Nuclear Receptor and Apoptosis Initiator NGFI-B Is a Substrate for Kinase ERK2

Slagsvold, Hege Holte; Østvold, Anne Carine; Fallgren, Åsa B.; Paulsen, Ragnhild E.

doi:10.1006/bbrc.2002.6579

Cited by 57 publications

(47 citation statements)

References 26 publications

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“…In our study, PD98059 almost completely blocked the 6-MP-induced expression of Nur77 and HIF-1a, indicating that 6-MP functions primarily through the activation of the ERK-signaling pathway (Figure 3d). Consistent with our results, Thr142 residue of nerve growth factor (NGF)I-B was identified as a substrate for ERK2 in vivo and Ser105 was also shown to be phosphorylated by MAPK pathway when stimulated by NGF (Slagsvold et al, 2002). Activation of MAPK signaling pathway by 6-MP seems to be unique for the Nur77-induced stabilization of HIF-1a, because 6-MP suppresses mitogen-induced extracellular kinase (MEK) phosphorylation when it leads to the mitochondrial apoptotic pathway in primary human CD4 þ T lymphocytes (Tiede et al, 2003).…”

Section: -Mp Increases the Capillary-tube Formation Of Human Umbilicsupporting

confidence: 89%

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

et al. 2006

Oncogene

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Hypoxia-inducible factor-1a (HIF-1a) plays a central role in oxygen homeostasis. Previously, we reported that the orphan nuclear receptor Nur77 functions in stabilizing HIF-1a. Here, we demonstrate that 6-mercaptopurine (6-MP), an activator of the NR4A family members, enhances transcriptional activity of HIF-1. 6-MP enhanced the protein-level of HIF-1a as well as vascular endothelial growth factor (VEGF) in a dose-and timedependent manner. The induction of HIF-1a was abolished by the transfection of either a dominant-negative Nur77 mutant or si-Nur77, indicating a critical role of Nur77 in the 6-MP action. The HIF-1a protein level remained up to 60 min in the presence of 6-MP when de novo protein synthesis was blocked by cycloheximide, suggesting that 6-MP induces stabilization of the HIF-1a protein. The fact that 6-MP decreased the association of HIF-1a with von Hippel-Lindau protein and the acetylation of HIF-1a, may explain how 6-MP induced stability of HIF-1a. Further, 6-MP induced the transactivation function of HIF-1a by recruiting co-activator cyclic-AMP-responseelement-binding protein. Finally, 6-MP enhanced the expression of HIF-1a and VEGF, and the formation of capillary tubes in human umbilical vascular endothelial cells. Together, our results provide a new insight for 6-MP action in the stabilization of HIF-1a and imply a potential application of 6-MP in hypoxia-associated human vascular diseases.

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Section: -Mp Increases the Capillary-tube Formation Of Human Umbilicsupporting

confidence: 89%

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

et al. 2006

Oncogene

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“…We have previously shown that acute haloperidol strongly increased NGFI-B mRNA levels in the rat forebrain (Beaudry et al, 2000), but the intracellular signaling events triggering by neuroleptics and leading to modulation of NGFI-B are unknown. It has been shown in vitro that NGFI-B is a direct target of kinases associated with G proteincoupled receptors intracellular signaling such as cyclic AMP (cAMP) and MAPK pathways (Kovalovsky et al, 2002;Slagsvold et al, 2002;Maira et al, 2003). Since activation of the dopamine D 2 receptor normally reduces cAMP levels and striatal levels of NGFI-B (Gervais et al, 1999), blockade of the D 2 receptor by neuroleptics may increase or release inhibition of cAMP-dependent protein kinase activity (PKA) and result in an upregulation NGFI-B expression (Beaudry et al, 2000).…”

