Chemical Genetic Analysis of the Time Course of Signal Transduction by JNK

Ventura, Juan-José; Hübner, Anette; Zhang, Chao; Flavell, Richard A.; Shokat, Kevan M.; Davis, Roger J.

doi:10.1016/j.molcel.2006.01.018

Cited by 298 publications

(257 citation statements)

References 72 publications

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“…29,30 Our data are consistent with these findings, in that JNK activation was most enhanced during the sustained phase in RASSF7-knockdown cells, and these cells were highly sensitive to cellular stress. We detected the presence of cleaved caspases, which are prototypical markers of apoptosis, as early as 3 or 6 h after UV irradiation (see Figures 1 and 2).…”

Section: Discussionsupporting

confidence: 88%

RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7

et al. 2010

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Members of the Ras-association domain family (RASSF) of proteins influence apoptosis and cell cycling but little is known about the mechanisms. Here, we show that RASSF7 interacts with N-Ras and mitogen-activated protein kinase kinase 7 (MKK7) to negatively regulate c-Jun N-terminal kinase (JNK) signaling. Stress-induced JNK activation and apoptosis were markedly enhanced in cells depleted of RASSF7 or N-Ras by RNAi knockdown. An interaction with RASSF7 promoted the phosphorylated state of MKK7 but inhibited this kinase's ability to activate JNK. RASSF7 required its RA domain for both interaction with GTP-bound N-Ras and the anti-apoptotic response to stress stimuli. Following prolonged stress, however, RASSF7's antiapoptotic effect was eliminated because of degradation of RASSF7 protein via the ubiquitin-proteasome pathway. Our results indicate that RASSF7 acts in concert with N-Ras to constitute a stress-sensitive temporary mechanism of apoptotic regulation. With initial stress, RASSF7/N-Ras promotes cell survival by inhibiting the MKK7/JNK pathway. However, with prolonged stress, RASSF7 protein undergoes degradation that allows cell death signaling to proceed. Our findings may account for the association of elevated RASSF7 with tumorigenesis. Members of the Ras-association domain family (RASSF) share a conserved motif called the RalGDS/AF6-type Ras association (RA) domain. 1-3 The vertebrate RASSF comprises the classical RASSF members, RASSF1-6, and the more recently identified N-terminal (NT) RASSF members, RASSF7-10. 1-3 Epigenetic silencing of most of RASSF genes has been observed at high frequencies in various tumor types. 1,2 In contrast, upregulation of RASSF7 has been noted in pancreatic, endometrial and ovarian cancers, 4-8 although no direct evidence exists indicating that RASSF7 promotes tumorigenesis.RASSF7 was originally identified as HRAS cluster 1 (HRC1), located within a cluster of genes situated about 32-kb upstream of HRAS1 on human chromosome 11p15. In Xenopus, knockdown of the RASSF7 homolog prevented cells from completing mitosis and caused a striking loss of tissue architecture in the neural tube. 9 However, the physiological functions of RASSF7 in mammals are unknown, and the signaling pathways in which RASSF7 participates remain a mystery.The c-Jun N-terminal kinase (JNK) enzymes function primarily in stress-activated signaling and are important as both positive and negative modulators of apoptosis, depending on the cellular context. 10,11 In response to cell stresses, such as heat shock, ultraviolet (UV) irradiation, hyperosmolarity and ischemia/reperfusion injury, MAP kinase kinase kinases (MAPKKKs) are activated. These enzymes then activate MAP kinase kinase 4 (MKK4; also known as SEK1) and/or MKK7, which in turn activate JNKs. 12,13 The extent and specificity of JNK activation serve as important signals for promoting the stabilization and transcriptional activity of JNK substrates, which then mediate cell survival and/or apoptosis. Although phosphatases capable of dephosphorylating ...

