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T Yabu H Shiba Y Shibasaki T Nakanishi S Imamura K Touhata M Yamashita 《Cell death and differentiation》2015,22(2):258-273
Neutral sphingomyelinase (nSMase) activation in response to environmental stress or inflammatory cytokine stimuli generates the second messenger ceramide, which mediates the stress-induced apoptosis. However, the signaling pathways and activation mechanism underlying this process have yet to be elucidated. Here we show that the phosphorylation of nSMase1 (sphingomyelin phosphodiesterase 2, SMPD2) by c-Jun N-terminal kinase (JNK) signaling stimulates ceramide generation and apoptosis and provide evidence for a signaling mechanism that integrates stress- and cytokine-activated apoptosis in vertebrate cells. An nSMase1 was identified as a JNK substrate, and the phosphorylation site responsible for its effects on stress and cytokine induction was Ser-270. In zebrafish cells, the substitution of Ser-270 for alanine blocked the phosphorylation and activation of nSMase1, whereas the substitution of Ser-270 for negatively charged glutamic acid mimicked the effect of phosphorylation. The JNK inhibitor SP600125 blocked the phosphorylation and activation of nSMase1, which in turn blocked ceramide signaling and apoptosis. A variety of stress conditions, including heat shock, UV exposure, hydrogen peroxide treatment, and anti-Fas antibody stimulation, led to the phosphorylation of nSMase1, activated nSMase1, and induced ceramide generation and apoptosis in zebrafish embryonic ZE and human Jurkat T cells. In addition, the depletion of MAPK8/9 or SMPD2 by RNAi knockdown decreased ceramide generation and stress- and cytokine-induced apoptosis in Jurkat cells. Therefore the phosphorylation of nSMase1 is a pivotal step in JNK signaling, which leads to ceramide generation and apoptosis under stress conditions and in response to cytokine stimulation. nSMase1 has a common central role in ceramide signaling during the stress and cytokine responses and apoptosis.The sphingomyelin pathway is initiated by the hydrolysis of sphingomyelin to generate the second messenger ceramide.1 Sphingomyelin hydrolysis is a major pathway for stress-induced ceramide generation. Neutral sphingomyelinase (nSMase) is activated by a variety of environmental stress conditions, such as heat shock,1, 2, 3 oxidative stress (hydrogen peroxide (H2O2), oxidized lipoproteins),1 ultraviolet (UV) radiation,1 chemotherapeutic agents,4 and β-amyloid peptides.5, 6 Cytokines, including tumor necrosis factor (TNF)-α,7, 8, 9 interleukin (IL)-1β,10 Fas ligand,11 and their associated proteins, also trigger the activation of nSMase.12 Membrane-bound Mg2+-dependent nSMase is considered to be a strong candidate for mediating the effects of stress and inflammatory cytokines on ceramide.3Among the four vertebrate nSMases, nSMase1 (SMPD2) was the first to be cloned and is localized in the endoplasmic reticulum (ER) and Golgi apparatus.13 Several studies have focused on the potential signaling roles of nSMase1, and some reports have suggested that nSMase1 is important for ceramide generation in response to stress.5, 6, 14, 15 In addition, nSMase1 is responsible for heat-induced apoptosis in zebrafish embryonic cultured (ZE) cells, and a loss-of-function study showed a reduction in ceramide generation, caspase-3 activation, and apoptosis in zebrafish embryos.16 However, nSMase1-knockout mice showed no lipid storage diseases or abnormalities in sphingomyelin metabolism.17 Therefore, the molecular mechanisms by which nSMase1 is activated have yet to be elucidated.Environmental stress and inflammatory cytokines1, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 stimulate stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) signaling, which involves the sequential activation of members of the mitogen-activated protein kinase (MAPK) family, including MAPK/ERK kinase kinase (MEKK)1/MAPK kinase (MKK)4, and/or SAPK/ERK kinase (SEK)1/MKK7, JNK, and c-jun. Both the JNK and sphingomyelin signaling pathways coordinately mediate the induction of apoptosis.1 However, possible crosstalk between the JNK and sphingomyelin signaling pathways has not yet been characterized. Previously, we used SDS-PAGE to determine that nSMase1 polypeptides migrated at higher molecular masses,16 suggesting that the sphingomyelin signaling pathway might cause the production of a chemically modified phosphorylated nSMase1, which is stimulated under stressed conditions in ZE cells.16 Here, we demonstrate that JNK signaling results in the phosphorylation of Ser-270 of nSMase1, which initiates ceramide generation and apoptosis. We also provide evidence for a signaling mechanism that integrates cytokine- and stress-activated apoptosis in vertebrate cells. We studied stress-induced ceramide generation in two cell types: ZE cells and human leukemia Jurkat T-lymphoid cells. Stress-induced apoptosis has been investigated in these systems previously.16, 28 相似文献
