Proapoptotic role of Hsp90 by its interaction with c-Jun N-terminal kinase in lipid rafts in edelfosine-mediated antileukemic therapy

Nieto-Miguel, Teresa; Gajate, Consuelo; González-Camacho, Fernando; Mollinedo, Faustino

doi:10.1038/sj.onc.1210816

Cited by 55 publications

(66 citation statements)

References 29 publications

(41 reference statements)

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“…JNK has been shown to be recruited to lipid rafts, where it can initiate downstream pathways. 27 We thus examined the role of palmitoylation in lipid raft targeting of JNK3. Lipid rafts are plasma membrane micro-domains rich in cholesterol, which resist extraction with detergents.…”

Section: Resultsmentioning

confidence: 99%

Isoform-specific palmitoylation of JNK regulates axonal development

et al. 2011

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The c-jun N-terminal kinase (JNK) proteins are encoded by three genes (Jnk1-3), giving rise to 10 isoforms in the mammalian brain. The differential roles of JNK isoforms in neuronal cell death and development have been noticed in several pathological and physiological contexts. However, the mechanisms underlying the regulation of different JNK isoforms to fulfill their specific roles are poorly understood. Here, we report an isoform-specific regulation of JNK3 by palmitoylation, a posttranslational modification, and the involvement of JNK3 palmitoylation in axonal development and morphogenesis. Two cysteine residues at the COOH-terminus of JNK3 are required for dynamic palmitoylation, which regulates JNK3's distribution on the actin cytoskeleton. Expression of palmitoylation-deficient JNK3 increases axonal branching and the motility of axonal filopodia in cultured hippocampal neurons. The Wnt family member Wnt7a, a known modulator of axonal branching and remodelling, regulates the palmitoylation and distribution of JNK3. Palmitoylation-deficient JNK3 mimics the effect of Wnt7a application on axonal branching, whereas constitutively palmitoylated JNK3 results in reduced axonal branches and blocked Wnt7a induction. Our results demonstrate that protein palmitoylation is a novel mechanism for isoform-specific regulation of JNK3 and suggests a potential role of JNK3 palmitoylation in modulating axonal branching. The c-jun N-terminal kinase (JNK) family consists of JNK1, JNK2 and JNK3 subgroups, which participate in diverse biological and pathological processes. 1,2 At least 10 JNK isoforms of varied sizes, with most between 46 and 54 kDa, are produced from the Jnk1-3 genes, giving rise to JNK isoforms. 1 In the nervous system, JNKs (particularly isoform JNK3) have been extensively studied as the key players in apoptosis and neurodegeneration. [3][4][5][6] However, accumulating evidence supports a physiological role of JNK in regulating neurite formation and morphogenesis. 7-12 Pharmacological inhibition of JNK activity blocks axogenesis in hippocampal neurons, arguing for an essential role of JNK in neurite development. 13 Growth factors and signalling molecules, including secreted proteins of the Wnt family, have also been found to activate JNK for remodelling dendrites and axons, a process that relies on cytoskeletal rearrangement. 11,[14][15][16] This has led to the identification of several actin-or microtubule-associated proteins as JNK substrates that modulate different aspects of cytoskeletal activity. 17 However, all the 10 JNK isoforms share the same kinase domain and activation mechanism. 17 The differential roles of JNK isoforms in neurite development and the mechanisms underlying isoform-specific regulation are poorly understood.Analysis of animals null for particular JNK isoforms provides the first evidence to support isoform-specific roles of JNKs in the brain. Mice with Jnk1 À/À show abnormalities in neurite development, 7 whereas mice null for Jnk1 and Jnk2 show embryonic lethality due to severe neuro...

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Section: Resultsmentioning

confidence: 99%

Isoform-specific palmitoylation of JNK regulates axonal development

et al. 2011

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“…In the intrinsic apoptosis pathway, the functions of the Fas receptor and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 were also found to depend on their translocation into lipid rafts, as the depletion of membrane cholesterol attenuated the apoptosis mediated by these factors (Gajate et al, 2004). Subsequent studies revealed that other apoptosis-related signaling molecules, such as Fas-associated death domain protein (FADD), caspase-8, BH3-interacting domain death agonist (Bid), and c-jun N-terminal kinase (JNK) are also translocated to lipid rafts upon treatment with anti-tumor agents (Gajate and Mollinedo, 2007;Nieto-Miguel et al, 2008;Mollinedo et al, 2010a,b) (Table 1). In addition, certain cancer cell types with higher membrane cholesterol levels are more sensitive to the cholesterol-depletion-induced apoptosis, suggesting that apoptosis is another target in the therapeutic application of cholesterol lowering for cancer (Li et al, 2006).…”

