ERK2 Prohibits Apoptosis-induced Subcellular Translocation of Orphan Nuclear Receptor NGFI-B/TR3

Jacobs, Chris M.; Boldingh, Karen A.; Slagsvold, Hege Holte; Thoresen, G. Hege; Paulsen, Ragnhild E.

doi:10.1074/jbc.m409145200

Cited by 49 publications

(39 citation statements)

References 35 publications

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“…Nur77 mitochondrial targeting also plays a role in neuronal cell death. Nur77 rapidly translocates to mitochondria in cerebellar granule neurons exposed to glutamate, which is blocked by EGF through its activation of ERK2 (Jacobs et al, 2004). We have also observed that neurotoxin causes extensive mitochondrial localization in dopaminergic neurons (Zhang et al, unpublished results).…”

Section: Mitochondrial Targeting As a Mechanism For Initiating Apoptosismentioning

confidence: 63%

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

2006

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The complex apoptotic functions of the p53 tumor suppressor are central to its antineoplastic activity in vivo. Conversely, p53 function is altered or attenuated in one way or another in the majority of human cancers. Besides its well-understood action as a transcriptional regulator of multiple apoptotic genes, p53 also exerts a direct pro-apoptotic role at the mitochondria by engaging in protein-protein interactions with anti-and pro-apoptotic Bcl2 family members, thereby executing the shortest known circuitry of p53 death signaling. Nur77, also known as TR3 or NGFI-B, is a unique transcription factor belonging to the orphan nuclear receptor superfamily. Even more extreme than p53, Nur77 can exert opposing biological activities of survival and death. Its activities are regulated by subcellular distribution, expression levels, protein modification and heterodimerization with retinoid X receptor. In cancer cells, Nur77 functions in the nucleus as an oncogenic survival factor, but becomes a potent killer when certain death stimuli induce its migration to mitochondria, where it binds to Bcl2 and conformationally converts it to a killer that triggers cytochrome c release and apoptosis. This review focuses on their unexpected transcription-independent pro-death programs at mitochondria and highlights the remarkable mechanistic similarities between them. Moreover, an accumulating body of evidence provides ample rationale to further investigate how these mitochondrial p53 and Nur77 pathways could become exploitable targets for new cancer therapeutics.

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Section: Mitochondrial Targeting As a Mechanism For Initiating Apoptosismentioning

confidence: 63%

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

2006

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“…ERK2, an upstream activator of RSK (Frodin and Gammeltoft, 1999), prohibits apoptosis-induced Nur77 nuclear export (Jacobs et al, 2004), raising the possibility that phosphorylation of Ser351 by RSK may be responsible for the inhibitory effect of ERK2 on Nur77 nuclear export. TPA, which induces Nur77 nuclear export and apoptosis in LNCaP cells (Li et al, 2000;Lin et al, 2004), is unable to induce Nur77 nuclear export in H460 lung cancer cells (data not shown), in which it strongly activates RSK (Figure 6a).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrated a new paradigm in cancer cell apoptosis, in which Nur77 is induced, then translocates from the nucleus to the mitochondria, leading to release of cytochrome c from the mitochondria (Li et al, 2000). The apoptosis-associated nuclear egress of Nur77 has been observed in cancer cells from the lung, ovary, colon, stomach and breast (Dawson et al, 2001;Holmes et al, 2002Holmes et al, , 2003Liu et al, 2002;Wu et al, 2002;Jeong et al, 2003;Kolluri et al, 2003;Wilson et al, 2003;Cao et al, 2004;Jacobs et al, 2004;Lin et al, 2004;Lee et al, 2005). Nur77 mitochondrial localization is also involved in Sindbis virus-induced apoptosis (Lee et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

et al. 2006

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Proapoptotic nuclear receptor family member Nur77 translocates from the nucleus to the mitochondria, where it interacts with Bcl-2 to trigger apoptosis. Nur77 translocation is induced by certain apoptotic stimuli, including the synthetic retinoid-related 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN)/ CD437 class. In this study, we investigated the molecular mechanism by which AHPN/CD437 analog (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces Nur77 nuclear export. Our results demonstrate that 3-Cl-AHPC effectively activated Jun N-terminal kinase (JNK), which phosphorylates Nur77. Inhibition of JNK activation by a JNK inhibitor suppressed 3-Cl-AHPC-induced Nur77 nuclear export and apoptosis. In addition, several JNK upstream activators, including the phorbol ester TPA, anisomycin and MAPK kinase kinase-1 (MEKK1), phosphorylated Nur77 and induced its nuclear export. However, Nur77 phosphorylation by JNK, although essential, was not sufficient for inducing Nur77 nuclear export. Induction of Nur77 nuclear export by MEKK1 required a prolonged MEKK1 activation and was attenuated by Akt activation. Expression of constitutively active Akt prevented MEKK1-induced Nur77 nuclear export. Conversely, transfection of dominant-negative Akt or treatment with a phosphatidylinositol 3-kinase (PI3-K) inhibitor accelerated MEKK1-induced Nur77 nuclear export. Furthermore, mutation of an Akt phosphorylation residue Ser351 in Nur77 abolished the effect of Akt or the PI3-K inhibitor. Together, our results demonstrate that both activation of JNK and inhibition of Akt play a role in translocation of Nur77 from the nucleus to the cytoplasm.

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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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ERK2 Prohibits Apoptosis-induced Subcellular Translocation of Orphan Nuclear Receptor NGFI-B/TR3

Cited by 49 publications

References 35 publications

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

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

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