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Xavier Bertagna

Publications and source records attributed to Xavier Bertagna.

At least 37 records · Page 2Linked to original sources
PubMed2004

Synergistic signaling by corticotropin-releasing hormone and leukemia inhibitory factor bridged by phosphorylated 3',5'-cyclic adenosine monophosphate response element binding protein at the Nur response element (NurRE)-signal transducers and activators of transcription (STAT) element of the proopiomelanocortin promoter.

Leukemia inhibitory factor (LIF) cooperates with CRH at the pituitary level to induce POMC gene transcription, resulting in activation of the pituitary-adrenal axis. However, the underlying molecular mechanisms remain elusive. Here, we show that the NurRE-signal transducers and activators of transcription (STAT) composite element of the POMC promoter was the predominant target of the LIF-CRH synergy. Whereas NurRE or STAT sites alone conferred synergy, the maximal response was found with the NurRE-STAT reporter, suggesting that direct DNA binding of both transcription factors is required for an optimal synergy. During LIF-CRH stimulation, Nur77 and activated STAT1-3 were bound to the composite element, and the binding of each factor was abolished by appropriate mutations. CREB was also detected in this complex in a stimulation-dependent and DNA binding-independent manner. Nur77 and STAT1-3 bound to the NurRE-STAT site were each sufficient for CREB recruitment. Recombinant CREB directly interacted with recombinant Nur77 or STAT1-3. Moreover, CREB-Nur77 interaction was increased by CREB phosphorylation at Ser-133 and the dominant-negative mutant CREB-M1 efficiently inhibited the synergistic LIF-CRH response. This synergism was also inhibited after transfection of CREB-small interfering RNA. We conclude that both CREB phosphorylation at Ser-133 and level of CREB expression are crucial in LIF-CRH synergism where CREB, without direct DNA binding, could improve the stability of Nur77 and STAT1-3 binding to POMC promoter and facilitate the recruitment of coactivators. This novel intrapituitary signaling mechanism may have more general implications in cross talks between cAMP-protein kinase A and Janus kinase-STAT pathways.

Animals↗
PubMed2004

The Nelson's syndrome... revisited.

Adrenalectomy is a radical therapeutic approach to control hypercortisolism in some patients with Cushing's disease. However it may be complicated by the Nelson's syndrome, defined by the association of a pituitary macroadenoma and high ACTH secretion after adrenalectomy. This definition has not changed since the end of the fifties. Today the Nelson's syndrome must be revisited with new to criteria using more sensitive diagnostic tools, especially the pituitary magnetic resonance imaging. In this paper we will review the pathophysiological aspects of corticotroph tumor growth, with reference to the impact of adrenalectomy. The main epidemiological data on the Nelson's syndrome will be presented. More importantly, we will propose a new pathophysiological and practical approach to this question which attempts to evaluate the Corticotroph Tumor Progression after adrenalectomy, rather than to diagnose the Nelson's syndrome. We will discuss the consequences for the management of Cushing's disease patients after adrenalectomy, and will also draw some perspectives.

ACTH-Secreting Pituitary Adenoma↗
PubMed2004

Midnight salivary cortisol for the initial diagnosis of Cushing's syndrome of various causes.

We assessed the value of midnight salivary cortisol for the initial diagnosis of Cushing's syndrome. Sixty-three patients with various causes of Cushing's syndrome (37 with Cushing's disease, 17 with adrenal Cushing's syndrome, and nine with ectopic ACTH syndrome) and 54 control subjects with simple obesity were studied. All patients with Cushing's syndrome excreted more than 90 microg urinary free cortisol (UFC)/d (248 nmol/d), and all controls excreted less than 90 microg/d UFC. All patients with Cushing's syndrome had a midnight salivary cortisol concentration above 2.0 ng/ml (5.52 nmol/liter), whereas only three controls did so [2.0 ng/ml (5.52 nmol/liter); 2.05 ng/ml (5.66 nmol/liter); and 3.6 ng/ml (9.96 nmol/liter)]. This cut-off provides a sensitivity of 100% and a specificity of 96%. In patients with Cushing's syndrome, midnight salivary cortisol concentrations were correlated with UFC collected over the same period of time (0800-0800 h). Salivary cortisol measurements taken every 4 h showed a typical lack of circadian variation. The daily measurement of midnight salivary cortisol concentrations for 2 wk or more in five other out-patients (with obvious Cushing's disease, subclinical adrenal Cushing's syndrome, suspected Cushing's syndrome, pituitary incidentaloma, and prolactinoma) demonstrated the clinical utility of this factor. Measuring midnight salivary cortisol is an easy and noninvasive means of diagnosing hypercortisolism. Its diagnostic accuracy is identical to, if not better than, that of previously described gold standards.

