce adrenal tumor formation. However, following gonadectomy, INH(-/-)-LH-CTP mice develop large, sex steroid-producing adrenal tumors that arise from the x zone, indicating a growth-promoting effect of high levels of LH on the adrenal cortex in the absence of ovarian tumors. In addition, in vivo and in vitro data indicate that activin induces apoptosis specifically in the adrenal x zone. The restricted expression of activin receptor subunits and Smad2 in cells of the adrenal x zone, together with the elevated activin levels in INH(-/-)-LH-CTP mice, supports the conclusion that activin inhibits adrenal tumor growth by inducing x-zone regression.
Mol Cell Biol 2003 Jun
PMID:Activin induces x-zone apoptosis that inhibits luteinizing hormone-dependent adrenocortical tumor formation in inhibin-deficient mice. 1274 96

In this report we demonstrate that in human adrenocortical carcinoma NCI H295R cells, a model for adrenal glomerulosa cells, PLD was activated both by AngII and protein kinase C (PKC)-activating phorbol 12-myristate 13-acetate (PMA). However, while PMA triggered sustained PLD activation, AngII induced transient PLD activation, in contrast to results in bovine glomerulosa cells in primary culture. Despite the transient effect of AngII on PLD activity, PLD-derived lipid signals were required for maximal AngII-elicited aldosterone secretion. AngII-induced PLD activation was inhibited by PKC inhibitors, but not by tyrosine kinase or calcium/calmodulin-dependent kinase inhibitors or a calmodulin antagonist. Both AngII- and PMA-stimulated PLD activity was enhanced by phosphoinositide 3-kinase (PI3K) inhibitors. Akt, a downstream protein kinase activated by the products of PI3K, was constitutively active in H295R cells, and this activity was blocked by PI3K inhibitors. These results suggested that in H295R adrenocortical carcinoma cells, AngII-induced PLD activation was promoted by PKC and inhibited by the constitutively active PI3K pathway.
Mol Cell Endocrinol 2003 Aug 29
PMID:AngII induces transient phospholipase D activity in the H295R glomerulosa cell model. 1294 94

Pediatric nonfunctioning adrenocortical carcinoma is a very rare tumor. A 4-year-old girl was admitted complaining of abdominal pain. Physical examination revealed an abdominal mass. There were no clinical or laboratory signs of hormonal abnormality. Abdominal ultrasonography revealed a polylobular mass. Intravenous pyelography showed marked compression of the kidney by a tumor. The tumor was excised together with the right kidney. The histopathological diagnosis was adrenocortical carcinoma. Although there is a greater incidence of germ line p53 mutations with adrenocortical carcinoma, the tumor suppressor gene p53 was not mutated in our case. The girl died 2 months after surgery from complications of chemotherapy.
Pediatr Pathol Mol Med
PMID:Nonfunctioning adrenocortical carcinoma in a child. 1469 92

Vasoactive intestinal peptide (VIP) shows a wide tissue distribution and exerts numerous physiological actions. VIP was shown in a dose-dependent manner to increase cortisol secretion in the NCI-H295R human adrenocortical carcinoma (H295) cell line (threshold dose 3.3x10(-10) M, maximal dose 10(-7) M), coupled with a parallel increase in cAMP accumulation. Receptor-specific agonists were employed to determine which of the two known VIP receptor subtypes was involved in cortisol secretion. Treatment with the VPAC1 receptor agonist, [K(15), R(16), L(27)]VIP(1-7)/GRF(8-27), produced a dose-dependent increase in H295 cell cortisol secretion (threshold dose 10(-11) M, maximal dose 10(-7) M) similar to that seen with VIP. Meanwhile, the high-affinity VPAC2 receptor agonist, RO-25-1553, failed to stimulate significantly cortisol or cAMP production from H295 cells. Inhibition of VIP-mediated H295 cell cortisol secretion by PG97-269, a competitive VPAC1-specific antagonist, produced parallel shifts of the dose-response curve and a Schild regression slope of 0.99, indicating competitive inhibition at a single receptor subtype. VIP is known also to interact with the PAC1 receptor, albeit with lower affinity (EC(50) of approximately 200 nM) than the homologous ligand, PACAP (EC(50) of approximately 0.5 nM). PACAP stimulated cortisol secretion from H295 cells (EC(50) of 0.3 nM), suggesting the presence of functional PAC1 receptors. However, stimulation of cortisol secretion by nanomolar concentrations of VIP (EC(50) of 5 nM), coupled with real-time PCR estimation that VPAC1 receptor transcripts appear 1000-fold more abundant than PAC1 transcripts in H295 cells, makes it unlikely that VIP signals via PAC1 receptors. Together, these data suggest that VIP directly stimulates cortisol secretion from H295 cells via activation of the VPAC1 receptor subtype.
J Mol Endocrinol 2004 Jun
PMID:Vasoactive intestinal peptide (VIP) stimulates cortisol secretion from the H295 human adrenocortical tumour cell line via VPAC1 receptors. 1517 18