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Chemoresistance in cancer has previously been attributed to gene mutations or deficiencies. Bax or p53 deficiency can lead to resistance to cancer drugs. We aimed to find an agent to overcome chemoresistance induced by Bax or p53 deficiency. Here, we used immunoblot, flow-cytometry analysis, gene interference, etc. to show that genistein, a major component of isoflavone that is known to have anti-tumor activities in a variety of models, induces Bax/p53-independent cell death in HCT116 Bax knockout (KO), HCT116 p53 KO, DU145 Bax KO, or DU145 p53 KO cells that express wild-type (WT) Bak. Bak knockdown (KD) only partially attenuated genistein-induced apoptosis. Further results indicated that the release of AIF and endoG also contributes to genistein-induced cell death, which is independent of Bak activation. Conversely, AIF and endoG knockdown had little effect on Bak activation. Knockdown of either AIF or endoG alone could not efficiently inhibit apoptosis in cells treated with genistein, whereas an AIF, endoG, and Bak triple knockdown almost completely attenuated apoptosis. Next, we found that the Akt-Bid pathway mediates Bak-induced caspase-dependent and AIF- and endoG-induced caspase-independent cell death. Moreover, downstream caspase-3 could enhance the release of AIF and endoG as well as Bak activation via a positive feedback loop. Taken together, our data elaborate the detailed mechanisms of genistein in Bax/p53-independent apoptosis and indicate that caspase-3-enhanced Bid activation initiates the cell death pathway. Our results also suggest that genistein may be an effective agent for overcoming chemoresistance in cancers with dysfunctional Bax and p53.Mammalian cell death proceeds through a highly regulated program called apoptosis that is highly dependent on the mitochondria.1 Mitochondrial outer membrane (MOM) multiple apoptotic stresses permeabilize the MOM, resulting in the release of apoptogenic factors including cytochrome c, Smac, AIF, and endoG.2, 3, 4 Released cytochrome c activates Apaf-1, which assists in caspase activation. Then, activated caspases cleave cellular proteins and contribute to the morphological and biochemical changes associated with apoptosis. Bcl-2 family proteins control a crucial apoptosis checkpoint in the mitochondria.2, 5, 6, 7 Multidomain proapoptotic Bax and Bak are essential effectors responsible for the permeabilization of the MOM, whereas anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 preserve mitochondrial integrity and prevent cytochrome c efflux triggered by apoptotic stimuli. The third Bcl-2 subfamily of proteins, BH3-only molecules (BH3s), promotes apoptosis by either activating Bax/Bak or inactivating Bcl-2/Bcl-xL/Mcl-1.8, 9, 10, 11, 12 Upon apoptosis, the ‘activator'' BH3s, including truncated Bid (tBid), Bim, and Puma, activate Bax and Bak to mediate cytochrome c efflux, leading to caspase activation.8, 11, 12 Conversely, antiapoptotic Bcl-2, Bcl-xL, and Mcl-1 sequester activator BH3s into inert complexes, which prevents Bax/Bak activation.8, 9 Although it has been proposed that Bax and Bak activation occurs by default as long as all of the anti-apoptotic Bcl-2 proteins are neutralized by BH3s,13 liposome studies clearly recapitulate the direct activation model in which tBid or BH3 domain peptides derived from Bid or Bim induce Bax or Bak oligomerization and membrane permeabilization.12, 14, 15Numerous studies have demonstrated a critical role for Bax in determining tumor cell sensitivity to drug induction and in tumor development. Bax has been reported to be mutated in colon16, 17 and prostate cancers,18, 19 contributing to tumor cell survival and promoting clonal expansion. Bax has been shown to restrain tumorigenesis20 and is necessary for tBid-induced cancer cell apoptosis.21 Loss of Bax has been reported to promote tumor development in animal models.22 Bax knockout (KO) renders HCT116 cells resistant to a series of apoptosis inducers.23, 24, 25 p53 has been reported to be a tumor suppressor,26 and its mutant can cause chemoresistance in cancer cells.27, 28, 29 Moreover, p53 is often inactivated in solid tumors via deletions or point mutations.30, 31 Thus, it is necessary to find an efficient approach or agent to overcome chemoresistance caused by Bax and/or p53 mutants.Few studies have focused on the role of Bak in tumor cell apoptosis and cancer development. Bak mutations have only been shown in gastric and colon cancer cells.32 Some studies have revealed that Bak is a determinant of cancer cell apoptosis.33, 34 Some studies have even demonstrated that Bak renders Bax KO cells sensitive to drug induction.33, 35 In this study, we are the first group to show that tBid induces Bak activation and the release of AIF and endoG in colon cancer cells, which causes cellular apoptosis independent of Bax/p53. We also found that caspase-3 is activated in apoptosis. Interestingly, downstream caspase-3 can strengthen Bak activation and the release of AIF and endoG during apoptosis via a feedback loop. Furthermore, we reveal that Akt upregulates apoptosis progression. These results will help us to better understand the function of mitochondrial apoptotic protein members in apoptosis and cancer therapies. Furthermore, our experiments may provide a theoretical basis for overcoming chemoresistance in cancer cells. 相似文献
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Y-C Cho J E Park B C Park J-H Kim D G Jeong S G Park S Cho 《Cell death and differentiation》2015,22(10):1605-1617
