CEP-1347 (KT7515), a Semisynthetic Inhibitor of the Mixed Lineage Kinase Family

Maroney, Anna C.; Finn, James P.; Connors, Thomas J.; Durkin, John T.; Angeles, Thelma S.; Gessner, George; Xu, Zhiheng; Meyer, Sheryl L.; Savage, Mary J.; Greene, Lloyd A.; Scott, Richard W.; Vaught, Jeffry L.

doi:10.1074/jbc.m011601200

Cited by 198 publications

(160 citation statements)

References 67 publications

(63 reference statements)

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“…The cooperative role of p38 and JNK/c-Jun pathway remained to be addressed. Although the result was previously suggested in two articles, in each the specificity of pharmacological agents is contestable: Le Niculescu et al used the p38 inhibitor SB202190 at high unspecific doses to also inhibit JNKs (Manthey et al, 1998;Le-Niculescu et al, 1999); Namgung and Xia used CEP1347 as a JNK inhibitor in cooperation with a p38 inhibitor (Namgung and Xia, 2000), but CEP1347 has since been shown to affect mixed lineage kinase family rather than directly JNKs (Maroney et al, 2001). In this study we have employed an alternative approach using p38 kinase inhibitor SB203580 and DNcJun.…”

Section: Discussionmentioning

confidence: 99%

C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

Willaime‐Morawek¹,

Brami‐Cherrier²,

Mariani³

et al. 2003

Neuroscience

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Section: Discussionmentioning

confidence: 99%

C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

Willaime‐Morawek¹,

Brami‐Cherrier²,

Mariani³

et al. 2003

Neuroscience

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“…CEP-1347 only modestly inhibited MEKK1-and ASK1-induced JNK activation, inhibiting 10 and 30% at a concentration of 500 nM, whereas 95 and 98% of MLK1-and MLK3-induced JNK activation was blocked by CEP-1347 (Maroney et al 2001). These two kinases have been implicated in neuronal apoptosis because their constitutively active forms can kill neurons.…”

Section: Mlks Are Key Activators Of Jnk In Neuronsmentioning

confidence: 99%

“…The relative importance of the various MLKs in neuronal apoptosis is still unclear. Although CEP-1347 inhibits MLK3 most potently, it also inhibits MLK1 robustly (Maroney et al 2001). Detailed expression analysis and gene deletion experiments will delineate the roles of the various MLKs in neuronal apoptosis.…”

Section: Mlks Are Key Activators Of Jnk In Neuronsmentioning

confidence: 99%

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Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

