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:10.1016/s0022-5347(05)68051-2

Cited by 21 publications

(6 citation statements)

References 17 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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“…PNMT expression in the adrenal medulla is also regulated by the SA system via splanchnic nerve innervation; this involves the neurotransmitters acetylcholine and pituitary adenylate cyclase-activating polypeptide (PACAP), whose signaling cascades regulate the transcription factors Egr-1, Sp1 and AP-2 (Morita et al 1996, Tai et al 2010b. Egr-1, expressed exclusively in adrenergic cells of the adrenal medulla (Criado et al 1997), is well-known for its regulatory role in the expression of genes involved in catecholamine biosynthesis, particularly its induction associated with elevated PNMT expression in pheochromocytoma (Isobe et al 2000). Also, it has been shown to be induced in response to stress in vivo together with GR (Tai et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Prenatal glucocorticoid exposure programs adrenal PNMT expression and adult hypertension

Nguyen¹,

Khurana

Peltsch

et al. 2015

Journal of Endocrinology

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Prenatal exposure to glucocorticoids (GCs) programs for hypertension later in life. The aim of the current study was to examine the impact of prenatal GC exposure on the postnatal regulation of the gene encoding for phenylethanolamine N-methyltransferase (PNMT), the enzyme involved in the biosynthesis of the catecholamine, epinephrine. PNMT has been linked to hypertension and is elevated in animal models of hypertension. Male offspring of Wistar-Kyoto dams treated with dexamethasone (DEX) developed elevated systolic, diastolic and mean arterial blood pressure compared to saline-treated controls. Plasma epinephrine levels were also elevated in adult rats exposed to DEX in utero. RT-PCR analysis revealed adrenal PNMT mRNA was higher in DEX exposed adult rats. This was associated with increased mRNA levels of transcriptional regulators of the PNMT gene: Egr-1, AP-2, and GR. Western blot analyses showed increased expression of PNMT protein, along with increased Egr-1 and GR in adult rats exposed to DEX in utero. Furthermore, gel mobility shift assays showed increased binding of Egr-1 and GR to DNA. These results suggest that increased PNMT gene expression via altered transcriptional activity is a possible mechanism by which prenatal exposure to elevated levels of GCs may program for hypertension later in life.

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“…Much of the heterogeneity is due to wide ranging variations in the types and relative amounts of catecholamines produced by the tumours and differences in episodic versus continuous secretion (Eisenhofer, et al 2001; Feldman 1981; Feldman, et al 1979; Ito, et al 1992). This in turn appears to reflect differences in expression of genes regulating catecholamine biosynthetic and secretory processes (Eisenhofer, et al 2008; Isobe, et al 2000; Timmers, et al 2008). …”

Section: Introductionmentioning

confidence: 99%

Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma

Eisenhofer¹,

Pacák²,

Huynh³

et al. 2010

Endocrine Related Cancer

176

123

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Phaeochromocytomas and paragangliomas (PPGLs) are highly heterogeneous tumours with variable catecholamine biochemical phenotypes and diverse hereditary backgrounds. This analysis of 18 catecholamine-related plasma and urinary biomarkers in 365 patients with and 846 subjects without PPGLs examined how catecholamine metabolomic profiles are impacted by hereditary background and relate to variable hormone secretion. Catecholamine secretion was assessed in a subgroup of 156 patients from whom tumour tissue was available for measurements of catecholamine contents. Among all analytes, the free catecholamine O-methylated metabolites measured in plasma showed the largest tumour-related increases relative to the reference group. Patients with tumours due to multiple endocrine neoplasia type 2 and neurofibromatosis type 1 (NF1) showed similar catecholamine metabolite and secretory profiles to patients with adrenaline-producing tumours and no evident hereditary background. Tumours from these three groups of patients contained higher contents of catecholamines, but secreted the hormones at lower rates compared to tumours that did not produce appreciable adrenaline, the latter including PPGLs due to von Hippel-Lindau and succinate dehydrogenase gene mutations. Large increases of plasma dopamine and its metabolites additionally characterized patients with PPGLs due to the latter mutations, whereas patients with NF1 were characterized by large increases in plasma dihydroxyphenylglycol and dihydroxyphenylacetic acid, the deaminated metabolites of noradrenaline and dopamine. This analysis establishes the utility of comprehensive catecholamine metabolite profiling for characterizing the distinct and highly diverse catecholamine metabolomic and secretory signatures among different groups of patients with PPGLs. The data further suggest developmental origins of PPGLs from different populations of chromaffin cell progenitors.

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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 21 publications

References 17 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

Prenatal glucocorticoid exposure programs adrenal PNMT expression and adult hypertension

Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma

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