Cdc25C (cell division cycle 25C) phosphatase triggers entry into mitosis in the cell cycle by dephosphorylating cyclin B-Cdk1. Cdc25C exhibits basal phosphatase activity during interphase and then becomes activated at the G2/M transition after hyperphosphorylation on multiple sites and dissociation from 14-3-3. Although the role of Cdc25C in mitosis has been extensively studied, its function in interphase remains elusive. Here, we show that during interphase Cdc25C suppresses apoptosis signal-regulating kinase 1 (ASK1), a member of mitogen-activated protein (MAP) kinase kinase kinase family that mediates apoptosis. Cdc25C phosphatase dephosphorylates phospho-Thr-838 in the activation loop of ASK1 in vitro and in interphase cells. In addition, knockdown of Cdc25C increases the activity of ASK1 and ASK1 downstream targets in interphase cells, and overexpression of Cdc25C inhibits ASK1-mediated apoptosis, suggesting that Cdc25C binds to and negatively regulates ASK1. Furthermore, we showed that ASK1 kinase activity correlated with Cdc25C activation during mitotic arrest and enhanced ASK1 activity in the presence of activated Cdc25C resulted from the weak association between ASK1 and Cdc25C. In cells synchronized in mitosis following nocodazole treatment, phosphorylation of Thr-838 in the activation loop of ASK1 increased. Compared with hypophosphorylated Cdc25C, which exhibited basal phosphatase activity in interphase, hyperphosphorylated Cdc25C exhibited enhanced phosphatase activity during mitotic arrest, but had significantly reduced affinity to ASK1, suggesting that enhanced ASK1 activity in mitosis was due to reduced binding of hyperphosphorylated Cdc25C to ASK1. These findings suggest that Cdc25C negatively regulates proapoptotic ASK1 in a cell cycle-dependent manner and may play a role in G2/M checkpoint-mediated apoptosis.Cell division cycle 25 (Cdc25) phosphatases are dual-specificity phosphatases involved in cell cycle regulation. By removing inhibitory phosphate groups from phospho-Thr and phospho-Tyr residues of cyclin-dependent kinases (CDKs),1 Cdc25 proteins regulate cell cycle progression in S phase and mitosis. In mammals, three isoforms of Cdc25 phosphatases have been reported: Cdc25A, which controls the G1/S transition;2, 3 Cdc25B, which is a mitotic starter;4 and Cdc25C, which controls the G2/M phase.5 Overexpression of Cdc25 phosphatases is frequently associated with various cancers.6 Upon exposure to DNA-damaging reagents like UV radiation or free oxygen radicals, Cdc25 phosphatases are key targets of the checkpoint machinery, resulting in cell cycle arrest and apoptosis. The 14-3-3 proteins bind to phosphorylated Ser-216 of Cdc25C and induce Cdc25C export from the nucleus during interphase in response to DNA damage,7, 8 but they have no apparent effect on Cdc25C phosphatase activity.9, 10 In addition, hyperphosphorylation of Cdc25C correlates to its enhanced phosphatase activity.11 Most studies with Cdc25C have focused on its role in mitotic progression. However, the role of Cdc25C is not clear when it is sequestered in the cytoplasm by binding to 14-3-3.Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase 5 (MAPKKK5), is a ubiquitously expressed enzyme with a molecular weight of 170 kDa. The kinase activity of ASK1 is stimulated by various cellular stresses, such as H2O2,12, 13 tumor necrosis factor-α (TNF-α),14 Fas ligand,15 serum withdrawal,13 and ER stress.16 Stimulated ASK1 phosphorylates and activates downstream MAP kinase kinases (MKKs) involved in c-Jun N-terminal kinase (JNK) and p38 pathways.17, 18, 19 Phosphorylation and activation of ASK1 can induce apoptosis, differentiation, or other cellular responses, depending on the cell type. ASK1 is regulated either positively or negatively depending on its binding proteins.12, 13, 15, 18, 19, 20, 21, 22, 23, 24, 25ASK1 is regulated by phosphorylation at several Ser/Thr/Tyr residues. Phosphorylation at Thr-838 leads to activation of ASK1, whereas phosphorylation at Ser-83, Ser-967, or Ser-1034 inactivates ASK1.24, 26, 27, 28 ASK1 is basally phosphorylated at Ser-967 by an unidentified kinase, and 14-3-3 binds to this site to inhibit ASK1.24 Phosphorylation at Ser-83 is known to be catalyzed by Akt or PIM1.27, 29 Oligomerization-dependent autophosphorylation at Thr-838, which is located in the activation loop of the kinase domain, is essential for ASK1 activation.14, 18, 30 Phosphorylation at Tyr-718 by JAK2 induces ASK1 degradation.31 Several phosphatases that dephosphorylate some of these sites have been identified. Serine/threonine protein phosphatase type 5 (PP5) and PP2C dephosphorylate phosphorylated (p)-Thr-838,28, 32 whereas PP2A and SHP2 dephosphorylate p-Ser-967 and p-Tyr-718, respectively.31, 33 Little is known about the kinase or phosphatase that regulates phosphorylation at Ser-1034. Although ASK1 phosphorylation is known to be involved in the regulation of apoptosis, only a few reports show that ASK1 phosphorylation or activity is dependent on the cell cycle.21, 34In this study, we examined the functional relationship between Cdc25C and ASK1 and identified a novel function of Cdc25C phosphatase that can dephosphorylate and inhibit ASK1 in interphase but not in mitosis. Furthermore, we demonstrated that Cdc25C phosphorylation status plays a critical role in the interaction with and the activity of ASK1. These results reveal a novel regulatory function of Cdc25C in the ASK1-mediated apoptosis signaling pathway. 相似文献
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A Fauster M Rebsamen K V M Huber J W Bigenzahn A Stukalov C-H Lardeau S Scorzoni M Bruckner M Gridling K Parapatics J Colinge K L Bennett S Kubicek S Krautwald A Linkermann G Superti-Furga 《Cell death & disease》2015,6(5):e1767