Harris¹,

Maroney²,

Johnson

2002

Journal of Neurochemistry

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Cerebellar granule neurons grown in high potassium undergo rapid apoptosis when switched to medium containing 5 mM potassium, a stimulus mimicking deafferentation. This cell death can be blocked by genetic deletion of Bax, a member of the pro-apoptotic Bcl-2 family, cycloheximide an inhibitor of macromolecular synthesis or expression of dominant-negative c-jun. These observations suggest that Bax activation is the result of c-jun target gene(s) up-regulation following trophic withdrawal. Candidate genes include the BH3-only Bcl-2 family members Dp5 and Bim. The molecular mechanisms underlying granule cell neuronal apoptosis in response to low potassium were investigated using CEP-1347 (KT7515), an inhibitor of the MLK family of JNKKK. CEP-1347 provided protection of potassium-serum-deprived granule cells, but such neuroprotection was not long term. The incomplete protection was not due to incomplete blockade of the JNK signaling pathway because c-jun phosphorylation as well as induction of c-jun RNA and protein were completely blocked by CEP-1347. Following potassium-serum deprivation the JNKK MKK4 becomes phosphorylated, an event blocked by CEP-1347. Cells that die in the presence of CEP-1347 activate caspases; and dual inhibition of caspases and MLKs has additive, not synergistic, effects on survival. A lack of synergism was also seen with the p38 inhibitor SB203580, indicating that the neuroprotective effect of the JNK pathway inhibitor cannot be explained by p38 activation. Activation of the JNK signaling pathway seems to be a key event in granule cell apoptosis, but these neurons cannot survive long term in the absence of sustained PI3 kinase signaling. Neuronal survival is controlled in vivo by both retrograde signaling from neuronal targets as well as anterogradely via synaptic input. Cerebellar granule neurons are one such population whose survival is regulated by retrograde and anterograde signaling both in vivo and in vitro. In the lurcher mouse, cerebellar granule neurons die in response to the death of their targets, Purkinje neurons (Wetts and Herrup 1982). If the afferent activity to granule neurons is eliminated by mossy fiber axotomy, they undergo massive apoptosis (Borsello et al. 2000). These findings have been mimicked in vitro. Target-derived neurotrophic factors such as brain-derived growth factor (BDNF) and insulin-like growth factor (IGF)-1 promote the survival of cerebellar granule cells (Lindholm et al. 1993;Miller et al. 1997b). These neurons also undergo massive cell death when deafferentation is mimicked by removing the survival stimulus provided by depolarizing levels of potassium (Gallo et al. 1987). Abbreviations used: ASK, apoptosis signal regulating kinase 1; BAF, boc-aspartyl(OMe)-fluoromethylketone; BME, b-mercaptoethanol; CMV, cytomegalovirus; DEVD-amc, DEVD-aminomethylcoumarin; DIV, days in vitro; DTT, dithiothreitol; IP3, inositol-1,4,5-triphosphate; JNK, c-Jun N-terminal kinase; JNKKK, JNK kinase kinase; K5 ) S, buffer containing 5 mM KCl without serum; K25 + S, buf...

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“…Some DLK inhibitors have been shown to suppress DLK functions in neurons and retinal ganglion cells. 46,47 It will be interesting to examine effects of these DLK inhibitors in 2i plus LIF medium, or to develop a new cocktail for the expansion of mouse ES cells.…”

Section: Discussionmentioning

confidence: 99%

Akt suppresses DLK for maintaining self-renewal of mouse embryonic stem cells

Wang

et al. 2015

Cell Cycle

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Mouse embryonic stem cells (ES cells) can proliferate indefinitely. To identify potential signals involved in suppression of self-renewal, we previously screened a kinase/phosphatase expression library in ES cells, and observed that inhibition of Dual Leucine zipper-bearing Kinase (DLK) increased relative cell numbers. DLK protein was detected in both the pluripotent and differentiated states of mouse ES cells while DLK kinase activity increased upon differentiation. Overexpression of DLK in mouse ES cells displayed reductions in relative cell/colony numbers and Nanog expression, suggesting a suppressive role of DLK in self-renewal. By examining protein sequences of DLK, we identified 2 putative Akt phosphorylation sites at S584 and T659. Blocking PI3K/Akt signaling with LY-294002 enhanced DLK kinase activity dramatically. We found that Akt interacts with and phosphorylates DLK. Mutations of DLK amino acid residues at putative Akt phosphorylation sites (S584A, T659A, or S584A and T659A) diminished the level of DLK phosphorylation. While the mutated DLKs (S584A, T659A, or S584A and T659A) were expressed, a further reduction in cell/colony numbers and Nanog expression appeared in mouse ES cells. In addition, these mutant DLKs (S584A, T659A, or S584A and T659A) exhibited more robust kinase activity and cell death compared to wild type DLK or green fluorescence (GFP) controls. In summary, our results show that DLK functions to suppress self-renewal of mouse ES cells and is restrained by Akt phosphorylation.

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CEP-1347 (KT7515), a Semisynthetic Inhibitor of the Mixed Lineage Kinase Family

Cited by 198 publications

References 67 publications

C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

Akt suppresses DLK for maintaining self-renewal of mouse embryonic stem cells

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