Mixed lineage kinase activity of indolocarbazole analogues

Murakata, Chikara; Kaneko, Masami; Gessner, George; Angeles, Thelma S.; Ator, Mark A.; O'Kane, Teresa M.; McKenna, Beth Ann; Thomas, Beth Ann; Mathiasen, Joanne R.; Saporito, Michael S.; Bozyczko–Coyne, Donna; Hudkins, Robert L.

doi:10.1016/s0960-894x(01)00690-4

Cited by 90 publications

(83 citation statements)

References 23 publications

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“…4D and E). Interestingly, CEP-11004This is consistent with CEP-11004 having approximately 3 fold higher specificity towards MLK3 as compared to MLK2 [11]. Thus, these data support MLK3 as the major MLK isoform targeted by CEP-11004.…”

Section: Cep-11004 Inhibits Mlk3 But Not Other Related Kinasessupporting

confidence: 74%

“…MLK proteins have been proposed to play a critical role in the progression of neurodegenerative diseases such as Parkinson's, Huntington's, and Alzheimer's through a mechanism involving MLK induced JNK activation, cytochrome c release, and caspase activation of apoptotic pathways [6,8]. Thus, several small molecule inhibitors of MLK activity belonging to the indolocarbazole family, which include CEP-1347 (KT7515) and CEP-11004 (KT-8138), are being tested in clinical trials and may prove beneficial in preventing premature neuronal cell death [6][7][8]11,12].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of mixed-lineage kinase (MLK) activity during G2-phase disrupts microtubule formation and mitotic progression in HeLa cells

Cha

Dangi

Machamer

et al. 2006

Cellular Signalling

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The mixed-lineage kinases (MLK) are serine/threonine protein kinases that regulate mitogenactivated protein (MAP) kinase signaling pathways in response to extracellular signals. Recent studies indicate that MLK activity may promote neuronal cell death through activation of the c-Jun NH 2 -terminal kinase (JNK) family of MAP kinases. Thus, inhibitors of MLK activity may be clinically useful for delaying the progression of neurodegenerative diseases, such as Parkinson's. In proliferating non-neuronal cells, MLK may have the opposite effect of promoting cell proliferation. In the current studies we examined the requirement for MLK proteins in regulating cell proliferation by examining MLK function during G2 and M-phase of the cell cycle. The MLK inhibitor CEP-11004 prevented HeLa cell proliferation by delaying mitotic progression. Closer examination revealed that HeLa cells treated with CEP-11004 during G2-phase entered mitosis similar to untreated G2-phase cells. However, CEP-11004 treated cells failed to properly exit mitosis and arrested in a prometaphase state. Partial reversal of the CEP-11004 induced mitotic arrest could be achieved by overexpression of exogenous MLK3. The effects of CEP-11004 treatment on mitotic events included the inhibition of histone H3 phosphorylation during prophase and prior to nuclear envelope breakdown and the formation of aberrant mitotic spindles. These data indicate that MLK3 might be a unique target to selectively inhibit transformed cell proliferation by disrupting mitotic spindle formation resulting in mitotic arrest.

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Section: Cep-11004 Inhibits Mlk3 But Not Other Related Kinasessupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Inhibition of mixed-lineage kinase (MLK) activity during G2-phase disrupts microtubule formation and mitotic progression in HeLa cells

Cha

Dangi

Machamer

et al. 2006

Cellular Signalling

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“…Although untreated neurons showed virtually no phospho-c-Jun staining, by 18 h neurons treated with TU showed high levels of nuclear localized phosphorylated To determine if the MLK-mediated JNK pathway was required for ER stress-induced apoptosis, we treated sympathetic neurons with TU in the presence of a MLK inhibitor, CEP-11004. 21,26 Following 48 h of treatment, at a time when only about 10% of the TU-treated neurons were alive, greater than 85% of the TU and CEP-11004-treated neurons remained viable (Figure 2b). CEP-11004 was also protective against TG-induced neuronal death (Supplemental Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum stress-induced apoptosis requires bax for commitment and Apaf-1 for execution in primary neurons

Smith

Deshmukh

2007

Cell Death Differ

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Apoptosis triggered by endoplasmic reticulum (ER) stress is associated with various pathophysiological conditions including neurodegenerative diseases and ischemia. However, the mechanism by which ER stress induces neuronal apoptosis remains controversial. Here we identify the pathway of apoptosis carried out in sympathetic neurons triggered to die by ER stressinducing agent tunicamycin. We find that ER stress induces a neuronal apoptotic pathway which upregulates BH3-only genes DP5 and Puma. Importantly, we show that ER stress commits neurons to die before cytochrome c release and this commitment requires Bax activation and c-jun N-terminal kinase signaling. Furthermore, ER stress engages the mitochondrial pathway of death as neurons release cytochrome c and Apaf-1 deficiency is sufficient to block apoptosis. Our findings identify a critical function of Bax in committing neurons to ER stress-induced apoptosis and clarify the importance of the apoptosome as the non-redundant caspase activation pathway to execute neuronal apoptosis in response to ER stress.