Evidence indicates that ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, controls the growth of several human and rat cell types cultured in vitro. Hence, we have investigated, by using both TUNEL and ELISA assays, the effects of 10(-8) M ghrelin on the basal apoptotic deletion rate of rat osteoblasts and thymocytes, rat and human adrenocortical cells, human umbilical vein endothelial cells, and human aldosteronoma cells cultured in vitro, as well as of the human adrenocortical carcinoma-derived cell lines NCI-H295 and SW-13. Both assays consistently showed that ghrelin did not affect apoptotic rate of normal rat and human cells, but significantly enhanced apoptotic deletion in aldosteronoma, NCI-H295 and SW-13 cell cultures. Due to the central role of apoptosis in the control of tumor growth, these findings, if confirmed in other tumor cell types, could suggest an antitumoral action of ghrelin.
Int J Mol Med 2004 Aug
PMID:Effect of ghrelin on the apoptotic deletion rate of different types of cells cultured in vitro. 1525 59

The human adrenocortical carcinoma-derived SW-13 cell line is currently used to study the interrelationships occurring between cytokines and growth factors and endothelins (ET) and adrenomedullin (AM). SW-13 cells express either ET-1 and AM or growth factors, and several cytokines stimulate ET-1 and AM release from SW-13 cells. However, neither the morphology and steroid-hormone secretion of SW-13 cells nor the expression of ET and AM receptors and the effects of ET and AM on SW-13 cell growth have been investigated. Electron microscopy showed that SW-13 cells were deprived of the typical organelles involved in steroid-hormone synthesis (i.e. mitochondrial with tubular cristae, smooth endoplasmic reticulum and lipid droplets), their prominent ultrastructural features being rough endoplasmic reticulum cisternae, free ribosomes and mitochondria with laminar cristae. Accordingly, steroid-hormone secretion was very low: no cortisol was produced and only very small amounts of aldosterone and its precursors were released. No appreciable secretory response to physiological concentrations of ACTH was observed. Reverse transcription-polymerase chain reaction showed the expression of pro ET-1 and proAM genes, as well as detected the mRNAs of only the ET- and AM-receptor subtypes, which are currently thought to mediate the growth-promoting action of these peptides: i.e. the ETA and AM2 receptors. In keeping with these observations, both ET-1 and AM markedly stimulated the growth of SW-13 cells, by enhancing the proliferation and lowering the apoptosis rate. Taken together, our findings allow us to conclude that SW-13 cannot be used for investigating the mechanisms involved in the regulation of steroid-hormone secretion, but are a suitable and useful model to study the role of endogenous ET and AM systems in the autocrine-paracrine control of human adrenocortical-cell growth.
Int J Mol Med 2005 Mar
PMID:Endothelin-1 and adrenomedullin enhance the growth of human adrenocortical carcinoma-derived SW-13 cell line by stimulating proliferation and inhibiting apoptosis. 1570 40