Section: Ngfi-b(+/+) Ngfi-b(-/-) Ngfi-b(+/+) Ngfi-b(-/mentioning

confidence: 99%

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

Éthier

Beaudry

St-Hilaire

et al. 2003

Neuropsychopharmacol

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Despite extensive investigation, the cellular mechanisms responsible for neuroleptic actions remain elusive. We have previously shown that neuroleptics modulated the expression of some members of the ligand-activated transcription factors (nuclear receptors) including the nerve-growth factor inducible gene B (NGFI-B or Nur77) and retinoid X receptor (RXR) isoforms. Using genetic and pharmacological approaches, we investigated the role of NGFI-B and retinoids in acute behavioral and biochemical responses to dopamine antagonists. NGFI-B knockout (KO) mice display a profound alteration of haloperidol-induced catalepsy and striatal neuropeptide gene expression. Haloperidol-induced increase of striatal enkephalin mRNA is totally abolished in NGFI-B KO mice whereas the increase of neurotensin mRNA expression is reduced by 50%. Interestingly, catalepsy induced by raclopride, a specific dopamine D 2 /D 3 antagonist is completely abolished in NGFI-B-deficient mice whereas the cataleptic response to SCH 23390, a dopamine D 1 agonist, is preserved. Accordingly, the effects of haloperidol on striatal c-fos, Nor-1, and dynorphin mRNA expression are also preserved in NGFI-B-deficient mice. The cataleptic response and the increase of enkephalin mRNA expression induced by haloperidol can also be suppressed by administration of retinoid ligands 9-cis retinoic acid and docosahexaenoic acid. In addition, we demonstrate that haloperidol enhances colocalization of NGFI-B and RXRg1 isoform mRNAs, suggesting that both NGFI-B and a RXR isoform are highly coexpressed after haloperidol administration. Our data demonstrate, for the first time, that NGFI-B and retinoids are actively involved in the molecular cascade induced by neuroleptic drugs.

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“…TR3 is a hyperphosphorylated protein that can be phosphorylated by a number of protein kinases including ERK2 (Katagiri et al, 2000;Slagsvold et al, 2002;Jacobs et al, 2004) and JNK1 (Kolluri et al, 2003;Han et al, 2006;Liu et al, 2007). Several studies have highlighted the importance of the ERK signal pathway in controlling TR3 translocation (Katagiri et al, 2000;Jacobs et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…When cell lysates containing HA-TR3 were incubated with calf intestinal alkaline phosphatase (CIAP), which catalyzes protein dephosphorylation, GST-Pin1 failed to pull down TR3 (Figure 1b). Conversely, the treatment of epidermal growth factor (EGF), which has been reported to induce TR3 phosphorylation (Slagsvold et al, 2002;Jacobs et al, 2004), evidently enhanced the interaction between TR3 and Pin1 ( Figure 1c). These results strongly suggest that Pin1 prefers to interact with phosphorylated TR3.…”

Section: Tr3 Is a Novel Substrate For Pin1 Isomerizationmentioning

confidence: 99%

Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis

Wang

et al. 2011

Oncogene

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Pin1 regulates a subset of phosphoproteins by isomerizing phospho-Ser/Thr-Pro motifs via a 'post-phosphorylation' mechanism. Here, we characterize TR3 as a novel Pin1 substrate, and the mitogenic function of TR3 depends on Pin1-induced isomerization. There are at least three phospho-Ser-Pro motifs on TR3 that bind to Pin1. The Ser95-Pro motif of TR3 is the key site through which Pin1 enhances TR3 stability by retarding its degradation. Pin1 can also catalyze TR3 through phospho-Ser431-Pro motif, which is phosphorylated by extracellular signalregulated kinase 2 (ERK2), resulting in enhanced TR3 transactivation. Furthermore, Pin1 not only facilitates TR3 targeting to the promoter of cyclin D2, a novel downstream target of TR3, but also promotes TR3 to recruit p300, thereby inducing cell proliferation. Importantly, we found that Pin1 is indispensable for TR3 to promote tumor growth both in vitro and in vivo. Our study thus suggests that Pin1 has an important role in cell proliferation by isomerizing TR3.

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Nuclear Receptor and Apoptosis Initiator NGFI-B Is a Substrate for Kinase ERK2

Cited by 57 publications

References 26 publications

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis

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