Necroptosis is a form of regulated necrotic cell death mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3. Necroptotic cell death contributes to the pathophysiology of several disorders involving tissue damage, including myocardial infarction, stroke and ischemia-reperfusion injury. However, no inhibitors of necroptosis are currently in clinical use. Here we performed a phenotypic screen for small-molecule inhibitors of tumor necrosis factor-alpha (TNF-α)-induced necroptosis in Fas-associated protein with death domain (FADD)-deficient Jurkat cells using a representative panel of Food and Drug Administration (FDA)-approved drugs. We identified two anti-cancer agents, ponatinib and pazopanib, as submicromolar inhibitors of necroptosis. Both compounds inhibited necroptotic cell death induced by various cell death receptor ligands in human cells, while not protecting from apoptosis. Ponatinib and pazopanib abrogated phosphorylation of mixed lineage kinase domain-like protein (MLKL) upon TNF-α-induced necroptosis, indicating that both agents target a component upstream of MLKL. An unbiased chemical proteomic approach determined the cellular target spectrum of ponatinib, revealing key members of the necroptosis signaling pathway. We validated RIPK1, RIPK3 and transforming growth factor-β-activated kinase 1 (TAK1) as novel, direct targets of ponatinib by using competitive binding, cellular thermal shift and recombinant kinase assays. Ponatinib inhibited both RIPK1 and RIPK3, while pazopanib preferentially targeted RIPK1. The identification of the FDA-approved drugs ponatinib and pazopanib as cellular inhibitors of necroptosis highlights them as potentially interesting for the treatment of pathologies caused or aggravated by necroptotic cell death.Programmed cell death has a crucial role in a variety of biological processes ranging from normal tissue development to diverse pathological conditions.1, 2 Necroptosis is a form of regulated cell death that has been shown to occur during pathogen infection or sterile injury-induced inflammation in conditions where apoptosis signaling is compromised.3, 4, 5, 6 Given that many viruses have developed strategies to circumvent apoptotic cell death, necroptosis constitutes an important, pro-inflammatory back-up mechanism that limits viral spread in vivo.7, 8, 9 In contrast, in the context of sterile inflammation, necroptotic cell death contributes to disease pathology, outlining potential benefits of therapeutic intervention.10 Necroptosis can be initiated by death receptors of the tumor necrosis factor (TNF) superfamily,11 Toll-like receptor 3 (TLR3),12 TLR4,13 DNA-dependent activator of IFN-regulatory factors14 or interferon receptors.15 Downstream signaling is subsequently conveyed via RIPK116 or TIR-domain-containing adapter-inducing interferon-β,8, 17 and converges on RIPK3-mediated13, 18, 19, 20 activation of MLKL.21 Phosphorylated MLKL triggers membrane rupture,22, 23, 24, 25, 26 releasing pro-inflammatory cellular contents to the extracellular space.27 Studies using the RIPK1 inhibitor necrostatin-1 (Nec-1) 28 or RIPK3-deficient mice have established a role for necroptosis in the pathophysiology of pancreatitis,19 artherosclerosis,29 retinal cell death,30 ischemic organ damage and ischemia-reperfusion injury in both the kidney31 and the heart.32 Moreover, allografts from RIPK3-deficient mice are better protected from rejection, suggesting necroptosis inhibition as a therapeutic option to improve transplant outcome.33 Besides Nec-1, several tool compounds inhibiting different pathway members have been described,12, 16, 21, 34, 35 however, no inhibitors of necroptosis are available for clinical use so far.2, 10 In this study we screened a library of FDA approved drugs for the precise purpose of identifying already existing and generally safe chemical agents that could be used as necroptosis inhibitors. We identified the two structurally distinct kinase inhibitors pazopanib and ponatinib as potent blockers of necroptosis targeting the key enzymes RIPK1/3. 相似文献
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W-T Kuo T-C Lee H-Y Yang C-Y Chen Y-C Au Y-Z Lu L-L Wu S-C Wei Y-H Ni B-R Lin Y Chen Y-H Tsai J T Kung F Sheu L-W Lin L C-H Yu 《Cell death and differentiation》2015,22(10):1590-1604
Colorectal carcinoma (CRC) is characterized by unlimited proliferation and suppression of apoptosis, selective advantages for tumor survival, and chemoresistance. Lipopolysaccharide (LPS) signaling is involved in both epithelial homeostasis and tumorigenesis, but the relative roles had by LPS receptor subunits CD14 and Toll-like receptor 4 (TLR4) are poorly understood. Our study showed that normal human colonocytes were CD14+TLR4−, whereas cancerous tissues were CD14+TLR4+, by immunofluorescent staining. Using a chemical-induced CRC model, increased epithelial apoptosis and decreased tumor multiplicity and sizes were observed in TLR4-mutant mice compared with wild-type (WT) mice with CD14+TLR4+ colonocytes. WT mice intracolonically administered a TLR4 antagonist displayed tumor reduction associated with enhanced apoptosis in cancerous tissues. Mucosa-associated LPS content was elevated in response to CRC induction. Epithelial apoptosis induced by LPS hypersensitivity in TLR4-mutant mice was prevented by intracolonic administration of neutralizing anti-CD14. Moreover, LPS-induced apoptosis was observed in primary colonic organoid cultures derived from TLR4 mutant but not WT murine crypts. Gene silencing of TLR4 increased cell apoptosis in WT organoids, whereas knockdown of CD14 ablated cell death in TLR4-mutant organoids. In vitro studies showed that LPS challenge caused apoptosis in Caco-2 cells (CD14+TLR4−) in a CD14-, phosphatidylcholine-specific phospholipase C-, sphingomyelinase-, and protein kinase C-ζ-dependent manner. Conversely, expression of functional but not mutant TLR4 (Asp299Gly, Thr399Ile, and Pro714His) rescued cells from LPS/CD14-induced apoptosis. In summary, CD14-mediated lipid signaling induced epithelial apoptosis, whereas TLR4 antagonistically promoted cell survival and cancer development. Our findings indicate that dysfunction in the CD14/TLR4 antagonism may contribute to normal epithelial transition to carcinogenesis, and provide novel strategies for intervention against colorectal cancer.Colorectal