Cross‐talk of vitamin D and glucocorticoids in hippocampal cells

Obradovic, Darja; Gronemeyer, Hinrich; Lutz, Beat; Rein, Theo

doi:10.1111/j.1471-4159.2005.03579.x

Cited by 127 publications

(97 citation statements)

References 50 publications

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“…Consistent with previous results, 26 Dex decreases neurite outgrowth. Expression of wt FKBP51 abolishes the effect of Dex treatment while K422R mutant fails to prevent it (Figure 3d).…”

Section: Resultssupporting

confidence: 93%

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

et al. 2016

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FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context.

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“…Consistent with previous results, 26 Dex decreases neurite outgrowth. Expression of wt FKBP51 abolishes the effect of Dex treatment while K422R mutant fails to prevent it (Figure 3d).…”

Section: Resultssupporting

confidence: 93%

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

et al. 2016

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“…This provides a plausible context for interpretation of recently published data linking FLASH to transcriptional activity of the glucocorticoid and mineralocorticoid receptors (15,16). 16306505) from normal epidermal human keratinocytes (American Type Culture Collection, Manassas, VA) RNA were cloned in-frame with the HA tag into pcDNA by using the NheI and XhoI unique restriction sites.…”

Section: Discussionmentioning

confidence: 99%

“…However, this role of FLASH has been questioned (14). More recently it has been shown that, in response to TNF␣, FLASH translocates to the nucleus and binds the glucocorticoid receptor-interacting protein (GRIP-1), inhibiting both its interaction with, and the transcriptional activity of, the glucocorticoid receptor (15,16).…”

mentioning

confidence: 99%

FLASH is an essential component of Cajal bodies

Barcaroli

Dinsdale

Neale

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cajal bodies are small nuclear organelles with a number of nuclear functions. Here we show that FLICE-associated huge protein (FLASH), originally described as a component of the apoptosis signaling pathway, is mainly localized in Cajal bodies and is essential for their structure. Reduction in FLASH expression by short hairpin RNA results in disruption of the normal architecture of the Cajal body and relocalization of its components. Because the function of FLASH in the apoptosis receptor signaling pathway has been strongly questioned, we have now identified a clear function for this protein.coiled bodies ͉ nuclear organelles C ajal bodies (CBs) are small nuclear organelles described in vertebrate cells a century ago by Ramon y Cajal and which have since been observed in a variety of animal and plant nuclei. Many components of CBs are shared with the nucleolus, and CBs frequently localize to the nucleolar periphery or within the nucleoli (1-3). CBs disappear from prophase nuclei and reappear in late G 1 after resumption of transcription in the daughter nuclei (for review see refs. 1, 4, and 5). Although their function is still in part elusive, recent work suggests that they are involved in several nuclear functions, including modification of small nuclear RNAs and small nuclear ribonucleoproteins, important for spliceosome formation, and assembly of the three eukaryotic RNA polymerases (pol I, pol II, and pol III) with their respective transcription and processing factors that are then transported as multiprotein complexes to the sites of transcription (1). More recently CBs have been implicated in replication-dependent histone gene transcription and mRNA maturation (1, 6-10), and a subset of CBs is physically associated with histone gene clusters on chromosomes 1 and 6 (11). Here we identify FLASH (FLICEassociated huge protein) (12) as a new component of CBs and show that it is essential for their structure.FLASH was initially identified as a component of the apoptosis signaling complex known as the death-inducing signaling complex (12, 13), which is associated with caspase 8 in the death-inducing signaling complex and thus essential for caspase 8 activation. However, this role of FLASH has been questioned (14). More recently it has been shown that, in response to TNF␣, FLASH translocates to the nucleus and binds the glucocorticoid receptor-interacting protein (GRIP-1), inhibiting both its interaction with, and the transcriptional activity of, the glucocorticoid receptor (15, 16). Results FLASH Has a Nuclear Localization.Despite the presence of three nuclear localization signals FLASH was originally described as a cytoplasmic protein (12,17). Staining endogenous FLASH with four different anti-FLASH antibodies, however, showed that FLASH only localized to the nucleus with a clear punctate appearance (Fig. 5a, which is published as supporting information on the PNAS web site). The specificity of the antibodies used was confirmed by the disappearance of the staining after short hairpin RNA for FLASH (Fig. 4a). West...