Section: Lipid Rafts and Apoptosismentioning

confidence: 99%

Cholesterol lowering: role in cancer prevention and treatment

Murai

2014

Biological Chemistry

168

147

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Abstract:The accumulation of cholesterol is a general feature of cancer tissue, and recent evidence suggests that cholesterol plays critical roles in the progression of cancers, including breast, prostate, and colorectal cancers. The dysregulation of metabolic pathways, including those involved in cholesterol biosynthesis, is implicated in tumor development and cancer progression. Lipid rafts are highly dynamic cholesterol-enriched domains of the cell membrane, involved in various cellular functions, including the regulation of transmembrane signaling at the cell surface. It was recently demonstrated that lipid rafts also play critical roles in cancer cell adhesion and migration. This review focuses on our current understanding of how cholesterol regulation, lipid rafts, and dysregulated cholesterol biosynthesis contribute to cancer development and progression, and the therapeutic potential of cholesterol lowering for cancer prevention and treatment.

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“…This Fas/CD95-raft coclustering plays a key role in the proapoptotic action of some anticancer drugs, including edelfosine, perifosine and aplidin (Gajate and Mollinedo, 2001Gajate et al, 2004;Nieto-Miguel et al, 2006;Mollinedo and Gajate, 2006a;Nieto-Miguel et al, 2008). Chemotherapeutic agent-induced recruitment of Fas/CD95 and downstream signaling molecules in membrane rafts leads to the generation of the deathinducing signaling complex (DISC) in lipid rafts, made up of Fas/CD95, Fas-associated death domain-containing protein (FADD) and procaspase-8 (Gajate and Mollinedo, 2007;Gajate et al, 2009a), and eventually to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Involvement of mitochondria and recruitment of Fas/CD95 signaling in lipid rafts in resveratrol-mediated antimyeloma and antileukemia actions

2009

Self Cite

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We have found that resveratrol (trans-3,4 0 ,5-trihydroxystilbene) induced apoptosis in multiple myeloma (MM) and T-cell leukemia cells through coclustering of Fas/ CD95 death receptor and lipid rafts, whereas normal lymphocytes were spared. Tumor necrosis factor-related apoptosis-inducing ligand receptors, Fas-associated death domain-containing protein (FADD), procaspase-8, procaspase-10, c-Jun amino-terminal kinase and Bid were also recruited into lipid rafts on resveratrol incubation with MM and T-cell leukemia cells. Raft disruption inhibited resveratrol-induced apoptosis. Bcl-X L overexpression prevented resveratrol-induced disruption of mitochondrial transmembrane potential (DW m ) and apoptosis. A FADD dominant-negative mutant, that blocked Fas/CD95 downstream signaling, precluded resveratrolinduced DW m loss and apoptosis, indicating a sequence of Fas/CD95 signaling-mitochondrion in the apoptotic response triggered by resveratrol. Cells deficient in Fas/CD95 did not undergo resveratrol-induced apoptosis. Pretreatment of MM cells with interferon-g upregulated Fas/CD95 and caspase-8, and potentiated resveratrolinduced apoptosis. Our data indicate that recruitment of Fas/CD95 death receptor and downstream signaling molecules into lipid rafts, followed by DW m disruption, underlies the apoptotic action of resveratrol in MM and T-cell leukemic cells. Combination of resveratrol with perifosine or bortezomib potentiated the apoptotic response induced by each single drug. These results also highlight the role of recruitment of Fas/CD95 signaling in lipid rafts in antimyeloma and antileukemia chemotherapy.

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Proapoptotic role of Hsp90 by its interaction with c-Jun N-terminal kinase in lipid rafts in edelfosine-mediated antileukemic therapy

Cited by 55 publications

References 29 publications

Isoform-specific palmitoylation of JNK regulates axonal development

Isoform-specific palmitoylation of JNK regulates axonal development

Cholesterol lowering: role in cancer prevention and treatment

Involvement of mitochondria and recruitment of Fas/CD95 signaling in lipid rafts in resveratrol-mediated antimyeloma and antileukemia actions

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