Dexamethasone regulates expression of BRUCE/Apollon and the proliferation of neural progenitor cells

Sippel, Maria; Rajala, Raili; Korhonen, Laura; Bornhäuser, Beat; Sokka, Anna-Leena; Naito, Mikihiko; Lindholm, Dan

doi:10.1016/j.febslet.2009.06.018

Cited by 16 publications

(14 citation statements)

References 19 publications

(54 reference statements)

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“…Consistent with this result, USP8 protein expression levels were shown to be higher in USP8-mutant than in WT corticotroph adenomas (9). A previous study reported that a dexamethasone treatment increased USP8 protein expression levels in a glucocorticoid receptor-dependent manner in human embryonic kidney cells, suggesting the regulation of corticotroph USP8 expression by the positive feedback system of the hypothalamic-pituitary-adrenal gland axis (29). However, this does not explain why USP8-mutant adenomas expressed USP8 mRNA more strongly than WT adenomas because no significant differences were observed in serum cortisol levels between mutant and WT adenomas (Table 1).…”

Section: Discussionsupporting

confidence: 75%

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

Hayashi

Inoshita

Kawaguchi

et al. 2016

European Journal of Endocrinology

136

156

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Context: Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one-to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion. Objective: Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. Subjects and methods: USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry. Results: USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT. Conclusions: Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.

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Section: Discussionsupporting

confidence: 75%

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

Hayashi

Inoshita

Kawaguchi

et al. 2016

European Journal of Endocrinology

136

156

View full text Add to dashboard Cite

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“…S3C). GC effects on neuronal migration and ubiquitin-proteasome mediated degradation have previously been observed in neural stem cells (9,36) and may be influenced by Cav-1. To summarize, in addition to identifying many novel primary GC responsive genes in NPSCs, our microarray data implicated Cav-1 as a modulator of both rapid signaling and genomic action of GR.…”

Section: Resultsmentioning

confidence: 74%

“…In embryonic rat cells, Dex treatment increases the expression of a deubiquitinating enzyme, Usp8/ Ubpy that can indirectly cause increased degradation of the BRUCE/Apollo inhibitor of apoptosis protein. As a result of increased BRUCE degradation, there is a consequent decrease in cell proliferation (36). Interestingly, Cav-1 interacts with and regulates the polyubiquitinylation of active Rac1 (46).…”

Section: Discussionmentioning

confidence: 99%

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Peffer

Chandran

Luthra

et al. 2014

Molecular and Cellular Biology

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While glucocorticoids (GCs) are used clinically to treat many conditions, their neonatal and prenatal usage is increasingly controversial due to reports of delayed adverse outcomes, especially their effects on brain development. Such alterations may reflect the impact of GCs on neural progenitor/stem cell (NPSC) function. We previously demonstrated that the lipid raft protein caveolin-1 (Cav-1) was required for rapid GC signaling in embryonic mouse NPSCs operating through plasma membranebound glucocorticoid receptors (GRs). We show here that genomic GR signaling in NPSCs requires Cav-1. Loss of Cav-1 impacts the transcriptional response of many GR target genes (e.g., the serum-and glucocorticoid-regulated kinase 1 gene) that are likely to mediate the antiproliferative effects of GCs. Microarray analysis of wild-type C57 or Cav-1-deficient NPSCs identified approximately 100 genes that are differentially regulated by GC treatment. These changes in hormone responsiveness in Cav-1 knockout NPSCs are associated with the loss of GC-regulated phosphorylation of GR at serine 211 but not at serine 226. Chromatin recruitment of total GR to regulatory regions of target genes such as Fkbp-5, RhoJ, and Sgk-1, as well as p211-GR recruitment to Sgk-1, are compromised in Cav-1 knockout NPSCs. Cav-1 is therefore a multifunctional regulator of GR in NPSCs influencing both rapid and genomic action of the receptor to impact cell proliferation.

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“…Recently, the responsiveness of embryonic NSCs to glucocorticoid was linked to the direct, acute genomic effects of the activated GRs, known as transcriptional regulators (Androutsellis-Theotokis et al, 2013; Peffer et al, 2014). Moreover, in vitro exposure of rat ES cells to DEX induced heritable alterations and changes in the expression of genes associated with cellular senescence and proliferation (Sippel et al, 2009; Bose et al, 2010). Notably, the expression pattern of GRs in mouse embryonic NSCs changes with differentiation, in vivo or in vitro .…”

Section: Negative and Positive Effects Of Stress Hormones On Nscsmentioning

confidence: 99%

Neural stem cells respond to stress hormones: distinguishing beneficial from detrimental stress

Koutmani

Karalis

2015

Front. Physiol.

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Neural stem cells (NSCs), the progenitors of the nervous system, control distinct, position-specific functions and are critically involved in the maintenance of homeostasis in the brain. The responses of these cells to various stressful stimuli are shaped by genetic, epigenetic, and environmental factors via mechanisms that are age and developmental stage-dependent and still remain, to a great extent, elusive. Increasing evidence advocates for the beneficial impact of the stress response in various settings, complementing the extensive number of studies on the detrimental effects of stress, particularly in the developing brain. In this review, we discuss suggested mechanisms mediating both the beneficial and detrimental effects of stressors on NSC activity across the lifespan. We focus on the specific effects of secreted factors and we propose NSCs as a “sensor,” capable of distinguishing among the different stressors and adapting its functions accordingly. All the above suggest the intriguing hypothesis that NSCs are an important part of the adaptive response to stressors via direct and indirect, specific mechanisms.

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Dexamethasone regulates expression of BRUCE/Apollon and the proliferation of neural progenitor cells

Cited by 16 publications

References 19 publications

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Neural stem cells respond to stress hormones: distinguishing beneficial from detrimental stress

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