ACTH Syndrome, Ectopic↗
PubMed2004

Decreased expression of cyclic adenosine monophosphate-regulated aldose reductase (AKR1B1) is associated with malignancy in human sporadic adrenocortical tumors.

The human aldose reductase, AKR1B1, participates in glucose metabolism and osmoregulation and is supposed to play a protective role against toxic aldehydes derived from lipid peroxidation and steroidogenesis that could affect cell growth/differentiation when accumulated. Adrenal gland is a major site of expression of AKR1B1, and we asked whether changes in its expression could be associated with adrenal disorders. Therefore, we examined AKR1B1 gene expression in human fetal adrenals, adrenocortical cell line, and tumors and compared the results with the expression of steroidogenic genes (StAR and CYP11A) and regulators of adrenal cortex development [steroidogenic factor-1 (SF-1) and dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1)]. Using specific antibodies, Northern blotting, and enzymatic assays, we present evidences that AKR1B1 detectable in 15-wk-old fetal glands is regulated by cAMP in NCI-H295 cells and thus that AKR1B1 is functionally related to the ACTH-responsive murine akr1b7/mvdp gene rather than to its direct ortholog, the mouse aldose reductase akr1b3 gene. Although low DAX1 expression in aldosterone-producing adenomas (n = 5) was confirmed (P < 0.05), no correlation was found between the expression of all other genes and the tumors endocrine activity. In contrast, relative abundance of AKR1B1 mRNA was decreased in adrenocortical carcinomas (n = 5; mean +/- sem, 0.95 +/- 0.2) when compared with adenomas (n = 12; 9.29 +/- 3.05; P < 0.001). Most (seven of eight) adrenocortical carcinomas (19.0 +/- 5.4) had very low relative AKR1B1 protein levels when compared with benign tumors (cortisol-producing adenomas, n = 5, 63.0 +/- 9.8; nonfunctional adenomas, n = 5, 58.0 +/- 10.4; aldosterone-producing adenomas, n = 4, 65.3 +/- 7.7; P < 0.001), Cushing's hyperplasia (n = 5, 54.6 +/- 5.3; P < 0.01), or normal adrenals (n = 4; 37.1 +/- 5.3; P < 0.001). These properties provide the first evidence that expression of cAMP-regulated AKR1B1 is decreased in adrenocortical cancer. This might take part in adrenal tumorigenesis and could be investigated as a marker of malignancy for the diagnosis of adrenal tumors.

Adenoma↗
PubMed2004

Clinical, hormonal and magnetic resonance imaging (MRI) predictors of transsphenoidal surgery outcome in acromegaly.

OBJECTIVE: Progress in the treatment of acromegaly with drugs is making it necessary to improve the prediction of the outcome of transsphenoidal surgery. DESIGN: We evaluated clinical, hormonal and radiologic predictors based on magnetic resonance imaging (MRI) of surgical outcome in patients with acromegaly. METHODS: This retrospective analysis included 125 consecutive patients investigated for acromegaly in a single endocrine unit since the use of MRI imaging began (1988). Eighty-three of these patients (50 women) underwent transsphenoidal surgery and were investigated before and after surgery in our department. A neuroradiologist unaware of the surgical outcome analyzed the results of pituitary gland MRI investigations. RESULTS: Surgical remission rates were 44%, 43%, 61% and 59% based on mean basal GH concentration under 2.5 microg/l, GH/oral glucose tolerance test (OGTT) of <1 microg/l, GH/OGTT of <2 microg/l or IGF-I concentration normal for age and sex respectively. In univariate logistic regression analysis with IGF-I concentration used as the criterion for cure, young age (P<0.001), high IGF-I concentration before surgery (P<0.01), high basal GH concentration before surgery (P<0.02), and high nadir GH/OGTT before surgery (P=0.03) were predictors of poor outcome. The following results in standardized MRI analysis were associated with a higher probability of not being cured: adenoma greater than 15 mm in diameter (P<0.02), infrasellar extension (P=0.04), suprasellar extension (P<0.005) and invasive adenoma (0.02) according to MRI staging. MRI analysis of the intracavernous extension showed that stages above B2 (possible sinus extension with sign of invasion of the space below the carotid artery) were associated with a lower probability of postoperative normal GH plasma levels (P=0.01). In multivariate analysis, age, preoperative hormonal levels and adenoma size remained the major predictors of surgical outcome. CONCLUSIONS: This report provides the first evidence that detailed MRI analysis of adenoma size, location and potential invasion, together with preoperative clinical and hormonal parameters, can be used for the prediction of hormonal outcome after transsphenoidal surgery for acromegaly.

