Enhancement of p53 activity and inhibition of neural cell proliferation by glucocorticoid receptor activation

Crochemore, Christophe; Michaelidis, Theologos M.; Fischer, Dieter; Loeffler, Jean‐Philippe; Almeida, Osborne F. X.

doi:10.1096/fj.01-0577com

Cited by 77 publications

(64 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, indirect regulation of Bnip3 gene transcription through glucocorticoid modulation of NF-κB remains a possibility. Conversely, Bnip3 gene transcription appears to be independent of p53 activity (Guo et al, 2001, Fei et al, 2004, despite reports of glucocorticoid regulation of p53 (Crochemore et al, 2002).…”

Section: Discussionmentioning

confidence: 79%

“…Furthermore, activated GR directly regulates Bnip3 gene transcription via a GRE site within the Bnip3 promoter. Notwithstanding, earlier studies show that glucocorticoids can act indirectly to regulate expression of the Bcl-2 gene family by modulating NF-κB (Ramdas andHarmon, 1998, Dhandapani et al, 2005) and p53 transcriptional activity (Miyashita et al, 1994, Miyashita and Reed, 1995, Maiyar et al, 1997, Crochemore et al, 2002, Iyer et al, 2003. Bnip3 expression has similarly been shown to be attenuated following inhibition of NF-κB (Baetz et al, 2005), a gene that is glucocorticoid regulated (Webster and Cidlowski, 1999).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

Sandau

Handa

2007

Neuroscience

View full text Add to dashboard Cite

Neonatal administration of the synthetic glucocorticoid, dexamethasone (DEX) retards brain growth, alters adult behaviors and induces cell death in the rat brain, thereby implicating glucocorticoids as developmentally neuroendangering compounds. Glucocorticoids also increase expression of proapoptotic Bcl-2 family members and exacerbate expression of hypoxic responsive genes. Bnip3 is a pro-apoptotic Bcl-2 family member that is upregulated in response to hypoxia. In these studies, we investigated the interactions of glucocorticoid receptor and hypoxia in the regulation of Bnip3 mRNA in cortical neurons. Using quantitative real time RT-PCR, we found that DEX treatment of postnatal day 4-6 rat pups caused a significant increase in Bnip3 mRNA expression compared to vehicle controls. A significant increase in Bnip3 mRNA was also measured in primary cortical neurons 72 hours after treatment with RU28362, a glucocorticoid receptor selective agonist. In primary cortical neurons, hypoxia increased Bnip3 mRNA expression and this was exacerbated with RU28362 treatment. To elucidate the mechanism of glucocorticoid and hypoxia mediated regulation of Bnip3 transcription, a Bnip3 promoter -luciferase reporter construct was utilized in primary cortical neurons. Upregulation of the Bnip3 promoter was mediated by a single glucocorticoid response element and a hypoxic response element. Bnip3 overexpression in primary cortical neurons significantly increased cell death, which is dependent on the Bnip3 transmembrane domain. However, despite the increased expression of Bnip3 following glucocorticoid and hypoxia treatment, corresponding decreases in cell survival were minimal. These studies identify a novel pathway in the developing cortex through which glucocorticoids may enhance a metabolic insult, such as hypoxia. KeywordsBcl-2; glucocorticoid receptor; dexamethasone; primary cortical neurons; postnatal; apoptosis Corticosterone, the endogenous glucocorticoid secreted by the rat adrenal gland, binds with high affinity to two different receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) (Reagan and McEwen, 1997). MR activation is associated with a neuroprotective phenotype (Almeida et al., 2000), whereas GR activation is implicated in the induction of an endangered neural phenotype (Sapolsky et al., 1986, Reagan andMcEwen, 1997). For example, in the adult, GR activation by the synthetic glucocorticoid Name and address of corresponding author: Robert J. Handa, Colorado State University, Department of Biomedical Sciences, W103 Anatomy, 1617 Campus Delivery, Fort Collins, CO 80523-1617, Phone: (970) Facsimile: (970) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process er...