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“…Little is known about whether and how disturbing the function of the VDR affects the development of post-traumatic stress disorder, since the regulators of VDR expression in the CNS remains unknown (22). However in vitro evidence indicates that there is cross-talk between the VDR and glucocorticoid receptors in the hippocampus, and that vitamin D is involved in neuronal differentiation and/or apoptosis in this region (23). Mice lacking VDR have exhibited substantial behavioral impairment and increased anxiety (24).…”

Section: Discussionmentioning

confidence: 99%

Changes in the expression of the vitamin D receptor and LVSCC-A1C in the rat hippocampus submitted to single prolonged stress

Tong

Peng

et al. 2014

Molecular Medicine Reports

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Abstract. Vitamin D signaling not only controls calcium (Ca 2+ ) and phosphorus uptake and transport, but also correlates with neurocognitive decline and neurodegenerative diseases. Almost all actions of Vitamin D are mediated by the transcription factor, vitamin D receptor (VDR), which has been widely identified in the central nervous system. Although previous studies have substantially advanced the understanding of the action of VDR in the brain, much remains unknown concerning how VDR relates to stress. Multiple lines of evidence indicate that the downregulation of L-type voltage-sensitive Ca 2+ -channels α-1C (LVSCC-A1C) by vitamin D in hippocampal neurons is able to reduce the influx and excitotoxic effects of Ca 2+ to neurons. Along these lines, the purpose of the present study was to analyze the relative expression of VDR in the hippocampus of rats exposed to single prolonged stress (SPS) as a putative animal model for human post-traumatic stress disorder (PTSD). Furthermore, changes in the levels of expression of LVSCC-A1C and Ca 2+ (neurotransmitter content) were examined during the onset periods of PTSD. The results revealed an increase in the expression of VDR at 1, 3 and 7 days post-stress compared with the control group. The intracellular free Ca 2+ levels in the hippocampus increased 1 day after SPS exposure, and then decreased gradually to the normal level at 14 days, consistent with the expression pattern of LVSCC-A1C. These results indicated that VDR may be involved in the pathogenesis of SPS rats, thereby providing an alternative preparation to search for optimal therapeutic strategies for PTSD. IntroductionPost-traumatic stress disorder (PTSD) is a severe anxiety disorder that may develop following exposure to any threat or injury that results in psychological trauma. Diagnostic symptoms for PTSD include re-experiencing the original trauma through flashbacks or nightmares, avoidance of stimuli associated with the trauma and increased arousal. Single-prolonged stress (SPS), an animal model of PTSD, has been extensively developed and employed in the investigation of PTSD (1-3). The three areas of the brain whose function may be altered in PTSD have been identified as the prefrontal cortex, the amygdala and the hippocampus, among which, the hippocampus is a key organ of the limbic system involved in learning and memory, as well as being a regulatory center for the stress response (4).Alterations in brain neurochemistry have been linked with neuropsychiatric disorders, including schizophrenia, Alzheimer's disease, depression and cognitive decline. Previous studies have identified a positive association between vitamin D signaling and cognitive function (5). Vitamin D may regulate neurotransmission, neuroprotection and neuroimmunomodulation as a neurosteroid hormone (5,6), in addition to its critical role in calcium (Ca 2+ ) and phosphorous regulation and skeletal mineralization (7). Hypovitaminosis D is associated with several neuropsychiatric disorders, including dementia, Parkinson's d...

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Cross‐talk of vitamin D and glucocorticoids in hippocampal cells

Cited by 127 publications

References 50 publications

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

FLASH is an essential component of Cajal bodies

Changes in the expression of the vitamin D receptor and LVSCC-A1C in the rat hippocampus submitted to single prolonged stress

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