Acromegaly↗
PubMed2004

18F-fluorodeoxyglucose positron emission tomography as a diagnostic tool for malignancy of adrenocortical tumours? Preliminary results in 13 consecutive patients.

DESIGN: This study is a preliminary report on 18F-fluorodeoxyglucose (18F-FDG) uptake for the characterization of hypersecretory or non-hypersecretory adrenocortical masses in patients without known neoplastic disease, thereby minimizing the presence of adrenal metastases, and without phaeochromocytoma, in comparison with computed tomography (CT) scanning and with iodocholesterol scintigraphy. METHODS: Thirteen consecutive patients with an adrenal mass scheduled to have surgery, underwent hormonal exploration, a CT scan for tumour size measurement and an 18F-FDG positron emission tomography scan. Eleven of these patients also had unenhanced density measurement at CT scan and iodocholesterol scintigraphy. RESULTS: CT-scanned adrenal masses ranged in size from 2.2 to 10 cm; attenuation value was <10 Hounsfield units (HUs) in two cases and >10 HU in nine. All benign lesions demonstrated iodocholesterol uptake. In the case of malignant tumours, results were non-homogeneous: no uptake, uptake and non-informative scintigraphy. All patients with an adrenocortical carcinoma had positive adrenal 18F-FDG uptake (n=3), one had a liver metastasis with positive 18F-FDG uptake, one showed 18F-FDG uptake in an adrenal metastasis from an unknown primary kidney tumour. All patients with a benign adrenocortical lesion had negative 18F-FDG uptake (n=9). Patients' lesions were hypersecretory (n=5), or non-hypersecretory (n=8), regardless of the pathology. CONCLUSION: This short preliminary study indicates that 18F-FDG gave a correct classification of tissue characterization with accurate identification of malignant lesions, as well as the disease stage (metastasis or primary). These promising preliminary results on adrenocortical lesions, seldom studied with 18F-FDG, are to be confirmed in larger series.

Adrenal Cortex↗
PubMed2004

Cyclin E correlates with malignancy and adverse prognosis in adrenocortical tumors.

OBJECTIVE: In many cases, the prognosis of an adrenocortical tumor cannot be determined from pathologic findings alone. We investigated cyclin E levels as a potential marker. METHODS: We studied 57 tumors by immunohistochemical staining with an anticyclin E antibody. We also evaluated clinical and pathologic factors (McFarlane staging and Weiss score) and previously validated genetic markers (17p13 loss of heterozygosity, 11p15 uniparental disomy, and overexpression of the IGF-II gene) for these tumors. Disease-free survival was estimated in 49 patients who underwent curative surgery. RESULTS: Cyclin E overproduction (> or =5%) was associated with the malignant phenotype and was strongly correlated with tumor size (P<0.0001), Weiss score (P<0.0001) and the presence of genetic abnormalities in tumors (P<0.001) (nonparametric Wilcoxon test and Fisher's exact test). Within a median follow-up of 44.1 months, seven patients exhibited a recurrence and two patients died from other causes. Cyclin E overproduction was significantly associated with shorter disease-free survival in univariate analysis (P=0.016; RR: 7.6), as were histologic grade (Weiss score > or =4; P=0.0006; RR: 18), 17p13 LOH (P=0.014, RR: 14.9), 11p15 UPD (P=0.003, RR: 11.8) and overexpression of the IGF-II gene (P=0.015, RR: 13.8). CONCLUSION: This study shows that cyclin E overproduction is of adverse prognostic significance in adrenocortical tumors.

Adrenal Cortex Neoplasms↗
PubMed2004

A thyroid nodule revealing a paraganglioma in a patient with a new germline mutation in the succinate dehydrogenase B gene.