show abstract

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

Sandau

Handa

2007

Neuroscience

View full text Add to dashboard Cite

show abstract

“…[39][40][41] Further, the apoptotic effects of DEX were previously shown to be blocked with a GR antagonist; 36 GR are transcription factors and we have previously shown that their activation by DEX can trigger a molecular death cascade in the hippocampus and cell cycle arrest in a neural cell line. 13,25 The issue of whether DEX acts directly on neurons to stimulate their demise cannot be resolved easily in vivo. We therefore attempted to address this question in primary neuronal cultures derived from early postnatal rats.…”

Section: Discussionmentioning

confidence: 99%

“…For GR Western blots, cells were lysed, processed and evaluated using semi-quantitative densitometry as described previously. 25 …”

Section: Reverse-transcriptase Pcrmentioning

confidence: 99%

Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation

et al. 2005

View full text Add to dashboard Cite

An important question arising from previous observations in vivo is whether glucocorticoids can directly influence neuronal survival in the hippocampus. To this end, a primary postnatal hippocampal culture system containing mature neurons and expressing both glucocorticoid (GR) and mineralocorticoid (MR) receptors was developed. Results show that the GR agonist dexamethasone (DEX) targets neurons (microtubule-associated protein 2-positive cells) for death through apoptosis. GR-mediated cell death was counteracted by the MR agonist aldosterone (ALDO). Antagonism of MR with spironolactone ([7a-(acetylthio)-3-oxo-17a-pregn-4-ene-21 carbolactone] (SPIRO)) causes a dose-dependent increase in neuronal apoptosis in the absence of DEX, indicating that nanomolar levels of corticosterone present in the culture medium, which are sufficient to activate MR, can mask the apoptotic response to DEX. Indeed, both SPIRO and another MR antagonist, oxprenoate potassium ((7a,17a)-17-hydroxy-3-oxo-7-propylpregn-4-ene-21-carboxylic acid, potassium salt (RU28318)), accentuated DEX-induced apoptosis. These results demonstrate that GRs can act directly to induce hippocampal neuronal death and that demonstration of their full apoptotic potency depends on abolition of survival-promoting actions mediated by MR. Molecular Psychiatry (2005) 10, 790-798.

show abstract

“…Images are representative of three experiments with consistent results proliferation. 30 Moreover, experiments using antisense p53 oligonucleotides show that blocking p53 expression reverses DEX-induced p21 upregulation and inhibition of proliferation. 31 Furthermore, p53 was recently found to be involved in GR-mediated repression of nuclear factor-kB transcription.…”

mentioning

confidence: 99%

L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells

et al. 2014

View full text Add to dashboard Cite

The transcription factor p53 regulates the expression of genes crucial for biological processes such as cell proliferation, metabolism, cell repair, senescence and apoptosis. Activation of p53 also suppresses neoplastic transformations, thereby inhibiting the growth of mutated and/or damaged cells. p53-binding proteins, such as mouse double minute 2 homolog (MDM2), inhibit p53 activation and thus regulate p53-mediated stress responses. Here, we found that long glucocorticoid-induced leucine zipper (L-GILZ), a recently identified isoform of GILZ, activates p53 and that the overexpression of L-GILZ in p53 þ / þ HCT116 human colorectal carcinoma cells suppresses the growth of xenografts in mice. In the presence of both p53 and MDM2, L-GILZ binds preferentially to MDM2 and interferes with p53/MDM2 complex formation, making p53 available for downstream gene activation. Consistent with this finding, L-GILZ induced p21 and p53 upregulated modulator of apoptosis (PUMA) expression only in p53 þ / þ cells, while L-GILZ silencing reversed the anti-proliferative activity of dexamethasone as well as expression of p53, p21 and PUMA. Furthermore, L-GILZ stabilizes p53 proteins by decreasing p53 ubiquitination and increasing MDM2 ubiquitination. These findings reveal L-GILZ as a regulator of p53 and a candidate for new therapeutic anti-cancer strategies for tumors associated with p53 deregulation.

show abstract

Enhancement of p53 activity and inhibition of neural cell proliferation by glucocorticoid receptor activation

Cited by 77 publications

References 84 publications

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation

L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells

Contact Info

Product

Resources

About