Phenylethanolamine N-methyltransferase gene expression: synergistic activation by Egr-1, AP-2 and the glucocorticoid receptor

Wong, Dona L.; Siddall, Brenda; Ebert, Steven N.; Bell, Rose Ann; Her, Song

doi:10.1016/s0169-328x(98)00225-3

Cited by 61 publications

(55 citation statements)

References 31 publications

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“…35 Sp 1, Egr-1 and the glucocorticoid receptor and AP-2 function cooperatively to stimulate PNMT promoter activity through poorly delineated mechanisms. 36 Glucocorticoid control of PNMT gene transcription and protein synthesis do not fully account for changes in PNMT expression in the present study. The capacity of ACTH injections to increase epinephrine biosynthesis while PNMT expression remains markedly decreased suggests that corticosteroids can posttranscriptionally regulate PNMT protein expression.…”

Section: Molecular Psychiatrycontrasting

confidence: 69%

Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice

et al. 2002

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Corticotropin-releasing hormone (CRH) is both a main regulator of the hypothalamic-pituitaryadrenocortical axis and the autonomic nervous system. CRH receptor type 1 (CRHR1)-deficient mice demonstrate alterations in behavior, impaired stress responses with adrenocortical insufficiency and aberrant neuroendocrine development, but the adrenal medulla has not been analyzed in these animals. Therefore we studied the production of adrenal catecholamines, expression of the enzyme responsible for catecholamine biosynthesis neuropeptides and the ultrastructure of chromaffin cells in CRHR1 null mice. In addition we examined whether treatment of CRHR1 null mice with adrenocorticotropic hormone (ACTH) could restore function of the adrenal medulla. CRHR1 null mice received saline or ACTH, and wildtype or heterozygous mice injected with saline served as controls. Adrenal epinephrine levels in saline-treated CRHR1 null mice were 44% those of controls (P Ͻ0.001), and the phenylethanolamine N-methyltransferase (PNMT) mRNA levels in CRHR1 null mice were only 25% of controls (P Ͻ0.001). ACTH treatment increased epinephrine and PNMT mRNA level in CRHR1 null mice but failed to restore them to normal levels. Proenkephalin mRNA in both saline-and ACTH-treated CRHR1 null mice were higher than in control animals (215.8% P Ͻ0.05, 268.9% P Ͻ0.01) whereas expression of neuropeptide Y and chromogranin B did not differ. On the ultrastructural level, chromaffin cells in saline-treated CRHR1 null mice exhibited a marked depletion in epinephrine-storing secretory granules that was not completely normalized by ACTH-treatment. In conclusion, CRHR1 is required for a normal chromaffin cell structure and function and deletion of this gene is associated with a significant impairment of epinephrine biosynthesis. Molecular Psychiatry (2002) 7, 967-974.

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Section: Molecular Psychiatrycontrasting

confidence: 69%

Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice

et al. 2002

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“…1A) upstream of the firefly luciferase reporter gene (pGL3RP893) were treated with varying concentrations of NGF up to 100 ng/ml, and PNMT promoter-driven luciferase reporter gene expression was de- (Ross et al, 1990;Ebert et al, 1994Ebert et al, , 1998Ebert and Wong, 1995;Wong et al, 1998;Her et al, 1999). B, transfected cells were treated with varying doses of NGF from 0 to 100 ng/ml, and luciferase activity was determined after 24 h. C, transfected cells were treated with 50 ng/ml NGF for times up to 24 h, and luciferase activity was determined.…”

Section: Ngf Activation Of the Pnmt Promotermentioning

confidence: 99%

“…Sp1, Egr-1, the GR, and AP2 bind as dimers to consensus sites in the promoter and thereby may impose alterations in promoter structure that facilitate transcription factor interaction. Finally, these possibilities are not mutually exclusive Wong et al, 1998).…”

mentioning

confidence: 99%

Nerve Growth Factor Regulates Adrenergic Expression

Tai

Wong-Faull²,

Claycomb³

et al. 2006

Mol Pharmacol

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The mechanism by which nerve growth factor (NGF) regulates adrenergic expression was examined in PC-12 cells transfected with a rat phenylethanolamine N-methyl-transferase (PNMT) promoter-luciferase reporter gene construct pGL3RP893. NGF treatment increased PNMT promoter-driven luciferase activity in a dose-and time-dependent manner. Induction was attenuated by inhibition of the extracellular signalregulated kinase mitogen-activated protein kinase (MAPK) pathway (ϳ60%) but not by inhibition of the protein kinase A (PKA), protein kinase C, phosphoinositol kinase, or p38 MAPK pathways. Deletion PNMT promoter-luciferase reporter gene constructs showed that the NGF-responsive sequences lay within the proximal Ϫ392 base pairs (bp) of PNMT promoter, wherein binding elements for Egr-1 (Ϫ165 bp) and Sp1 (Ϫ48 bp) reside. Western analysis further showed that NGF increased nuclear levels of Egr-1, but not Sp1 or the catalytic subunit of PKA. Gel mobility shift assays showed increased potential for Egr-1, but not Sp1, protein-DNA binding complex formation. Mutation of either the Egr-1 or Sp1 binding sites in the PNMT promoter attenuated NGF activation. NGF, combined with pituitary adenylyl cyclase-activating protein (PACAP), another PNMT transcriptional activator, cooperatively stimulated PNMT promoter driven-luciferase activity beyond levels observed with either neurotrophin alone. Finally, posttranscriptional control seems to be another important mechanism by which neurotrophins regulate the adrenergic phenotype. NGF, PACAP, and a combination of the two stimulated both intron-retaining and intronless PNMT mRNA and PNMT protein, but to different extents.