A 32-year-old asymptomatic female was diagnosed with an isolated thyroid nodule of 2.5 cm diameter. Fine needle aspiration suggested a medullary thyroid carcinoma. Consequently, a total thyroidectomy was performed. The nodule stained positive for chromogranin A, neurone-specific enolase and synaptophysin, but not for calcitonin. Finally, pathological analysis showed a thyroid paraganglioma. Although the tumour appeared to be sporadic in a patient with no personal or familial history of paraganglioma and/or pheochromocytoma, we have identified a new mutation (392delC) of the succinate dehydrogenase-B (SDHB) gene in the genomic DNA extracted from the leukocytes of the patient. That mutation induced a shift in the reading frame of the gene creating a premature stop codon (P131fsX135) which was predicted to result in a truncated SDHB protein of 135 amino acids. This report highlights the difficulties of this unexpected diagnosis of hereditary thyroid paraganglioma. It also discusses the clinical involvements in terms of familial screening and the necessary follow-up of the patient.

Adult↗
PubMed2003

Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity.

Germ-line protein kinase A (PKA) regulatory-subunit type-Ialpha (RIalpha; PRKAR1A)-inactivating mutations and loss-of-heterozygosity (LOH) of its 17q22-24 locus have been found in Cushing syndrome (CS) caused by primary pigmented nodular adrenocortical disease (PPNAD). We examined whether somatic 17q22-24, PRKAR1A, or PKA changes are present in 44 sporadic adrenocortical tumors (29 adenomas and 15 cancers); 26 of these tumors were responsible for CS. A probe containing the PRKAR1A gene-mapped by fluorescent in situ hybridization to 17q22-24-and corresponding microsatellite markers were used to study allelic losses; PRKAR1A was sequenced in all samples. 17q22-24 losses were seen in 23 and 53% of adenomas and cancers, respectively. In three tumors, somatic, PRKAR1A-inactivating mutations were identified: (a) a nonsense mutation in exon 6 (A751G); (b) a splicing mutation (9IVS-1G/A); and (c) a transition (1050T>C) followed by a 22-bp deletion, also in exon 9; all predicted premature RIalpha protein terminations. Quantitative message and protein studies showed RIalpha down-regulation in tumors with genetic changes; their cortisol secretion pattern was similar to that of PPNAD, and they had higher PKA activity by enzymatic studies. We conclude that somatic allelic losses of the 17q22-24 region, PRKAR1A-inactivating mutations or down-regulation, and corresponding PKA activity changes are present in at least some sporadic adrenocortical tumors, especially those with a PPNAD-like clinical presentation of CS.

Adrenal Cortex Neoplasms↗
PubMed2003

Aberrant receptor-mediated Cushing's syndrome.

Multiple alterations of G-protein-coupled receptors and G-proteins regulating intracellular transduction signal have been described in endocrine tumours. In Cushing's syndrome, aberrant or 'illicit' expression of membrane receptors (mainly G-protein-coupled receptors) has been observed in adrenal adenomas and adrenocorticotropic hormone (ACTH)-independent macronodular bilateral adrenal hyperplasia. The best characterized example to date is the aberrant expression of the gastric inhibitory polypeptide receptor that causes 'food-dependent hypercortisolism'. Aberrant expression of the luteinizing hormone, 2-adrenergic, interleukin receptors have also been reported. The level of expression of the vasopressin V1a receptor correlates with the direct (ACTH-independent) cortisol response to vasopressin.

Animals↗
PubMed2003

Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency.

We have previously described the only reported case of human proprotein convertase 1 (PC1) deficiency, in a female (Subject A) with obesity, hypogonadism, hypoadrenalism, and reactive hypoglycemia. We now report the second case of human PC1 deficiency (Subject B), also due to compound heterozygosity for novel missense and nonsense mutations. While both subjects shared the phenotypes of obesity, hypoadrenalism, reactive hypoglycemia, and elevated circulating levels of certain prohormones, the clinical presentation of Subject B was dominated by severe refractory neonatal diarrhea, malabsorptive in type. Subsequent investigation of Subject A revealed marked small-intestinal absorptive dysfunction, which was not previously clinically suspected. We postulate that PC1, presumably in the enteroendocrine cells, is essential for the normal absorptive function of the human small intestine. The differences in the nature and severity of presentation between the two cases cannot readily be explained on the basis of allelic heterogeneity, as the nonsense and missense mutations from both subjects had comparably severe effects on the catalytic activity of PC1. Despite Subject A's negligible PC1 activity, some mature ACTH and glucagon-like peptide 17-36(amide) were detectable in her plasma, suggesting that the production of these hormones, at least in humans, does not have an absolute dependence on PC1. The presence of severe obesity and the absence of growth retardation in both subjects contrast markedly with the phenotype of mice lacking PC1 and suggest that the precise physiological repertoire of this enzyme may vary between mammalian species.