tumorigenesis proceeds via the accumulation of genetic and epigenetic alterations that promote unlimited cell proliferation, self-sufficient growth signaling, neovascularization, tissue invasion, and resistance to cell death.1 The transformation of normal epithelium into colorectal carcinomas (CRC) is associated with the progressive inhibition of apoptosis; this confers a selective advantage for tumor cell survival and chemoresistance.2, 3 It is generally believed that sufficient epithelial apoptosis may hamper colon cancer formation in terms of incidence and growth rate.4, 5, 6 Direct evidence for this was recently reported in mice deficient in pro-apoptotic molecules.7, 8 To date, the regulatory mechanisms of physiological apoptosis to eliminate premalignant cells in the gut remain incompletely understood.Intestinal homeostasis is maintained by the dynamic, yet strictly regulated, turnover of epithelial cells. An imbalance in epithelial death versus survival/proliferative responses may lead to barrier dysfunction, chronic inflammation, and tumorigenesis.9, 10 Accumulating evidence indicates that gut microbiota and bacterial lipopolysaccharide (LPS) have critical roles in epithelial cell renewal under baseline conditions and on injury,11, 12 and are involved in the pathogenesis of colitis-associated CRC as well.13, 14, 15 Given the juxtaposition of commensal bacteria and the gut mucosa, it has been assumed that normal epithelial cells are not equipped with LPS receptor complexes (CD14/TLR4/MD2) or express altered forms of receptors and signaling molecules to achieve immunotolerance.15 Constitutive expression of CD14 was reported in the presence of negligible-to-low levels of Toll-like receptor 4 (TLR4) in normal human colonocytes,16, 17, 18 whereas strong TLR4 immunoreactivity was detected in CRC.18, 19 Nevertheless, divergent cellular responses to LPS (death versus survival) have been reported among human CRC cell lines. Several laboratories, using Caco-2 cells, have described increases in apoptotic cell death following apical LPS challenge,20, 21 whereas others have documented enhanced survival and proliferative responses of HT29 and SW480 cells to LPS.22, 23 Here we hypothesize that differing expression patterns of LPS receptor subunits on epithelial surfaces may have a determining role in cell death versus survival.CD14, as the membrane-bound subunit of LPS receptor complex and lacking a cytoplasmic tail, has traditionally been regarded as merely a binding component for transferring LPS to TLR4. TLR4 subsequently activates downstream adaptors and signaling pathways, such as myeloid differentiation factor (MyD88), mitogen-activated protein kinases (MAPKs), inhibitor of κB (IκB)/nuclear factor-κB (NFκB), and interferon regulatory factor 3 (IRF3).24, 25 Recent findings in monocytes have indicated that LPS/CD14 binding triggers a cascade of lipid messenger signals before TLR4 trafficking to lipid rafts for complex formation. CD14-dependent lipid signaling includes the conversion of membranous phosphatidylcholine (PC) to diacylglcerol by PC-specific phospholipase C (PC-PLC) and the activation of sphingomyelinase (SMase) for sphingolipid metabolism and ceramide production. This process leads to the phosphorylation of protein kinase C (PKC) ζ, which recruits TLR4 to interact with CD14 (Cuschieri et al.26 and Triantafilou et al.27). Lipid messengers, such as sphingolipids and ceramides, and their downstream PKCζ signals have been implicated in pro-apoptotic pathways and are considered tumor suppressors.28, 29, 30 Decreased SMase activity and PKCζ levels have been observed in human colorectal tumors, correlated with poor prognosis.31, 32 In contrast, the TLR4/MyD88 and IκB/NFκB pathways are associated with anti-apoptotic and hyperproliferative responses.5, 33, 34, 35 Reduced colorectal tumor formation has been documented in TLR4(−/−), MyD88(−/−), and epithelial-specific IκB kinase β-deficient mice as compared with wild-type (WT) mice.5, 19, 36 These findings led us to speculate that the expression of CD14 and TLR4 on epithelial cell surfaces may provide antagonistic signals to counteract apoptotic responses to LPS and to influence tumor progression.The aims of this study were to (1) investigate the expression patterns of LPS receptor subunits in normal and cancerous colonic epithelia in human and murine tissues; (2) examine the individual roles of CD14 and TLR4 in epithelial apoptosis and tumor formation using a mouse model of colitis-associated CRC; (3) assess the involvement of CD14-mediated lipid messengers and/or TLR4-dependent signaling in the mechanism of LPS-induced apoptosis using human carcinoma cell lines; and (4) evaluate whether TLR4 has an opposing role against CD14-mediated apoptosis to promote tumor cell survival. 相似文献
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S L Petersen T T Chen D A Lawrence S A Marsters F Gonzalvez A Ashkenazi 《Cell death and differentiation》2015,22(11):1846-1857