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“…7,8 There is little previous literature comparing plasma epinephrine in benign versus malignant pheochromocytomas. 1,2,9 Because phenylethanolamine N-methyltransferase is a glucocorticoid-responsive enzyme, 25 very large or extraadrenal pheochromocytomas may be relatively deficient in epinephrine because the chromaffin cells in such tumors are not in close apposition to glucocorticoid-producing adrenal cortical cells. The quantity of catecholamine release by pheochromocytoma may be an unreliable gauge of tumor size because there is substantial intratumoral catecholamine metabolism, resulting in even some large pheochromocytomas with relatively modest catecholamine release.…”

Section: Benign Versus Malignant Pheochromocytomamentioning

confidence: 99%

Malignant Pheochromocytoma

2000

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Abstract-Chromaffin granule transmitters such as chromogranin A and catecholamines have been used in the diagnosis of pheochromocytoma, but the diagnostic and prognostic value of chromogranin A have not been explored in malignant pheochromocytoma. We evaluated these transmitters in patients with pheochromocytoma (nϭ27), both benign (nϭ13) and malignant (nϭ14). Patients with benign pheochromocytoma were studied before and after surgical excision (nϭ6), whereas patients with malignant pheochromocytoma were evaluated before and after combination chemotherapy with regular cycles of cyclophosphamide/dacarbazine/vincristine (nonrandomized trial in nϭ9). During treatment, patient responses to chemotherapy were divided according to anatomic and clinical criteria: responders (nϭ5) versus nonresponders (nϭ4). Plasma chromogranin A rose progressively (PϽ0.0001) from control subjects (48.0Ϯ3.0 ng/mL) to benign pheochromocytoma (188Ϯ40.5 ng/mL) to malignant pheochromocytoma (2932Ϯ960 ng/mL). Parallel changes were seen for plasma norepinephrine (PϽ0.0001), though plasma epinephrine was actually lower in malignant than benign pheochromocytoma (Pϭ0.0182). In bivariate analyses, chromogranin A, norepinephrine, and epinephrine discriminated between pheochromocytoma and control subjects (all PϽ0.0001), whereas in a multivariate analyses, norepinephrine was the best discriminator (Pϭ0.011). Chromogranin A was significantly different in benign versus malignant pheochromocytoma on both bivariate (Pϭ0.0003) and multivariate (Pϭ0.011) analyses. After excision of benign pheochromocytoma, chromogranin A (Pϭ0.028), norepinephrine (Pϭ0.047), and epinephrine (Pϭ0.037) all fell to values near normal. During chemotherapy of malignant pheochromocytoma (nϭ9), plasma chromogranin A (Pϭ0.047) and norepinephrine (Pϭ0.02) fell but not epinephrine. In 5 responders to chemotherapy, there were significant declines in chromogranin A (Pϭ0.03) and norepinephrine (Pϭ0.03) but not epinephrine; in 4 nonresponders, none of the transmitters changed. Plasma chromogranin A varied longitudinally with tumor response and relapse. We conclude that plasma chromogranin A is an effective tool in the diagnosis of pheochromocytoma, and markedly elevated chromogranin A may point to malignant pheochromocytoma. During chemotherapy of malignant pheochromocytoma, chromogranin A can be used to gauge tumor response and relapse. (Hypertension. 2000;36:1045-1052.)Key Words: plasma Ⅲ chromogranins Ⅲ norepinephrine Ⅲ epinephrine M alignant pheochromocytoma presents several difficulties in management, both in diagnosis 1,2 and in effective treatment. [2][3][4] Even after excision, the diagnosis of malignant pheochromocytoma cannot be made reliably on histological grounds 2 ; thus, extensive evaluations of tumor location are required to ascertain the presence of local or distant invasion or metastases by either surgical exploration, imaging, or regional venous blood sampling. 2 Specific biochemical diagnosis of malignant pheochromocytoma has received only limited attention. 1 Once d...

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Phenylethanolamine N-methyltransferase gene expression: synergistic activation by Egr-1, AP-2 and the glucocorticoid receptor

Cited by 61 publications

References 31 publications

Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice

Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice

Nerve Growth Factor Regulates Adrenergic Expression

Malignant Pheochromocytoma

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