9 results on '"Grübler Y"'
Search Results
2. Normal Human Pituitary Gland and Pituitary Adenomas Express Cannabinoid Receptor Type 1 and Synthesize Endogenous Cannabinoids: First Evidence for a Direct Role of Cannabinoids on Hormone Modulation at the Human Pituitary Level*
- Author
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Pagotto, U, Marsicano, G, Fezza, F, Theodoropoulou, M, Grübler, Y, Stalla, J, Arzberger, T, Milone, A, Losa, M, Di Marzo, V, Lutz, B, and Stalla, G K
- Published
- 2001
3. Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function
- Author
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Günter K. Stalla, Cristina Cervino, Beat Lutz, Giovanni Marsicano, Michel-Alexander Steiner, Uberto Pagotto, James P. Herman, Daniela Cota, Renato Pasquali, Johanna Stalla, Yvonne Grübler, Cota D, Steiner MA, Marsicano G, Cervino C, Herman JP, Grübler Y, Stalla J, Pasquali R, Lutz B, Stalla GK, and Pagotto U.
- Subjects
Hypothalamo-Hypophyseal System ,medicine.medical_specialty ,endocrine system ,Corticotropin-Releasing Hormone ,Pituitary-Adrenal System ,Biology ,Hippocampus ,Mice ,chemistry.chemical_compound ,Endocrinology ,Glucocorticoid receptor ,Mineralocorticoid receptor ,Adrenocorticotropic Hormone ,Receptor, Cannabinoid, CB1 ,Corticosterone ,Internal medicine ,Cannabinoid receptor type 1 ,medicine ,Animals ,RNA, Messenger ,Mice, Knockout ,musculoskeletal, neural, and ocular physiology ,Endocannabinoid system ,Circadian Rhythm ,Mice, Inbred C57BL ,medicine.anatomical_structure ,chemistry ,nervous system ,Hypothalamus ,Growth Hormone ,Female ,lipids (amino acids, peptides, and proteins) ,Glucocorticoid ,Hypothalamic–pituitary–adrenal axis ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
The endocannabinoid system affects the neuroendocrine regulation of hormone secretion, including the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, the mechanisms by which endocannabinoids regulate HPA axis function have remained unclear. Here we demonstrate that mice lacking cannabinoid receptor type 1 (CB1−/−) display a significant dysregulation of the HPA axis. Although circadian HPA axis responsiveness is preserved, CB1−/− mice are characterized by an enhanced circadian drive on the HPA axis, resulting in elevated plasma corticosterone concentrations at the onset of the dark as compared with wild-type (CB1+/+) littermates. Moreover, CB1−/−-derived pituitary cells respond with a significantly higher ACTH secretion to CRH and forskolin challenges as compared with pituitary cells derived from CB1+/+ mice. Both CBL−/− and CB1+/+ mice properly respond to a high-dose dexamethasone test, but response to low-dose dexamethasone is influenced by genotype. In addition, CB1−/− mice show increased CRH mRNA levels in the paraventricular nucleus of the hypothalamus but not in other extrahypothalamic areas, such as the amygdala and piriform cortex, in which CB1 and CRH mRNA have been colocalized. Finally, CB1−/− mice have selective glucocorticoid receptor mRNA down-regulation in the CA1 region of the hippocampus but not in the dentate gyrus or paraventricular nucleus. Conversely, mineralocorticoid receptor mRNA expression levels were found unchanged in these brain areas. In conclusion, our findings indicate that CB1 deficiency enhances the circadian HPA axis activity peak and leads to central impairment of glucocorticoid feedback, thus further outlining the essential role of the endocannabinoid system in the modulation of neuroendocrine functions.
- Published
- 2007
4. Differential expression of menin in sporadic pituitary adenomas
- Author
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Uberto Pagotto, Ludwig Schaaf, Thomas Arzberger, Vincenzo Ciminale, Yvonne Grübler, Marco Losa, Francesco Fallo, Tiziana Ferro, Marily Theodoropoulou, Luisa Barzon, Ilaria Cavallari, Gk Stalla, Dm D'Agostino, Theodoropoulou, M., Cavallari, I., Barzon, L., D'Agostino, D. M., Ferro, T., Arzberger, T., Grübler, Y., Schaaf, L., Losa, M., Fallo, F., Ciminale, V., Stalla, G. K., Pagotto, U., THEODOROPOULOU M, CAVALLARI I, BARZON L, D'AGOSTINO DM, FERRO T, ARZBERGER T, GRUBLER Y, SCHAAF L, LOSA M, FALLO F, CIMINALE V, STALLA GK, and PAGOTTO U.