Tumor necrosis factor α (TNFα) triggers necroptotic cell death through an intracellular signaling complex containing receptor-interacting protein kinase (RIPK) 1 and RIPK3, called the necrosome. RIPK1 phosphorylates RIPK3, which phosphorylates the pseudokinase mixed lineage kinase-domain-like (MLKL)—driving its oligomerization and membrane-disrupting necroptotic activity. Here, we show that TNF receptor-associated factor 2 (TRAF2)—previously implicated in apoptosis suppression—also inhibits necroptotic signaling by TNFα. TRAF2 disruption in mouse fibroblasts augmented TNFα–driven necrosome formation and RIPK3-MLKL association, promoting necroptosis. TRAF2 constitutively associated with MLKL, whereas TNFα reversed this via cylindromatosis-dependent TRAF2 deubiquitination. Ectopic interaction of TRAF2 and MLKL required the C-terminal portion but not the N-terminal, RING, or CIM region of TRAF2. Induced TRAF2 knockout (KO) in adult mice caused rapid lethality, in conjunction with increased hepatic necrosome assembly. By contrast, TRAF2 KO on a RIPK3 KO background caused delayed mortality, in concert with elevated intestinal caspase-8 protein and activity. Combined injection of TNFR1-Fc, Fas-Fc and DR5-Fc decoys prevented death upon TRAF2 KO. However, Fas-Fc and DR5-Fc were ineffective, whereas TNFR1-Fc and interferon α receptor (IFNAR1)-Fc were partially protective against lethality upon combined TRAF2 and RIPK3 KO. These results identify TRAF2 as an important biological suppressor of necroptosis in vitro and in vivo.Apoptotic cell death is mediated by caspases and has distinct morphological features, including membrane blebbing, cell shrinkage and nuclear fragmentation.1, 2, 3, 4 In contrast, necroptotic cell death is caspase-independent and is characterized by loss of membrane integrity, cell swelling and implosion.1, 2, 5 Nevertheless, necroptosis is a highly regulated process, requiring activation of RIPK1 and RIPK3, which form the core necrosome complex.1, 2, 5 Necrosome assembly can be induced via specific death receptors or toll-like receptors, among other modules.6, 7, 8, 9 The activated necrosome engages MLKL by RIPK3-mediated phosphorylation.6, 10, 11 MLKL then oligomerizes and binds to membrane phospholipids, forming pores that cause necroptotic cell death.10, 12, 13, 14, 15 Unchecked necroptosis disrupts embryonic development in mice and contributes to several human diseases.7, 8, 16, 17, 18, 19, 20, 21, 22The apoptotic mediators FADD, caspase-8 and cFLIP suppress necroptosis.19, 20, 21, 23, 24 Elimination of any of these genes in mice causes embryonic lethality, subverted by additional deletion of RIPK3 or MLKL.19, 20, 21, 25 Necroptosis is also regulated at the level of RIPK1. Whereas TNFα engagement of TNFR1 leads to K63-linked ubiquitination of RIPK1 by cellular inhibitor of apoptosis proteins (cIAPs) to promote nuclear factor (NF)-κB activation,26 necroptosis requires suppression or reversal of this modification to allow RIPK1 autophosphorylation and consequent RIPK3 activation.2, 23, 27, 28 CYLD promotes necroptotic signaling by deubiquitinating RIPK1, augmenting its interaction with RIPK3.29 Conversely, caspase-8-mediated CYLD cleavage inhibits necroptosis.24TRAF2 recruits cIAPs to the TNFα-TNFR1 signaling complex, facilitating NF-κB activation.30, 31, 32, 33 TRAF2 also supports K48-linked ubiquitination and proteasomal degradation of death-receptor-activated caspase-8, curbing apoptosis.34
TRAF2 KO mice display embryonic lethality; some survive through birth but have severe developmental and immune deficiencies and die prematurely.35, 36 Conditional TRAF2 KO leads to rapid intestinal inflammation and mortality.37 Furthermore, hepatic TRAF2 depletion augments apoptosis activation via Fas/CD95.34 TRAF2 attenuates necroptosis induction in vitro by the death ligands Apo2L/TRAIL and Fas/CD95L.38 However, it remains unclear whether TRAF2 regulates TNFα-induced necroptosis—and if so—how. Our present findings reveal that TRAF2 inhibits TNFα necroptotic signaling. Furthermore, our results establish TRAF2 as a biologically important necroptosis suppressor in vitro and in vivo and provide initial insight into the mechanisms underlying this function. 相似文献
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M Shen L Wang B Wang T Wang G Yang L Shen T Wang X Guo Y Liu Y Xia L Jia X Wang 《Cell death & disease》2014,5(11):e1528
Endoplasmic reticulum (ER) stress occurring in stringent conditions is critically involved in cardiomyocytes apoptosis and cardiac contractile dysfunction (CCD). However, the molecular machinery that mediates cardiac ER stress and subsequent cell death remains to be fully deciphered, which will hopefully provide novel therapeutic targets for these disorders. Here, we establish tunicamycin-induced model of cardiomyocyte ER stress, which effectively mimicks pathological stimuli to trigger CCD. Tunicamycin activates volume-sensitive outward rectifying Cl− currents. Blockade of the volume-sensitive outwardly rectifying (VSOR) Cl− channel by 4,4''-diisothiocya-natostilbene-2,2''-disulfonic acid (DIDS), a non-selective Cl− channel blocker, and 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB), a selective VSOR Cl− channel blocker, improves cardiac contractility, which correlates with suppressed ER stress through inhibiting the canonical GRP78/eIF2α/ATF4 and XBP1 pathways, and promotes survival of cardiomyocytes by inverting tunicamycin-induced decrease of Wnt through the CHOP pathway. VSOR activation of tunicamycin-treated cardiomyocytes is attributed to increased intracellular levels of reactive oxygen species (ROS). Our study demonstrates a pivotal role of ROS/VSOR in mediating ER stress and functional impairment of cardiomyocytes via the CHOP-Wnt pathway, and suggests the therapeutic values of VSOR Cl− channel blockers against ER stress-associated cardiac anomalies.The endoplasmic reticulum (ER) is characterized as an organelle that participates in the folding of membrane and secretory proteins.1,2 Efficient functioning of the endoplasmic reticulum is important for cell function and survival. Perturbations of ER homeostasis by energy deprivation and glucose,3 viral infections4 and accumulation of misfolded and/or unfolded proteins2 interfere with ER function, leading to a state of ER stress.5, 6, 7 A cohort of chemicals, for example, tunicamycin