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Section: Discussionsupporting

confidence: 88%

RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7

et al. 2010

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“…Interestingly, both a transient (< 1 h) and a sustained activation of JNK contribute to induction of gene expression; however, only prolonged activation of JNK promotes apoptosis (Ventura et al 2006;Weston and Davis, 2007). As shown in Fig.…”

Section: Discussionmentioning

confidence: 86%

Apoptosis induced by domoic acid in mouse cerebellar granule neurons involves activation of p38 and JNK MAP kinases

Giordano

Klintworth

Kavanagh

et al. 2008

Neurochemistry International

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In mouse cerebellar granule neurons (CGN) the marine neurotoxin domoic acid (DomA) induces neuronal cell death, either by apoptosis or by necrosis, depending on its concentration, with apoptotic damage predominating in response to low concentrations (100 nM). DomA-induced apoptosis is due to selective activation of AMPA/kainate receptors, and is mediated by DomA-induced oxidative stress, leading to mitochondrial dysfunction and activation of caspase-3. The p38 MAP kinase and the c-Jun NH 2 -terminal protein kinase (JNK) have been shown to be preferentially activated by oxidative stress. Here we report that DomA increases p38 MAP kinase and JNK phosphorylation, and that this effect is more pronounced in CGNs from Gclm (−/−) mice, which lack the modifier subunit of glutamate-cysteine ligase, have very low glutathione (GSH) levels, and are more sensitive to DomA-induced apoptosis than CGNs from wild-type mice. The increased phosphorylation of JNK and p38 kinase was paralleled by a decreased phosphorylation of Erk 1/2. The AMPA/kainate receptor antagonist NBQX, but not the NMDA receptor antagonist MK-801, prevents DomAinduced activation of p38 and JNK kinases. Several antioxidants (GSH ethyl ester, catalase, phenylbutylnitrone) also prevent DomA-induced phosphorylation of JNK and p38 MAP kinases. Inhibitors of p38 (SB203580) and of JNK (SP600125) antagonize DomA-induced apoptosis. These results indicate the importance of oxidative stress-activated JNK and p38 MAP kinase pathways in DomA-induced apoptosis in CGNs.

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“…An early phase of JNK activation occurs by 5-30 min that is transient and robust. This is followed by a less robust phase that lasts for hours (11). Rho kinase activation is required for both the early and late phase of JNK activation, and the Rho kinase activity is similarly elevated at both the early and late phase of JNK activation.…”

Section: Discussionmentioning

confidence: 99%

“…TNF-␣ also induces activation of MAPK that often exhibit an early and robust activation phase (within 30 min) and a more prolonged and less robust activation phase (for hours). The early and late phase of MAPK activation is regulated by different mechanisms and may have different functions (11), although the mechanisms proximal to the receptor leading to MAPK activation are not completely understood.…”

mentioning

confidence: 99%

Activation of Rho Kinase by TNF-α Is Required for JNK Activation in Human Pulmonary Microvascular Endothelial Cells

Mong

Petrulio

Kaufman

et al. 2008

The Journal of Immunology

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TNF‐α induces complex signaling events in endothelial cells (ECs), resulting in gene transcription and increased junctional permeability. This study examined the activation of the RhoA/Rho kinase pathway induced by TNF‐α in primary human pulmonary microvascular ECs and its role in EC responses to TNF‐α. Activation of RhoA was induced by TNF‐α within five minutes. This increase in RhoA activity rapidly decreased, and a late activation of RhoA was induced three hours after TNF‐α treatment. This late but not early RhoA activation was associated with its accumulation in focal aggregates near EC edges. TNF‐α also induced Rho kinase activation that was observed within five minutes and lasted for at least three hours. Inhibition of Rho kinase prevented TNF‐α‐induced cytoskeletal changes and permeability increases. TNF‐α also induced activation of JNK that peaked at fifteen minutes and lasted for at least three hours, and inhibition of Rho kinase prevented TNF‐α‐induced early and late JNK activation. Inhibition of JNK activation, however, did not prevent TNF‐α‐induced cytoskeletal changes, suggesting that Rho kinase did not modulate cytoskeletal changes through JNK activation. These data demonstrate that RhoA/Rho kinase pathway is rapidly activated by TNF‐α and regulates several downstream responses that include JNK activation, cytoskeletal changes and increases in permeability. Supported by NIH HL070009.

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Chemical Genetic Analysis of the Time Course of Signal Transduction by JNK

Cited by 298 publications

References 72 publications

RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7

RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7

Apoptosis induced by domoic acid in mouse cerebellar granule neurons involves activation of p38 and JNK MAP kinases

Activation of Rho Kinase by TNF-α Is Required for JNK Activation in Human Pulmonary Microvascular Endothelial Cells

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