- Subjects
Adenoma ,Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Pathology ,medicine.medical_specialty ,Pituitary gland ,Cancer Research ,Adolescent ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Pituitary neoplasm ,Biology ,Immunoenzyme Techniques ,Endocrinology ,Proto-Oncogene Proteins ,medicine ,Humans ,Genes, Tumor Suppressor ,Neoplasm Invasiveness ,Pituitary Neoplasms ,MEN1 ,Nuclear protein ,Multiple endocrine neoplasia ,Aged ,Aged, 80 and over ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Pituitary Gland ,Pituitary carcinoma ,Immunohistochemistry ,Female - Abstract
Pituitary adenomas represent one of the key features of multiple endocrine neoplasia type 1. The gene involved in this syndrome (MEN1) is a putative tumor suppressor, that codes for a 610-amino acid nuclear protein termed 'menin'. Analyses of sporadic pituitary adenomas have so far failed to reveal MEN1 mutations or defects in MEN1 transcription in these tumors. In the present study we detected menin protein expression in a panel of normal and tumoral pituitary tissues, using a monoclonal antibody against the carboxy-terminus of menin. In the normal human pituitary gland, strong nuclear staining for menin was detectable in the majority of the endocrine cells of the anterior lobe, without a clear association with a particular hormone-producing type. In sporadic pituitary adenomas, menin expression was variable, with a high percentage of cases demonstrating a significant decrease in menin immunoreactivity when compared with the normal pituitary. Interestingly, metastatic tissues derived from one pituitary carcinoma had no detectable menin levels. Altogether, our data provide the first information regarding the status of menin expression in human normal and neoplastic pituitary as determined by immunohistochemistry (IHC).
- Published
- 2004
5. Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function.
- Author
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Cota D, Steiner MA, Marsicano G, Cervino C, Herman JP, Grübler Y, Stalla J, Pasquali R, Lutz B, Stalla GK, and Pagotto U
- Subjects
- Adrenocorticotropic Hormone metabolism, Animals, Circadian Rhythm, Corticotropin-Releasing Hormone metabolism, Female, Growth Hormone metabolism, Hippocampus metabolism, Hypothalamo-Hypophyseal System metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Pituitary-Adrenal System metabolism, RNA, Messenger metabolism, Receptor, Cannabinoid, CB1 genetics, Hypothalamo-Hypophyseal System physiology, Pituitary-Adrenal System physiology, Receptor, Cannabinoid, CB1 physiology
- Abstract
The endocannabinoid system affects the neuroendocrine regulation of hormone secretion, including the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, the mechanisms by which endocannabinoids regulate HPA axis function have remained unclear. Here we demonstrate that mice lacking cannabinoid receptor type 1 (CB1-/-) display a significant dysregulation of the HPA axis. Although circadian HPA axis responsiveness is preserved, CB1-/- mice are characterized by an enhanced circadian drive on the HPA axis, resulting in elevated plasma corticosterone concentrations at the onset of the dark as compared with wild-type (CB1+/+) littermates. Moreover, CB1-/--derived pituitary cells respond with a significantly higher ACTH secretion to CRH and forskolin challenges as compared with pituitary cells derived from CB1+/+ mice. Both CBL-/- and CB1+/+ mice properly respond to a high-dose dexamethasone test, but response to low-dose dexamethasone is influenced by genotype. In addition, CB1-/- mice show increased CRH mRNA levels in the paraventricular nucleus of the hypothalamus but not in other extrahypothalamic areas, such as the amygdala and piriform cortex, in which CB1 and CRH mRNA have been colocalized. Finally, CB1-/- mice have selective glucocorticoid receptor mRNA down-regulation in the CA1 region of the hippocampus but not in the dentate gyrus or paraventricular nucleus. Conversely, mineralocorticoid receptor mRNA expression levels were found unchanged in these brain areas. In conclusion, our findings indicate that CB1 deficiency enhances the circadian HPA axis activity peak and leads to central impairment of glucocorticoid feedback, thus further outlining the essential role of the endocannabinoid system in the modulation of neuroendocrine functions.
- Published
- 2007
- Full Text
- View/download PDF
6. Differential expression of menin in sporadic pituitary adenomas.
- Author
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Theodoropoulou M, Cavallari I, Barzon L, D'Agostino DM, Ferro T, Arzberger T, Grübler Y, Schaaf L, Losa M, Fallo F, Ciminale V, Stalla GK, and Pagotto U
- Subjects
- Adenoma pathology, Adolescent, Adult, Aged, Aged, 80 and over, Female, Genes, Tumor Suppressor, Humans, Immunoenzyme Techniques, Male, Middle Aged, Pituitary Gland metabolism, Pituitary Gland pathology, Pituitary Neoplasms pathology, Adenoma metabolism, Neoplasm Invasiveness pathology, Pituitary Neoplasms metabolism, Proto-Oncogene Proteins metabolism
- Abstract
Pituitary adenomas represent one of the key features of multiple endocrine neoplasia type 1. The gene involved in this syndrome (MEN1) is a putative tumor suppressor, that codes for a 610-amino acid nuclear protein termed 'menin'. Analyses of sporadic pituitary adenomas have so far failed to reveal MEN1 mutations or defects in MEN1 transcription in these tumors. In the present study we detected menin protein expression in a panel of normal and tumoral pituitary tissues, using a monoclonal antibody against the carboxy-terminus of menin. In the normal human pituitary gland, strong nuclear staining for menin was detectable in the majority of the endocrine cells of the anterior lobe, without a clear association with a particular hormone-producing type. In sporadic pituitary adenomas, menin expression was variable, with a high percentage of cases demonstrating a significant decrease in menin immunoreactivity when compared with the normal pituitary. Interestingly, metastatic tissues derived from one pituitary carcinoma had no detectable menin levels. Altogether, our data provide the first information regarding the status of menin expression in human normal and neoplastic pituitary as determined by immunohistochemistry (IHC)., (Copyright 2004 Society for Endocrinology)
- Published
- 2004
- Full Text
- View/download PDF
7. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis.