and thapsigargin, also trigger ER stress.8, 9, 10 Thapsigargin disrupts the calcium storage of ER by blocking calcium reuptake into the ER lumen, thus by depleting calcium from the organelle.11 In particular, tunicamycin is a highly specific ER stress inducer by inhibiting N-linked glycosylation of protein, representing a well-documented method to artificially elicit unfolded protein response.8 In response to ER stress, ER chaperones such as glucose-regulated protein 78 kDa (GRP78) and glucose-regulated protein 94 kDa (GRP94) are upregulated to facilitate the recovery of unfolded or misfolded proteins.12 ER stress may act as a defense mechanism against external insults; however, prolonged and/or severe ER stress may ultimately trigger apoptosis.8 The C/EBP homologous protein (CHOP) has been defined as a pivotal mediator of cell death signaling in ER stress.13, 14 Accumulating evidence has demonstrated that ER stress-induced cell death is an essential step in the pathogenesis of a wide variety of cardiovascular diseases such as ischemia reperfusion heart diseases,15 atherosclerosis,5, 16, 17, 18 myocardial infarction,19 hypertension20, 21 and heart failure.8, 22, 23 Inhibiting ER stress has great therapeutic values for cardiac anomalies. However, the precise mechanism involved in ER stress-induced cardiovascular diseases has not been well identified, which impedes the translation of our understanding of ER stress-induced cardiovascular anomalies into effective therapeutic strategies. Apoptosis induction requires persistent cell shrinkage, named apoptotic volume decrease (AVD).24, 25, 26, 27 It is an early prerequisite for the activation of caspases.24 In various types of cells including cardiomyocytes, AVD process is accomplished by the activation of volume-sensitive outwardly rectifying (VSOR) Cl− channel and is concomitant with the egress of water from the cells undergoing mitochondrion-initiated or death receptor-induced apoptosis.25, 28, 29, 30 Although inhibition of VSOR Cl− channel by DIDS (4,4''-diisothiocyanatostilbene-2,2''-disulphonic acid) and DCPIB (4-(2-butyl-6,7- dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid) blocked AVD and rescued cardiomyocytes from mitochondrial and death receptor pathway-induced apoptosis,31, 32 it remains largely unknown concerning the role of VSOR Cl− channel and how it is regulated in ER stress-induced apoptotic cardiomyocyte death.Emerging evidence indicates that Wnt signal pathways are found to be anti-apoptotic in the cardiovascular diseases,33, 34, 35 regulating crucial aspects of cardiovascular biology. However, up to now, its activity in ER stress-induced apoptosis and in the process of AVD in cardiomyocytes remains elusive.In the present study, we probed the role of VSOR Cl− channel in ER stress-induced apoptosis of cardiomyocytes, which intimately correlates with cardiac contractile dysfunction (CCD). We hypothesized that VSOR Cl− channel controls the process of AVD occurring concomitantly with ER stress-induced apoptosis of cardiomyocytes. To test this hypothesis, we investigated VSOR Cl− currents in cardiomyocytes treated with the ER stress inducer tunicamycin. The pathophysiological role of VSOR Cl− channel and the potential signaling mechanisms in the development of ER stress-induced apoptosis in CCD were also dissected. 相似文献
12.
A 5.5-y-old intact male cynomolgus macaque (Macaca fasicularis) presented with inappetence and weight loss 57 d after heterotopic heart and thymus transplantation while receiving an immunosuppressant regimen consisting of tacrolimus, mycophenolate mofetil, and methylprednisolone to prevent graft rejection. A serum chemistry panel, a glycated hemoglobin test, and urinalysis performed at presentation revealed elevated blood glucose and glycated hemoglobin (HbA1c) levels (727 mg/dL and 10.1%, respectively), glucosuria, and ketonuria. Diabetes mellitus was diagnosed, and insulin therapy was initiated immediately. The macaque was weaned off the immunosuppressive therapy as his clinical condition improved and stabilized. Approximately 74 d after discontinuation of the immunosuppressants, the blood glucose normalized, and the insulin therapy was stopped. The animal''s blood glucose and HbA1c values have remained within normal limits since this time. We suspect that our macaque experienced new-onset diabetes mellitus after transplantation, a condition that is commonly observed in human transplant patients but not well described in NHP. To our knowledge, this report represents the first documented case of new-onset diabetes mellitus after transplantation in a cynomolgus macaque.Abbreviations: NODAT, new-onset diabetes mellitus after transplantationNew-onset diabetes mellitus after transplantation (NODAT, formerly known as posttransplantation diabetes mellitus) is an important consequence of solid-organ transplantation in humans.7-10,15,17,19,21,25-28,31,33,34,37,38,42 A variety of risk factors have been identified including increased age, sex (male prevalence), elevated pretransplant fasting plasma glucose levels, and immunosuppressive therapy.7-10,15,17,19,21,25-28,31,33,34,37,38,42 The relationship between calcineurin inhibitors, such as tacrolimus and cyclosporin, and the development of NODAT is widely recognized in human medicine.7-10,15,17,19,21,25-28,31,33,34,37,38,42 Cynomolgus macaques (Macaca fasicularis) are a commonly used NHP model in organ transplantation research. Cases of natural and induced diabetes of cynomolgus monkeys have been described in the literature;14,43,45 however, NODAT in a macaque model of solid-organ transplantation has not been reported previously to our knowledge. 相似文献
13.