Animals↗
PubMed2003

Transcription factor 3',5'-cyclic adenosine 5'-monophosphate-responsive element-binding protein (CREB) is decreased during human adrenal cortex tumorigenesis and fetal development.

Various cellular and molecular alterations of the cAMP pathway have been observed in adrenal Cushing syndrome. We recently reported the loss of cAMP-responsive element-binding protein (CREB) expression in the adrenocortical cancer cell line H295R. CREB is the major nuclear target of the cAMP pathway. This study therefore aimed to analyze the status of the CREB protein in various types of human adrenocortical tumors and normal fetal adrenal cortex. CREB protein status was studied by Western blotting in adrenocortical adenomas (AAs, n = 27) and adrenocortical carcinomas (ACs, n = 24). A decrease of CREB protein was noticed in the majority of the adrenocortical tumors. The dramatic decrease in CREB protein levels was more pronounced in ACs than in AAs. Levels of the phosphorylated form of CREB were also low in adrenocortical tumors, with a greater decrease in ACs than in AAs. EMSAs also showed decreases in the amounts of CREB- containing complexes in nuclear extracts from adrenocortical tumors. The secretory status of adenomas was strongly correlated with CREB levels, significantly lower in nonfunctioning AAs (n = 9) than in functioning AAs (n = 9). CREB levels, determined by Western blotting and immunohistochemistry, were very low in the fetal zone of human fetal adrenal cortex, whereas they were normal in the definitive zone. In tumors, adrenocortical cells in several zones were weakly immunohistochemically stained for CREB, whereas CREB was uniformly detected in nonendocrine cell nuclei (e.g. vascular cells, fibroblasts). These results suggest that the absence of CREB may be linked to the development of a highly aggressive tumor with a dedifferentiated benign (nonfunctioning AA) or malignant (AC) phenotype. These findings highlight the similarities between the normal human fetal adrenal gland and adrenal cancers previously observed in terms of parallelism in IGF-II production.

Adolescent↗
PubMed2003

[Subacute motor neuropathy induced by T3 hyperthyroidism].

Subacute motor neuropathy involving bulbar nerves is an unusual complication of hyperthyroidism. Clinical and neurophysiologic follow-up of such patients has been rarely reported. We describe a 41-year-old Colombian patient who developed respiratory failure associated with motor neuropathy and severe weight loss. The major clinical features included diffuse amyotrophy, bilateral facial paresis, and fasciculations, suggesting motor neuropathy. Electromyography confirmed the presence of axonal neuropathy, with predominant motor involvement. Goiter with hypervascularization was noticed, associated with pure T3 hyperthyroidism (T3l=26 pg/ml; N<3.8). The patient was given carbimazole which induced a severe skin vasculitis 10 days later. Carbimazole was stopped and replaced by propylthiouracile, which also induced vasculitis with secondary cardiac failure. Total thyroidectomy was then performed. General status improved rapidly as well as motor deficit, amyotrophy and pyramidal syndrome. Electromyographic abnormalities improved significantly within 3 months. This observation demonstrates that hyperthyroidism can produce motor axonal neuropathy, curable with radical surgery.

Acute Disease↗
PubMed2002

Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD.

We studied 11 new kindreds with primary pigmented nodular adrenocortical disease (PPNAD) or Carney complex (CNC) and found that 82% of the kindreds had PRKAR1A gene defects (including seven novel inactivating mutations), most of which led to nonsense mRNA and, thus, were not expressed in patients' cells. However, a previously undescribed base substitution in intron 6 (exon 6 IVS +1G-->T) led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent protein kinase A (PKA) signaling at the nuclear level. This is the first demonstration of an inactivating PRKAR1A mutation being expressed at the protein level and leading to stimulation of the PKA pathway in CNC patients. Along with the lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggest that alteration of PRKAR1A function (not only its complete loss) is sufficient for augmenting PKA activity leading to tumorigenesis in tissues affected by CNC.