- Author
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Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thöne-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, and Pagotto U
- Subjects
- Adipocytes metabolism, Animals, Cannabinoid Receptor Modulators, Corticotropin-Releasing Hormone genetics, Corticotropin-Releasing Hormone physiology, Eating physiology, Gene Expression, Hypothalamus physiopathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuropeptides genetics, Neuropeptides physiology, Obesity physiopathology, Obesity therapy, Phenotype, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Cannabinoid, Receptors, Drug deficiency, Receptors, Drug genetics, Thinness physiopathology, Appetite physiology, Cannabinoids metabolism, Energy Metabolism, Fatty Acids, Unsaturated physiology, Lipids biosynthesis, Receptors, Drug physiology
- Abstract
The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1-/-) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1-/- mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1-/- mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity, body temperature, or energy expenditure. Hypothalamic CB1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and preproorexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1-/- mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced lipogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.
- Published
- 2003
- Full Text
- View/download PDF
8. Retinoic acid prevents experimental Cushing syndrome.
- Author
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Páez-Pereda M, Kovalovsky D, Hopfner U, Theodoropoulou M, Pagotto U, Uhl E, Losa M, Stalla J, Grübler Y, Missale C, Arzt E, and Stalla GK
- Subjects
- Adrenocorticotropic Hormone biosynthesis, Animals, COUP Transcription Factor I, Carcinoma, Non-Small-Cell Lung complications, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung metabolism, Cushing Syndrome etiology, Cushing Syndrome metabolism, DNA-Binding Proteins metabolism, Humans, Lung Neoplasms complications, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Mice, Mice, Nude, Neoplasm Transplantation, Neuroendocrine Tumors complications, Neuroendocrine Tumors drug therapy, Neuroendocrine Tumors metabolism, Pituitary Neoplasms complications, Pituitary Neoplasms drug therapy, Pituitary Neoplasms metabolism, Pro-Opiomelanocortin genetics, Transcription Factors metabolism, Transcription, Genetic drug effects, Transplantation, Heterologous, Tumor Cells, Cultured, Cushing Syndrome prevention & control, Tretinoin pharmacology
- Abstract
Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome.
- Published
- 2001
- Full Text
- View/download PDF
9. The expression of the antiproliferative gene ZAC is lost or highly reduced in nonfunctioning pituitary adenomas.
- Author
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Pagotto U, Arzberger T, Theodoropoulou M, Grübler Y, Pantaloni C, Saeger W, Losa M, Journot L, Stalla GK, and Spengler D
- Subjects
- Blotting, Western, Cell Division, DNA, Complementary metabolism, ErbB Receptors biosynthesis, Humans, Immunohistochemistry, In Situ Hybridization, Mutation, Oligonucleotides, Antisense metabolism, Pituitary Gland metabolism, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins, Zinc Fingers, Adenoma metabolism, Cell Cycle Proteins biosynthesis, Cell Cycle Proteins genetics, Genes, Tumor Suppressor, Pituitary Neoplasms metabolism, Trans-Activators biosynthesis, Trans-Activators genetics, Transcription Factors
- Abstract
The ZAC gene encodes a new zinc-finger protein that concomitantly induces apoptosis and cell cycle arrest and localizes to chromosome 6q24-q25, a well-known hot spot related to cancer. ZAC is highly expressed in the anterior pituitary gland, and its ablation by antisense targeting promotes pituitary cell proliferation. Here we investigate ZAC status in pituitary tumors to evaluate its role in pituitary tumorigenesis. Interest ingly, a strong reduction or absence of ZAC mRNA and protein expres sion was detected in nonfunctioning pituitary adenomas, whereas in clin ically active pituitary neoplasias, the decrease in ZAC expression was variable. Loss of expression was not associated with a mutation of the ZAC gene. Our observations suggest that alternative mechanisms of gene inactivation and/or altered regulation of the ZAC gene occur in nonfunctioning pituitary adenomas.
- Published
- 2000
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