CRHR1-dependent effects on protein expression and posttranslational modification in AtT-20 cells

Kronsbein, Helena C.; Jastorff, Archana; Maccarrone, Giuseppina; Stalla, Günter; Wurst, Wolfgang; Holsboer, Florian; Turck, Christoph W.; Deussing, Jan M.

doi:10.1016/j.mce.2008.05.017

Cited by 6 publications

(8 citation statements)

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“…As pituitary-derived corticotrope cell line, AtT-20 cells express CRHR1 but not CRHR2 [20] which permits specific analyses of CRHR1 signaling. A plethora of molecules regulated downstream of CRHR1 have been identified and studied in this cell line [12,19,20], however, the complex system of CRHR1-regulated signaling cascades is not fully understood. To further elucidate genes involved in CRH-activated signaling pathways we treated the cells with 100 nM CRH at five different time points (1, 3, 6, 12, 24 h).…”

Section: Resultsmentioning

confidence: 99%

“…Both genes were found to be connected via the peroxisomal proliferator-activated receptor α (PPARA) which maintains fatty acid homeostasis by induction of fatty acid oxidation and plays a role in controlling peroxisomal proliferation. Hmgcs1 was also found to be regulated on protein level after 100 nM CRH treatment of AtT-20 cells [19]. The Hmgcs1 gene contains a peroxisome proliferator response element (PPRE) in its promoter that binds PPARA/RXR heterodimers [61] and long-chain acyl-CoA synthetases (LC-ACS), like Acsl4, inhibit PPARA-mediated transcription [62].…”

Section: Resultsmentioning

confidence: 99%

“…Expression profiling applying high-throughput microarray technology allows monitoring thousands of genes simultaneously and to characterize changes in gene expression patterns induced by a defined stimulus on a genome-wide scale. In order to dissect signaling mechanisms of the CRHR1 in depth we used AtT-20 cells, which are a well established in vitro system to study CRHR1 signaling [12,19,20]. To gain insight into the dynamics of CRH-/CRHR1-dependent signaling pathways we investigated the alterations in expression patterns after CRH treatment at five different time points between 1 and 24 h on the Max Planck Institute of Psychiatry (MPIP) 24 k cDNA microarray platform [21].…”

Section: Introductionmentioning

confidence: 99%

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Deducing corticotropin-releasing hormone receptor type 1 signaling networks from gene expression data by usage of genetic algorithms and graphical Gaussian models

et al. 2010

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BackgroundDysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of complex and multifactorial psychiatric diseases such as anxiety and mood disorders. About 50-60% of patients with major depression show HPA axis dysfunction, i.e. hyperactivity and impaired negative feedback regulation. The neuropeptide corticotropin-releasing hormone (CRH) and its receptor type 1 (CRHR1) are key regulators of this neuroendocrine stress axis. Therefore, we analyzed CRH/CRHR1-dependent gene expression data obtained from the pituitary corticotrope cell line AtT-20, a well-established in vitro model for CRHR1-mediated signal transduction. To extract significantly regulated genes from a genome-wide microarray data set and to deduce underlying CRHR1-dependent signaling networks, we combined supervised and unsupervised algorithms.ResultsWe present an efficient variable selection strategy by consecutively applying univariate as well as multivariate methods followed by graphical models. First, feature preselection was used to exclude genes not differentially regulated over time from the dataset. For multivariate variable selection a maximum likelihood (MLHD) discriminant function within GALGO, an R package based on a genetic algorithm (GA), was chosen. The topmost genes representing major nodes in the expression network were ranked to find highly separating candidate genes. By using groups of five genes (chromosome size) in the discriminant function and repeating the genetic algorithm separately four times we found eleven genes occurring at least in three of the top ranked result lists of the four repetitions. In addition, we compared the results of GA/MLHD with the alternative optimization algorithms greedy selection and simulated annealing as well as with the state-of-the-art method random forest. In every case we obtained a clear overlap of the selected genes independently confirming the results of MLHD in combination with a genetic algorithm.With two unsupervised algorithms, principal component analysis and graphical Gaussian models, putative interactions of the candidate genes were determined and reconstructed by literature mining. Differential regulation of six candidate genes was validated by qRT-PCR.ConclusionsThe combination of supervised and unsupervised algorithms in this study allowed extracting a small subset of meaningful candidate genes from the genome-wide expression data set. Thereby, variable selection using different optimization algorithms based on linear classifiers as well as the nonlinear random forest method resulted in congruent candidate genes. The calculated interacting network connecting these new target genes was bioinformatically mapped to known CRHR1-dependent signaling pathways. Additionally, the differential expression of the identified target genes was confirmed experimentally.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deducing corticotropin-releasing hormone receptor type 1 signaling networks from gene expression data by usage of genetic algorithms and graphical Gaussian models