Adenocarcinoma↗
PubMed2002

cAMP pathway alterations from the cell surface to the nucleus in adrenocortical tumors.

The cyclic AMP (cAMP) pathway plays a major role in the development of endocrine tissues and various molecular defects of key components of this pathway (G protein, receptors, PKA, ...) have been observed in endocrine tumors. Hypersecretion of adrenocorticotropin hormone (ACTH), the key activator of the cAMP pathway in adrenal cortex, is associated with adrenocortical hyperplasia and cortisol oversecretion (Cushing's syndrome). The best example of "illegitimate" membrane receptors expression reported is the abnormal expression of the adenylyl cyclase activating gastric inhibitory peptide receptor (GIP-R) in ACTH-independent Cushing's syndrome (ACS). We have observed that ectopic expression of the GIP-R is frequent in ACTH-Independent Macronodular Adrenal Hyperplasia (AIMAH), rare in benign adrenal adenoma (AA), but seems absent in Adrenal Cancer (AC). In vivo systematic screening of AIMAH shows at least one abnormal response of cortisol (suggesting "illegitimate" membrane receptor expression) in almost all patients. Somatic and germ line inactivating mutations of PRKAR1 (regulatory subunit R1A of PKA) can be observed in patient with isolated primary pigmented nodular adrenocortical disease (PPNAD) and AA responsible for ACS. At the nuclear level, the cAMP pathway regulates transcription mainly by PKA-dependent phosphorylation of the cyclic AMP response element binding (CREB) family of transcription factors (CREB, CREM, and ATF-1). Cyclic AMP response element binding protein (CREB) is expressed in normal adrenal cortex. Alterations of CRE binding proteins with loss of CREB expression and compensatory overexpression of CREMtau is observed in the human adrenocortical cancer cell line H295R. Similar alterations are found at the protein level in human malignant adrenocortical tumors. In conclusion, various alterations leading to activation or inactivation of key components of the cAMP signaling pathway can be observed in adrenocortical tumorigenesis.

Adrenal Cortex Neoplasms↗
PubMed2002

Adrenal incidentalomas.

The term adrenal incidentaloma refers to an adrenal mass occasionally and unexpectedly discovered by an abdominal imaging procedure performed for reasons a priori unrelated to adrenal dysfunction. The prevalence of adrenal incidentalomas as discovered by computed tomographic scan examination is estimated to be between 1% and 4%. The vast majority of these lesions are of adrenocortical origin, most often adenomas. Identification of steroid or catecholamine-secreting tumors is important but usually solved with appropriate endocrinologic investigations. A difficult problem, however, is to distinguish between benign and malignant primary or secondary tumors. Size less than 4 cm and an unenhanced computed tomographic attenuation under 10 Hounsfield Units (HU) are findings in favor of a benign adrenocortical adenoma, as is a positive NP 59 scintigraphic examination. The pathogenesis of adrenal tumors is not well understood. However, alterations of the cyclic AMP signalling pathway have recently been observed in benign adrenocortical lesions and molecular defects associated with insulin-like growth factor-II overexpression in malignant adrenocortical tumors.

Adenoma↗
PubMed2002

Different mechanisms for leukemia inhibitory factor-dependent activation of two proopiomelanocortin promoter regions.

To better understand how leukemia inhibitory factor (LIF) activates proopiomelanocortin (POMC) gene transcription in pituitary corticotrophs, time-course studies of the induction of POMC promoter activity and specific tyrosine phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 were performed. It was found that both phosphorylation of STAT1 and -3 and activation of the promoter activity rapidly and transiently take place within minutes and 2-6 h, respectively, in favor of a direct effect of the LIF pathway on POMC promoter. Activated STAT1 and -3 form homo-/heterodimers able to bind the Sis-inducible element. The most abundant Sis-inducible element binding dimers are STAT3/3 and STAT1/3. Degenerated STAT1/3-binding sites from the POMC promoter were tested for their ability to bind activated STAT1 and 3; only the -390/-379 site, partially overlapping the Nur response element, binds with low affinity activated STAT1 and -3. Analysis of the three domains and subregions of the POMC promoter showed that two subregions are specifically responsive to LIF. The response of the distal subregion requires the intact STAT1 and -3 DNA-binding site -390/-379, whereas the responsiveness of the proximal subregion takes place despite the absence of direct STAT1 and -3 DNA binding and may imply interaction of activated STAT with basal transcription factors.

Animals↗