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“…Recently, it has been shown that overexpression of MLK3 or NGF withdrawal leads to neuronal cell death, which can be prevented by treatment with a small molecule inhibitor of MLKs, CEP-1347 (2). Similarly, CEP-11004, an analog of CEP-1347, has also been shown to prevent neuronal cell death upon NGF withdrawal (3). These results indicate a significant and direct involvement of MLKs in regulating cell death; however, the detailed mechanism by which MLKs are regulated is still unknown.…”

mentioning

confidence: 99%

Negative Regulation of Mixed Lineage Kinase 3 by Protein Kinase B/AKT Leads to Cell Survival

Barthwal¹,

Sathyanarayana²,

Kundu³

et al. 2003

Journal of Biological Chemistry

133

125

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Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates c-jun N-terminal kinase (JNK) and can induce cell death in neurons. By contrast, the activation of phosphatidylinositol 3-kinase and AKT/protein kinase B (PKB) acts to suppress neuronal apoptosis. Here, we report a functional interaction between MLK3 and AKT1/PKB␣. Endogenous MLK3 and AKT1 interact in HepG2 cells, and this interaction is regulated by insulin. The interaction domain maps to the C-terminal half of MLK3 (amino acids 511-847), and this region also contains a putative AKT phosphorylation consensus sequence. Endogenous JNK, MKK7, and MLK3 kinase activities in HepG2 cells are significantly attenuated by insulin treatment, whereas the phosphatidylinositol 3-kinase inhibitors LY294002 and wortmannin reversed the effect. Finally, MLK3-mediated JNK activation is inhibited by AKT1. AKT phosphorylates MLK3 on serine 674 both in vitro and in vivo. Furthermore, the expression of activated AKT1 inhibits MLK3-mediated cell death in a manner dependent on serine 674 phosphorylation. Thus, these data provide the first direct link between MLK3-mediated cell death and its regulation by a cell survival signaling protein, AKT1.The cellular decision to undergo either cell death or cell survival is determined by the integration of multiple survival and death signals. Mixed lineage kinase 3 (MLK3) 1 is a member of a growing family of mixed lineage kinases (1). Recently, it has been shown that overexpression of MLK3 or NGF withdrawal leads to neuronal cell death, which can be prevented by treatment with a small molecule inhibitor of MLKs, CEP-1347 (2). Similarly, CEP-11004, an analog of CEP-1347, has also been shown to prevent neuronal cell death upon NGF withdrawal (3). These results indicate a significant and direct involvement of MLKs in regulating cell death; however, the detailed mechanism by which MLKs are regulated is still unknown.The c-jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is stimulated by proinflammatory cytokines, oxidative stress, heat shock, UV, ␥-irradiation, and by other cellular stresses (4, 5). The signals in stress-activated JNK pathway are transmitted through three core modules: MAP3Ks such as members of the mixed lineage kinases or MEKK members, a MAP2K such as SEK1/MKK4 or MKK7, and MAPK such as JNK family members (4, 5). The activated MAP3K phosphorylates and activates MKK7 or SEK1, which in turn phosphorylates and activates JNK. JNKs phosphorylate several nuclear transcription factors that include ELK1, c-Jun, and ATF2 (4, 5). In several cell types, the activation of JNKs is directly linked to cell death (6 -8). Therefore, one mechanism of cell survival could be to block JNK pathway induction. The activation of phosphatidylinositol 3-kinase (PI3K) correlates with increased cell survival, and this effect is largely mediated through the activation of a serine/threonine kinase, AKT (also known as PKB). PI3K agonists such as insulin and insulin-like growth factor-1 (IGF-1) ...

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Mixed lineage kinase activity of indolocarbazole analogues

Cited by 90 publications

References 23 publications

Inhibition of mixed-lineage kinase (MLK) activity during G2-phase disrupts microtubule formation and mitotic progression in HeLa cells

Inhibition of mixed-lineage kinase (MLK) activity during G2-phase disrupts microtubule formation and mitotic progression in HeLa cells

Endoplasmic reticulum stress-induced apoptosis requires bax for commitment and Apaf-1 for execution in primary neurons

Negative Regulation of Mixed Lineage Kinase 3 by Protein Kinase B/AKT Leads to Cell Survival

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