The JNKK2-JNK1 Fusion Protein Acts As a Constitutively Active c-Jun Kinase That Stimulates c-Jun Transcription Activity

Zheng, Chaojun; Xiang, Jialing; Hunter, Tony; Lin, Anning

doi:10.1074/jbc.274.41.28966

Cited by 108 publications

(112 citation statements)

References 61 publications

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“…CNBr peptide mapping (18) was chosen to identify the regions of Itch phosphorylated by JNK1, because it generates three readily identifiable cleavage products containing potential MAPK phosphorylation sites. To phosphorylate Itch by JNK1 in living cells, it was coexpressed in HEK293 cells with a constitutively active JNKK2-JNK1 fusion protein (19). Alternatively, Itch was incubated in vitro with recombinant JNKK2-JNK1 in the presence of ␥-labeled ATP.…”

Section: Resultsmentioning

confidence: 99%

Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change

Gallagher

Gao

Liu

et al. 2006

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

247

237

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(2004) Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase itch. Science 306:271-275. Although the reference was included in the original text of the manuscript as ref. 7, the authors neglected to state in the figure legend that the blot used in Fig. 1F is the same blot (probed with a different antibody) shown in Fig. 3E of Gao et al. 2004. The figure and its corrected legend appear below.www.pnas.org/cgi/doi/10.1073/pnas.1002519107

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Section: Resultsmentioning

confidence: 99%

Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change

Gallagher

Gao

Liu

et al. 2006

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

247

237

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“…However, these JNK upstream stimuli also activate other signaling pathways. To determine to what degree that the JNK activation plays a role, we next evaluated the effect of JNKK2-JNK1 fusion protein that exhibits constitutive JNK activity (Zheng et al, 1999). The JNKK2-JNK1 fusion protein is specific for the JNK pathway, and it does not activate either p38 or ERK (Zheng et al, 1999).…”

Section: Phosphorylation Of Nur77 By Mekk1and Its Regulation Of Nur77mentioning

confidence: 99%

“…To determine to what degree that the JNK activation plays a role, we next evaluated the effect of JNKK2-JNK1 fusion protein that exhibits constitutive JNK activity (Zheng et al, 1999). The JNKK2-JNK1 fusion protein is specific for the JNK pathway, and it does not activate either p38 or ERK (Zheng et al, 1999). Unlike JNK that exclusively resides in the cytoplasm, and upon activation translocates into the nucleus to phosphorylate its nuclear targets (Minden and Karin, 1997), the JNKK2-JNK1 fusion resided in both the nucleus and the cytoplasm (Figure 4).…”

Section: Phosphorylation Of Nur77 By Mekk1and Its Regulation Of Nur77mentioning

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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“…To test this scenario, Jurkat cells were stably transfected with a mammalian expression vector encoding MKK7-JNK1, because it has been shown that MKK7-JNK1 fusion protein linked via a short peptide can express profound JNK activity in the absence of any stimulus (18). Immunoblotting analysis revealed weak expression of MKK7-JNK1 fusion protein in the two individual stable transfectants tested, Jurkat-y1 and Jurkat-y2 (Fig.…”

Section: Jnk Inhibitors Induce Cell Cycle Arrest and Apoptosis And Inmentioning

confidence: 99%

“…Transfection of Plasmid and siRNAs into T-ALL Cells pcDNA3.1 MKK7-JNK1 was constructed according to a previous report (18) and verified by DNA sequencing. MKK7-JNK1 stable transfectants and mock control were generated by Lipofectamine 2000-mediated transfection of Jurkat cells with pcDNA3.1 MKK7-JNK1 and pcDNA3.1, respectively, and selected against neomycin (800 μg/mL).…”

Section: Cells and Micementioning

confidence: 99%

Basal c-Jun NH2-terminal protein kinase activity is essential for survival and proliferation of T-cell acute lymphoblastic leukemia cells

Cui¹,

Wang²,

Wang³

et al. 2009

Molecular Cancer Therapeutics

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Hyperactivation of c-Jun NH2-terminal protein kinase (JNK) has been found in various malignant lymphocytes and inhibition of JNK activity leads to cell cycle arrest and apoptosis. However, the role of JNK activity in the oncogenic growth of T-cell acute lymphoblastic leukemia (T-ALL) cells remains largely unknown. Here, we report that treatment of T-ALL cells with JNK inhibitors led to cell cycle arrest and apoptosis and increased sensitivity to Fas-mediated apoptosis, whereas weak ectopic expression of MKK7-JNK1 fusion protein, which shows constitutive JNK activity, in T-ALL cells resulted in accelerated cell cycle progression and resistance to Fas-mediated apoptosis. The protein levels of c-Myc and Bcl-2 were reduced in the presence of JNK inhibitors but were enhanced with MKK7-JNK1. Small interfering RNA against JNK1, but not JNK2, exhibited similar effects to JNK inhibitors. These findings suggest that targeting JNK, especially JNK1 isoform, may have some important therapeutic implications in the treatment of T-ALL. Further exploration revealed that JNK protein and basal JNK activity in T-ALL cells showed aberrant subcellular localization, but no hyperactivation of JNK was observed. Thus, our work suggests that there might be novel mechanism(s) other than hyperactivation underlying the protumorigenic role of JNK activity. [Mol Cancer Ther 2009;8(12):3214–22]

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The JNKK2-JNK1 Fusion Protein Acts As a Constitutively Active c-Jun Kinase That Stimulates c-Jun Transcription Activity

Cited by 108 publications

References 61 publications

Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change

Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change

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

Basal c-Jun NH2-terminal protein kinase activity is essential for survival and proliferation of T-cell acute lymphoblastic leukemia cells

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