et al. 2010

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“…Peeters and colleagues (2004) used the induction of c-fos mRNA to control for the efficacy of CRH treatment. We chose treatment conditions similar to previous experiments (Kronsbein et al, 2008), which resulted in a robust release of ACTH from AtT-20 cells and increased Pomc mRNA expression. To address the question whether the identified candidate genes themselves are capable of directly modulating CRHR1-dependent signaling, we used suitable reporter assays.…”

Section: Discussionmentioning

confidence: 99%

Corticotropin-releasing hormone regulates common target genes with divergent functions in corticotrope and neuronal cells

Graf

Kuehne

Panhuysen

et al. 2012

Molecular and Cellular Endocrinology

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“…In order to further dissect the signal transduction cascades activated by CRH-R1, a comparative proteome approach was performed in vitro, utilizing murine corticotroph AtT-20 cells [54]. Amongst others, they identified alterations in PRKAR1A, the regulatory subunit of PKA; in PGK1 and PGAM1, key regulators of glycolysis; and in proteins involved in proteosome-mediated proteolysis, PSMC2 and PSMA3.…”

Section: Protective Activities Of Crhmentioning

confidence: 99%

The Corticotropin‐Releasing Hormone in Neuroprotection

Behl

Clement

2011

Hormones in Neurodegeneration, Neuroprotection, and Neurogenesis

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Corticotropin-releasing hormone (CRH) is a small peptide with diverse biological functions. Initially identified as the central modulator of the mammalian hypothalamic-pituitary-adrenal (HPA) axis and playing a key role in mediating neuroendocrine effects in response to stress, CRH research of the last decade has uncovered additional roles of the CRH. On the basis of findings that the CRH system is disturbed in neurodegenerative disorders and that the receptors for CRH are also widely expressed in brain areas not directly related to the stress response, a potential role for CRH in neuroprotection has been proposed. Until now, various investigations have demonstrated a direct protective role of CRH and its related peptides at the cellular level and also in vivo. The molecular downstream targets of the neuroprotective CRH activity are just starting to evolve. CRH and CRH receptors are back on the map and are in the focus of many researchers working on novel approaches to prevention and treatment of neurodegenerative syndromes. IntroductionCRH is the stress hormone of the body. CRH (also called corticotropin-releasing factor, CRF) regulates the activity of the HPA axis and is released upon stressful stimuli. It is secreted by the hypothalamus and mediates neuroendocrine effects [1]. CRH, an oligopeptide consisting of 41 amino acids, was discovered by Vale et al. in 1981 [2, 3] and has been found to regulate the stress response by turning on the HPA axis. As for other releasing hormones of the hypothalamus, CRH is derived from a larger precursor and is released following proteolytic processing. Neuroendocrine hypothalamic neurons are molecular interfaces that turn electrophysiological signals from the periphery into biochemical signals which then switch on the respective hormone axis, such as the HPA, activated by the molecular player CRH. Initially believed to be involved in just regulating the endocrine stress response, by studying the expression of CRH and its receptors it rapidly became clear that CRH has a rather broad spectrum of activities, including mediating the autonomic, behavioral, and immunological stress response. Owing to its central Hormones in Neurodegeneration, Neuroprotection, and Neurogenesis.

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CRHR1-dependent effects on protein expression and posttranslational modification in AtT-20 cells

Cited by 6 publications

References 54 publications

Deducing corticotropin-releasing hormone receptor type 1 signaling networks from gene expression data by usage of genetic algorithms and graphical Gaussian models

Deducing corticotropin-releasing hormone receptor type 1 signaling networks from gene expression data by usage of genetic algorithms and graphical Gaussian models

Corticotropin-releasing hormone regulates common target genes with divergent functions in corticotrope and neuronal cells

The Corticotropin‐Releasing Hormone in Neuroprotection

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