ENHANCED EXPRESSION OF mRNA CODING FOR THE ADRENALINE-SYNTHESIZING ENZYME PHENYLETHANOLAMINE-N-METHYL TRANSFERASE IN ADRENALINE-SECRETING PHEOCHROMOCYTOMAS

Isobe, Kazumasa; Nakai, Toshiaki; Yashiro, Tooru; NANMOKU, TOORU; Yukimasa, Nobuyasu; Ikezawa, Tsuyoshi; Suzuki, Emiko; Takekoshi, Kazuhiro; Nomura, Fumio

doi:10.1097/00005392-200001000-00094

Cited by 5 publications

(5 citation statements)

References 16 publications

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“…Our findings in hereditary pheochromocytomas contrast with previous findings by others of greater expression of Egr‐1 in sporadic adenergic than noradrenergic tumors 15 . Epinephrine production and the adrenergic phenotype in hereditary tumors may therefore reflect different mechanisms than in sporadic tumors.…”

Section: Discussioncontrasting

confidence: 96%

Transcriptional Regulation of Phenylethanolamine N‐Methyltransferase in Pheochromocytomas from Patients with von Hippel–Lindau Syndrome and Multiple Endocrine Neoplasia Type 2

Huynh

Pacák

Wong

et al. 2006

Annals of the New York Academy of Sciences

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Pheochromocytomas in multiple endocrine neoplasia type 2 (MEN-2) express phenylethanolamine N-methyltransferase (PNMT), the enzyme that catalyzes conversion of norepinephrine to epinephrine, whereas those in von Hippel-Lindau (VHL) syndrome do not. Consequently, pheochromocytomas in MEN-2 produce epinephrine, whereas those in VHL syndrome produce mainly norepinephrine. This study examined whether transcription factors known to regulate expression of PNMT explain the different tumor phenotypes in these syndromes. Quantitative polymerase chain reaction (PCR) and Western blotting were used to assess levels of mRNA and protein for the glucocorticoid receptor, early growth response 1 (Egr-1), the Sp1 transcription factor (Sp1), and MYC-associated zinc finger protein (MAZ) in 6 MEN-2 and 13 VHL tumors. Results were cross-checked with data obtained using microarray gene expression profiling in a further set of 10 MEN-2 and 12 VHL tumors. Pheochromocytomas in MEN-2 and VHL syndrome did not differ in expression of the glucocorticoid receptor, Egr-1, Sp1, or MAZ as assessed by quantitative PCR and Western blotting. Microarray data also indicated no relevant differences in expression of the glucocorticoid receptor, Egr-1, MAZ, and the AP2 transcription factor. Thus, our results do not support a role for the above transcription factors in determining differences in expression of PNMT in pheochromocytomas from patients with VHL syndrome and MEN-2. Microarray analysis, however, did indicate differences in expression of genes involved in neural crest cell lineage and chromaffin cell development, consistent with differential survival of PNMT-expressing cells in the two syndromes.

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Section: Discussioncontrasting

confidence: 96%

Transcriptional Regulation of Phenylethanolamine N‐Methyltransferase in Pheochromocytomas from Patients with von Hippel–Lindau Syndrome and Multiple Endocrine Neoplasia Type 2

Huynh

Pacák

Wong

et al. 2006

Annals of the New York Academy of Sciences

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“…As demonstrated by our HPLC analysis of catecholamine content in patients from Cohorts 2 and 3, only a small proportion of mixed tumours produce adrenaline as the predominantly stored and released catecholamine. In the majority of phaeochromocytomas, mRNA expression of PNMT is positively correlated with tissue levels of adrenaline, which in turn are correlated with high levels of cortisol expression (Isobe et al 2000). In our study, although the presence of PNMT immunoreactivity is correlated with the detection of adrenaline in all but one sample, the level of immunostaining does not always correlate with the proportion of adrenaline to noradrenaline as determined by using HPLC.…”

Section: Discussioncontrasting

confidence: 67%

“…This concurs with studies that have revealed low levels of PNMT mRNA expression in human phaeochromocytoma (Isobe et al 1998). Factors that have been shown to control PNMT expression include cortisol and glucocorticoid receptors (Isobe et al 2000;Finotto et al 1999), the immediate early gene transcription factor Egr-1 (Isobe et al 2000), neural-crest associated developmental transcription factor, AP2 (Ebert et al 1998) and pituitary adenylate cyclase-activating polypeptide (Isobe et al 2003). An alteration in any of these factors may play a role in the variable PNMT expression levels that we describe in human phaeochromocytoma.…”

