Crosstalk between ERK2 and RXR regulates nuclear import of transcription factor NGFI-B

Jacobs, Chris M.; Paulsen, Ragnhild E.

doi:10.1016/j.bbrc.2005.08.143

Cited by 15 publications

(9 citation statements)

References 22 publications

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“…The NGFI-B protein also has a function distinct from that of a transcription factor; it translocates to mitochochondria to initiate apoptosis (Hayashi et al 1996;Jacob et al 2004;Jacob and Paulsen 2005). NGFI-B can interact with Bcl-2 by inducing a conformational change in Bcl-2, converting it from a protector to a killer (Jacob et al 2004).…”

Section: Discussionmentioning

confidence: 97%

Gene expression profile and overexpression of apoptosis-related genes (NGFI-B and Gadd 45 γ) in early phase of Thy-1 nephritis model

Qiu

Wang

et al. 2006

Cell Tissue Res

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Mesangioproliferative glomerulonephritis (MPGN) is a disease of high incidence in humans. Rat Thy-1 nephritis (Thy-1 N), namely, anti-thymocyte serum (ATS)-induced nephritis, is considered to be an animal model for studying MPGN. Although previous studies have demonstrated that glomerular mesangial cell (GMCs) injury might be a feature of Thy-1 N, the mechanism of the disease (i.e., GMC apoptosis) remains unclear. We have examined the pathologic changes of GMCs and the gene expression profile of renal tissues in Thy-1 N. The pathologic changes of Thy-1 N include three phages: GMC apoptosis (40 min), necrosis (2 h), and proliferation (5 days). Many TUNEL-positive cells are found 40 min after administration of ATS. Concomitantly, 341 genes are up-regulated, whereas 392 genes are down-regulated, as shown by microarrays analysis. The mRNA and protein of two of the up-regulated genes (nerve growth factor induced protein I-B, NGFI-B; growth arrest- and DNA-damage-inducible protein 45 gamma, Gadd 45 gamma) in the GMC apoptotic phase of Thy-1 N are markedly elevated, as observed by real-time polymerase chain reaction and immunohistochemistry. Our data indicate that pathologic changes of Thy-1 N are involved in the abnormal gene profile. The overexpression of the NGFI-B and Gadd 45 gamma genes may be associated with GMC apoptosis of Thy-1 N.

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Section: Discussionmentioning

confidence: 97%

Gene expression profile and overexpression of apoptosis-related genes (NGFI-B and Gadd 45 γ) in early phase of Thy-1 nephritis model

Qiu

Wang

et al. 2006

Cell Tissue Res

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“…The RXRα is also required for Nur77 nuclear export in response to IGFBP-3 [26]. In addition, RXRα prevents EGF-induced nuclear accumulation of Nur77 [27]. RXRα-modulated Nur77 subcellular localization is ligand-dependent as the activation of RXRα nuclear export signaling is conformationally regulated by ligand binding [25].…”

Section: Discussionmentioning

confidence: 99%

“…ERK1/2 activation and deactivation both contribute to cell death, activated ERK1/2 pathway contributes to phosphorylation of Nur77 and apoptosis in human T cells and embryonic kidney FLP 293 cells [32, 33]. EGF inhibits glutamate-induced neuronal cell death by blocking nuclear export of Nur77 through activating ERK1/2 pathway [27, 34]. Consistent with the findings, our data also show that deactivation of ERK1/2 sensitizes fenretinide-resistant HepG2 cells to become susceptible to fenretinide-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

ERK1/2 deactivation enhances cytoplasmic Nur77 expression level and improves the apoptotic effect of fenretinide in human liver cancer cells

Yang¹,

Nie²,

Li³

et al. 2011

Biochemical Pharmacology

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Fenretinide, a synthetic retinoid, is a promising anticancer agent based on many in vitro, animal, and chemoprevention clinical trial studies. However, cells such as HepG2 human liver cancer cells are resistant to the apoptotic effect of fenretinide. Previously, we have shown that fenretinideinduced apoptosis is Nur77 dependent, and the sensitivity of the cancer cells to fenretinideinduced apoptosis is positively associated with cytoplasmic enrichment of Nur77. The goal of current study was to identify means to modulate nuclear export of Nur77 in order to improve the efficacy of fenretinide. Fenretinide treatment deactivated ERK1/2 in Huh7 cells, but activated ERK1/2 in HepG2 cells, which was positively associated with the sensitivity of cells to the apoptotic effect of fenretinide. Neither fenretinide nor ERK1/2 inhibitor PD98059 alone could affect the survival of HepG2 cells, but the combination of both induced cell death and increased caspase 3/7 activity. In fenretinide sensitive Huh7 cells, activation of ERK1/2 by epidermal growth factor (EGF) prevented fenretinide-induced cell death and caspase 3/7 induction. In addition, modulation of ERK1/2 changed the intracellular localization of Nur77. Fenretinide/ PD98059-induced cell death of HepG2 cell was positively associated with induction and cytoplasmic location as well as mitochondria enrichment of Nur77. The effect was specific for ERK1/2 because other mitogen activated protein kinases such as P38, Akt, and JNK did not have correlated changes in their phosphorylation levels. Taken together, the current study demonstrates that ERK1/2-modulated Nur77 intracellular location dictates the efficacy of fenretinide-induced apoptosis.

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“…9-cis-RA is known to potently inhibit the activation-induced apoptosis of T cells and thymocytes [72] , in which Nur77 plays a role. It is worth noting that 9-cis-RA is able to induce RXR-mediated nucleo-cytoplasmic shuttling of Nur77 and its translocation to mitochondria for apoptosis [73] and it can relieve the inhibitory effect of RXRα on EGF-induced Nur77 nuclear accumulation [74] , suggesting that certain RXRα ligands may act to promote RXR nuclear export and apoptosis under certain cellular conditions.…”

Section: Nongenomic Activity Of Rxr and Apoptosismentioning

confidence: 99%

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Zhang

Chen

et al. 2014

Acta Pharmacol Sin

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Retinoid X receptor-α (RXRα), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXRα ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeutic potential of RXRα remains unexplored. In addition to its conventional transcription regulation activity in the nucleus, RXRα can act in the cytoplasm to modulate important biological processes, such as mitochondria-dependent apoptosis, inflammation, and phosphatidylinositol 3-kinase (PI3K)/ AKT-mediated cell survival. Recently, new small-molecule-binding sites on the surface of RXRα have been identified, which mediate the regulation of the nongenomic actions of RXRα by a class of small molecules derived from the nonsteroidal anti-inflammatory drug (NSAID) Sulindac. This review discusses the emerging roles of the nongenomic actions of RXRα in the RXRα signaling network, and their possible implications in cancer, metabolic and neurodegenerative disorders, as well as our current understanding of RXRα regulation by targeting alternate binding sites on its surface.

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Crosstalk between ERK2 and RXR regulates nuclear import of transcription factor NGFI-B

Cited by 15 publications

References 22 publications

Gene expression profile and overexpression of apoptosis-related genes (NGFI-B and Gadd 45 γ) in early phase of Thy-1 nephritis model

Gene expression profile and overexpression of apoptosis-related genes (NGFI-B and Gadd 45 γ) in early phase of Thy-1 nephritis model

ERK1/2 deactivation enhances cytoplasmic Nur77 expression level and improves the apoptotic effect of fenretinide in human liver cancer cells

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

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