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Matthias Haase Department of Endocrinology, Diabetes and Rheumatology, University Hospital Duesseldorf, Moorenstr. 5, D-40225 Duesseldorf, Germany
University of Technology Dresden, University Clinic III, Dresden, Germany
School of Medicine, Department of Histology and Embryology, Poznan, Poland

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Matthias Schott Department of Endocrinology, Diabetes and Rheumatology, University Hospital Duesseldorf, Moorenstr. 5, D-40225 Duesseldorf, Germany
University of Technology Dresden, University Clinic III, Dresden, Germany
School of Medicine, Department of Histology and Embryology, Poznan, Poland

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Stefan R Bornstein Department of Endocrinology, Diabetes and Rheumatology, University Hospital Duesseldorf, Moorenstr. 5, D-40225 Duesseldorf, Germany
University of Technology Dresden, University Clinic III, Dresden, Germany
School of Medicine, Department of Histology and Embryology, Poznan, Poland

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Ludwik K Malendowicz Department of Endocrinology, Diabetes and Rheumatology, University Hospital Duesseldorf, Moorenstr. 5, D-40225 Duesseldorf, Germany
University of Technology Dresden, University Clinic III, Dresden, Germany
School of Medicine, Department of Histology and Embryology, Poznan, Poland

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Werner A Scherbaum Department of Endocrinology, Diabetes and Rheumatology, University Hospital Duesseldorf, Moorenstr. 5, D-40225 Duesseldorf, Germany
University of Technology Dresden, University Clinic III, Dresden, Germany
School of Medicine, Department of Histology and Embryology, Poznan, Poland

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Holger S Willenberg Department of Endocrinology, Diabetes and Rheumatology, University Hospital Duesseldorf, Moorenstr. 5, D-40225 Duesseldorf, Germany
University of Technology Dresden, University Clinic III, Dresden, Germany
School of Medicine, Department of Histology and Embryology, Poznan, Poland

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CITED2 gene deletion in mice leads to adrenal agenesis. Therefore, we analyzed CITED2, a CBP/p300 interacting transactivator with transforming activity, in the human adrenal gland. In this study, we examined CITED2 expression in human embryonic and adult adrenal glands as well as adrenocortical carcinomas. As ACTH and basic fibroblast growth factor (bFGF) are connected to the physiology and growth of adrenocortical cells we studied the regulation of CITED2 by these factors in the NCI-H295R adrenocortical carcinoma cell line. We found CITED2 expression in the adult adrenal cortex as well in adrenocortical carcinomas. At an early stage of human adrenal organogenesis CITED2 could be located to the definitive zone of the developing adrenal gland using immunohistochemistry. In NCI-H295R cells, stimulation by bFGF led to a dose-dependent increase in CITED2 promotor activity, mRNA and protein expression while ACTH had no significant effect. The stimulatory effect of bFGF could be reduced by blocking mitogen-activated protein kinase activity using the MAPkinase kinase (MEK1)-inhibitor PD98059. CITED2 is expressed in embryonic and adult human adrenal glands as well as in adrenocortical cancer. It is connected to the signaling cascades of bFGF and its expression is modulated by mitogen-activated protein kinases. This suggests a novel role for CITED2 in human adrenal growth and possibly in adrenal tumorigenesis.

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Manjunath Ramanjaneya Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK
Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK

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Bee K Tan Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK
Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK

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Marcin Rucinski Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK

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Mohamed Kawan Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK

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Jiamiao Hu Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK

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Jaspreet Kaur Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK

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Vanlata H Patel Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK

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Ludwik K Malendowicz Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK

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Hanna Komarowska Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK

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Hendrik Lehnert Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK
Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK

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Harpal S Randeva Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK
Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK
Warwick Medical School, Interim Translational Research Institute, Department of Obstetrics and Gynaecology, Department of Histology and Embryology, Department of Endocrinology, 1st Medical Department, Department of Diabetes, Aston Medical Research Institute, University of Warwick, Coventry CV4 7AL, UK

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NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexigenic hypothalamic neuroproteins involved in energy homeostasis. It is expressed both centrally and in peripheral tissues, and appears to have potent metabolic actions. NUCB2/nesfatin neurons are activated in response to stress. Central nesfatin-1 administration elevates circulating ACTH and corticosterone levels. Bilateral adrenalectomy increased NUCB2/nesfatin mRNA levels in rat paraventricular nuclei. To date, studies have not assessed the effects of nesfatin-1 stimulation on human adrenocortical cells. Therefore, we investigated the expression and effects of nesfatin-1 in a human adrenocortical cell model (H295R). Our findings demonstrate that NUCB2 and nesfatin-1 are expressed in human adrenal gland and human adrenocortical cells (H295R). Stimulation with nesfatin-1 inhibits the growth of H295R cells and promotes apoptosis, potentially via the involvement of Bax, BCL-XL and BCL-2 genes as well as ERK1/2, p38 and JNK1/2 signalling cascades. This has implications for understanding the role of NUCB2/nesfatin in adrenal zonal development. NUCB2/nesfatin may also be a therapeutic target for adrenal cancer. However, further studies using in vivo models are needed to clarify these concepts.

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