Section: Discussionmentioning

confidence: 99%

Expression of the noradrenaline transporter and phenylethanolamine N-methyltransferase in normal human adrenal gland and phaeochromocytoma

et al. 2005

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Expression of the noradrenaline transporter (NAT) was examined in normal human adrenal medulla and phaeochromocytoma by using immunohistochemistry and confocal microscopy. The enzymes tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) were used as catecholamine biosynthetic markers and chromogranin A (CGA) as a marker for secretory granules. Catecholamine content was measured by using high performance liquid chromatography (HPLC). In normal human adrenal medulla (n=5), all chromaffin cells demonstrated strong TH, PNMT and NAT immunoreactivity. NAT was co-localized with PNMT and was located within the cytoplasm with a punctate appearance. Human phaeochromocytomas demonstrated strong TH expression (n=20 samples tested) but variable NAT and PNMT expression (n=24). NAT immunoreactivity ranged from absent (n=3) to weak (n=10) and strong (n=11) and, in some cases, occupied an apparent nuclear location. Unlike the expression seen in normal human adrenal medullary tissue, NAT expression was not consistently co-localized with PNMT. PNMT also showed highly variable expression that was poorly correlated with tumour adrenaline content. Immunoreactivity for CGA was colocalized with NAT within the cytoplasm of normal human chromaffin cells (n=4). This co-localization was not consistent in phaeochromocytoma tumour cells (n=7). The altered pattern of expression for both NAT and PNMT in phaeochromocytoma indicates a significant disruption in the regulation and possibly in the function of these proteins in adrenal medullary tumours.

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“…Epinephrine production in the adrenal medulla depends on the expression of PNMT, which is regulated by glucocorticoids produced in the surrounding adrenal cortex 42 . According to previous understanding, mainly based on findings in Caucasian populations, this explains why epinephrine production is confined to adrenal pheochromocytoma 37 43 44 . Among the Chinese population, a substantial proportion of extra-adrenal PGLs produce epinephrine mainly associated with somatic mutations in HRAS and FGFR1 .…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-inducible Factor 2α: A Key Player in Tumorigenesis and Metastasis of Pheochromocytoma and Paraganglioma?

Bechmann

Eisenhofer

2021

Exp Clin Endocrinol Diabetes

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Germline or somatic driver mutations linked to specific phenotypic features are identified in approximately 70% of all catecholamine-producing pheochromocytomas and paragangliomas (PPGLs). Mutations leading to stabilization of hypoxia-inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are associated with a higher risk of metastatic disease. Patients with metastatic PPGLs have a variable prognosis and treatment options are limited. In most patients with PPGLs, germline mutations lead to the stabilization of HIF2α. Mutations in HIF2α itself are associated with adrenal pheochromocytomas and/or extra-adrenal paragangliomas and about 30% of these patients develop metastatic disease; nevertheless, the frequency of these specific mutations is low (1.6–6.2%). Generally, mutations that lead to stabilization of HIF2α result in distinct catecholamine phenotype through blockade of glucocorticoid-mediated induction of phenylethanolamine N-methyltransferase, leading to the formation of tumors that lack epinephrine. HIF2α, among other factors, also contributes importantly to the initiation of a motile and invasive phenotype. Specifically, the expression of HIF2α supports a neuroendocrine-to-mesenchymal transition and the associated invasion-metastasis cascade, which includes the formation of pseudopodia to facilitate penetration into adjacent vasculature. The HIF2α-mediated expression of adhesion and extracellular matrix genes also promotes the establishment of PPGL cells in distant tissues. The involvement of HIF2α in tumorigenesis and in multiple steps of invasion-metastasis cascade underscores the therapeutic relevance of targeting HIF2α signaling pathways in PPGLs. However, due to emerging resistance to current HIF2α inhibitors that target HIF2α binding to specific partners, alternative HIF2α signaling pathways and downstream actions should also be considered for therapeutic intervention.

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ENHANCED EXPRESSION OF mRNA CODING FOR THE ADRENALINE-SYNTHESIZING ENZYME PHENYLETHANOLAMINE-N-METHYL TRANSFERASE IN ADRENALINE-SECRETING PHEOCHROMOCYTOMAS

Abstract: These findings indicate that adrenaline production in adrenaline-secreting pheochromocytomas is primarily controlled by the level of PNMT gene expression, and that the gene expression may be enhanced by both cortisol and Egr-1.

Cited by 5 publications

References 16 publications

Transcriptional Regulation of Phenylethanolamine N‐Methyltransferase in Pheochromocytomas from Patients with von Hippel–Lindau Syndrome and Multiple Endocrine Neoplasia Type 2

Transcriptional Regulation of Phenylethanolamine N‐Methyltransferase in Pheochromocytomas from Patients with von Hippel–Lindau Syndrome and Multiple Endocrine Neoplasia Type 2

Expression of the noradrenaline transporter and phenylethanolamine N-methyltransferase in normal human adrenal gland and phaeochromocytoma

Hypoxia-inducible Factor 2α: A Key Player in Tumorigenesis and Metastasis of Pheochromocytoma and Paraganglioma?

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