Neuropeptides B and W (NPB and NPW) are endogenous ligands of two G protein-coupled receptors, named GPR7 and GPR8. GPR7 and GPR8 are expressed in the adrenal cortex, and there is evidence that NPB and NPW stimulate glucocorticoid secretion from human adrenocortical cells by activating protein kinase (PK) A and PKC signaling. To gain insight into the role of NPB and NPW in human adrenal functional regulation, we have investigated their effects on the secretion and growth of the human adrenocortical carcinoma-derived NCI-H295 cell line. NCI-H295 cells were found to express both GPR7 and GPR8 mRNAs, but neither NPB nor NPW (up to 10(-6) M) affected their secretory activity. In contrast, both peptides (from 10(-10) to 10(-6) M) enhanced the growth of NCI-H295 cells, by raising their proliferative activity and lowering their apoptotic deletion rate. NPB and NPW (10(-6) M) stimulated tyrosine kinase (TK) and mitogen-activated PK (MAPK) p42/p44 activities in NCI-H295 cells. Both these effects were blocked by the TK inhibitor tyrphostin-23, while the MAPK p42/p44 inhibitor PD-98059 annulled only MAPK p42/p44 activation. The growth-stimulating effect of 10(-6) M NPB and NPW were not affected by either the PKA and PKC inhibitors H-89 and calphostin-C or the MAPK p38 antagonist SB-293580, but were abolished by both tyrphostin-23 and PD-98059. Taken together, our findings allow us to conclude that GPR7 and GPR8 expressed in NCI-H295 cells: i) are, at variance with those present in normal human adrenocortical cells, uncoupled to PKA- and PKC-dependent cascades, thereby explaining the absence of any secretory response to NPB and NPW; and ii) are coupled to the TK-dependent MAPK p42/p44 signaling, whose activation mediates the proliferogenic and antiapoptotic effect of NPB and NPW.
Int J Mol Med 2005 Dec
PMID:Neuropeptides B and W enhance the growth of human adrenocortical carcinoma-derived NCI-H295 cells by exerting MAPK p42/p44-mediated proliferogenic and antiapoptotic effects. 1627 81

The differential diagnoses of hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and adrenocortical carcinoma (ACC) are sometimes difficult due to their overlapping histologic features. Immunohistochemistry is a helpful adjunct in supporting the histologic diagnosis. In this study, the authors used the tissue array technique to systemically analyze the efficacy of different immunohistochemical panels in discerning these neoplasms. Immunohistochemical stains were performed on a total of 895 tumors (including 170 HCCs, 176 RCCs, and 40 ACCs) using monoclonal antibodies against hepatocyte antigen (HPA), CD10, RCC marker, vimentin, alpha-inhibin, keratins (KL-1, CAM 5.2, 7, and 20), epithelial membrane antigen, and polyclonal antibodies against carcinoembryonic antigen (pCEA) and alpha-fetoprotein, and antibodies Melan-A (A103), MOC31, and BG8. HPA immunostain alone detected 85.9% of HCCs, and the addition of canalicular pattern of pCEA and CD10 immunostains raised the sensitivity to 94.7%. RCC marker was positive in 54.5% of RCCs but was negative in all non-RCC tumors. Using positive CD10 and negative HPA and pCEA together with RCC marker increased the sensitivity to 74.4%. Immunoreactivity for alpha-inhibin and A103 could be detected in 67.5% and 55% of ACCs, respectively. When the two antibodies were combined, 82.5% of ACCs were labeled. Proper selection of immunohistochemical stains aid in the differential diagnosis of the three neoplasms. Using the tissue array technique, the authors also showed an effective model for comprehensive antibody testing.
Appl Immunohistochem Mol Morphol 2005 Dec
PMID:Differential immunoprofiles of hepatocellular carcinoma, renal cell carcinoma, and adrenocortical carcinoma: a systemic immunohistochemical survey using tissue array technique. 1628 Jun 64

Phthalate esters are widely used as plasticizers for polyvinylchloride and are suspected of functioning as endocrine disrupters. Di-(2-ethylhexyl) phthalate (DEHP), the most important phthalate ester in commercial use, has been reported to act as a rodent reproductive toxicant. In the present study, we investigated the effects of phthalate esters on aromatase (CYP19) activity and on its gene expression in a human adrenocortical carcinoma cell line, NCI-H295R. Mono-(2-ethylhexyl) phthalate (MEHP), a principle metabolite of DEHP, dose-dependently suppressed aromatase activity and its transcription level. Furthermore, MEHP rapidly and transiently induced transcription of the genes which encode nuclear receptor 4A subfamily members (Nur77, Nurr1 and NOR-1), and up-regulated Nur77 promoter activation and Nur77 protein expression in the cells. MEHP-induced Nur77 transcription was inhibited by bisindolylmaleimide I (protein kinase C inhibitor) and wortmannin (phosphoinositide 3-kinase inhibitor). Finally, ectopic expression of Nur77 markedly suppressed forskolin-induced transcriptional activation of promoters I.3 and II of the CYP19 gene. These results suggest that the suppression of aromatase activity and its transcription level by MEHP exposure to NCI-H295R cells was regulated through the rapid and transient expression of Nur77 gene.
Mol Cell Endocrinol 2007 Aug 15
PMID:Mono-(2-ethylhexyl) phthalate (MEHP) induces nuclear receptor 4A subfamily in NCI-H295R cells: a possible mechanism of aromatase suppression by MEHP. 1757 28


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