X-N Wu Z-H Yang X-K Wang Y Zhang H Wan Y Song X Chen J Shao J Han 《Cell death and differentiation》2014,21(11):1709-1720
Necroptosis is mediated by a signaling complex called necrosome, containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL). It is known that RIP1 and RIP3 form heterodimeric filamentous scaffold in necrosomes through their RIP homotypic interaction motif (RHIM) domain-mediated oligomerization, but the signaling events based on this scaffold has not been fully addressed. By using inducible dimer systems we found that RIP1–RIP1 interaction is dispensable for necroptosis; RIP1–RIP3 interaction is required for necroptosis signaling, but there is no necroptosis if no additional RIP3 protein is recruited to the RIP1–RIP3 heterodimer, and the interaction with RIP1 promotes the RIP3 to recruit other RIP3; RIP3–RIP3 interaction is required for necroptosis and RIP3–RIP3 dimerization is sufficient to induce necroptosis; and RIP3 dimer-induced necroptosis requires MLKL. We further show that RIP3 oligomer is not more potent than RIP3 dimer in triggering necroptosis, suggesting that RIP3 homo-interaction in the complex, rather than whether RIP3 has formed homo polymer, is important for necroptosis. RIP3 dimerization leads to RIP3 intramolecule autophosphorylation, which is required for the recruitment of MLKL. Interestingly, phosphorylation of one of RIP3 in the dimer is sufficient to induce necroptosis. As RIP1–RIP3 heterodimer itself cannot induce necroptosis, the RIP1–RIP3 heterodimeric amyloid fibril is unlikely to directly propagate necroptosis. We propose that the signaling events after the RIP1–RIP3 amyloid complex assembly are the recruitment of free RIP3 by the RIP3 in the amyloid scaffold followed by autophosphorylation of RIP3 and subsequent recruitment of MLKL by RIP3 to execute necroptosis.Necroptosis is a type of programmed necrosis characterized by necrotic morphological changes, including cellular organelle swelling, cell membrane rupture,1, 2, 3 and dependence of receptor-interacting protein (RIP)14 and RIP3.5, 6, 7 Physiological function of necroptosis has been illustrated in host defense,8, 9, 10, 11 inflammation,12, 13, 14, 15, 16 tissue injury,10, 17, 18 and development.19, 20, 21Necroptosis can be induced by a number of different extracellular stimuli such as tumor necrosis factor (TNF). TNF stimulation leads to formation of TNF receptor 1 (TNFR1) signaling complex (named complex I), and complex II containing RIP1, TRADD, FAS-associated protein with a death domain (FADD), and caspase-8, of which the activation initiates apoptosis. If cells have high level of RIP3, RIP1 recruits RIP3 to form necrosome containing FADD,22, 23, 24 caspase-8, RIP1, and RIP3, and the cells undergo necroptosis.25, 26 Caspase-8 and FADD negatively regulates necroptosis,27, 28, 29, 30 because RIP1, RIP3, and CYLD are potential substrates of caspase-8.31, 32, 33, 34 Necrosome also suppresses apoptosis but the underlying mechanism has not been described yet. Mixed-lineage kinase domain-like (MLKL) is downstream of RIP3,35, 36 and phosphorylation of MLKL is required for necroptosis.37, 38, 39, 40, 41, 42Apoptosis inducing complex (complex II) and necrosome are both supramolecular complexes.43, 44, 45 A recent study showed that RIP1 and RIP3 form amyloidal fibrils through their RIP homotypic interaction motif46 (RHIM)-mediated polymerization, and suggested that amyloidal structure is essential for necroptosis signaling.47 The RIP1–RIP3 heterodimeric amyloid complex is believed to function as a scaffold that brings signaling proteins into proximity to permit their activation. However, RIP1 and RIP3 also can each form fibrils on their own RHIM domains in vitro. It is unclear how the homo- and hetero-interactions are coordinated and organized on the amyloid scaffold to execute their functions in necroptosis. Here, we used inducible dimerization systems to study the roles of RIP1–RIP1, RIP1–RIP3, and RIP3–RIP3 interactions in necroptosis signaling. Our data suggested that it is the RIP1–RIP3 interaction in the RIP1–RIP3 heterodimeric amyloid complex that empowers to recruit other free RIP3; homodimerization of RIP3 triggers its autophosphorylation and only the phosphorylated RIP3 can recruit MLKL to execute necroptosis. 相似文献
14.
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Q Xia Q Hu H Wang H Yang F Gao H Ren D Chen C Fu L Zheng X Zhen Z Ying G Wang 《Cell death & disease》2015,6(3):e1702
Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS.Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord.1 Most cases of ALS are sporadic, but 10% are familial. Familial ALS cases are associated with mutations in genes such as Cu/Zn superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TARDBP) and, most recently discovered, C9orf72. Currently, most available information obtained from ALS research is based on the study of SOD1, but new studies focusing on TARDBP and C9orf72 have come to the forefront of ALS research.1, 2 The discovery of the central role of the protein TDP-43, encoded by TARDBP, in ALS was a breakthrough in ALS research.3, 4, 5 Although pathogenic mutations of TDP-43 are genetically rare, abnormal TDP-43 function is thought to be associated with the majority of ALS cases.1 TDP-43 was identified as a key component of the ubiquitin-positive inclusions in most ALS patients and also in other neurodegenerative diseases such as frontotemporal lobar degeneration,6, 7 Alzheimer''s disease (AD)8, 9 and Parkinson''s disease (PD).10, 11 TDP-43 is a multifunctional RNA binding protein, and loss-of-function of TDP-43 has been increasingly recognized as a key contributor in TDP-43-mediated pathogenesis.5, 12, 13, 14Neuroinflammation, a striking and common hallmark involved in many neurodegenerative diseases, including ALS, is characterized by extensive activation of glial cells including microglia, astrocytes and oligodendrocytes.15, 16 Although numerous studies have focused on the intrinsic properties of motor neurons in ALS, a large amount of evidence showed that glial cells, such as astrocytes and microglia, could have critical roles in SOD1-mediated motor neuron degeneration and ALS progression,17, 18, 19, 20, 21, 22 indicating the importance of non-cell-autonomous toxicity in SOD1-mediated ALS pathogenesis.Very interestingly, a vital insight of neuroinflammation research in ALS was generated by the evidence that both the mRNA and protein levels of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) are upregulated in both transgenic mouse models and in human postmortem brain and spinal cord.23, 24, 25, 26, 27, 28, 29 The role of COX-2 neurotoxicity in ALS and other neurodegenerative disorders has been well explored.30, 31, 32 One of the key downstream products of COX-2, prostaglandin E2 (PGE2), can directly mediate COX-2 neurotoxicity both in vitro and in vivo.33, 34, 35, 36, 37 The levels of COX-2 expression and PGE2 production are controlled by multiple cell signaling pathways, including the mitogen-activated protein kinase (MAPK)/ERK pathway,38, 39, 40 and they have been found to be increased in neurodegenerative diseases including AD, PD and ALS.25, 28, 32, 41, 42, 43, 44, 45, 46 Importantly, COX-2 inhibitors such as celecoxib exhibited significant neuroprotective effects and prolonged survival or delayed disease onset in a SOD1-ALS transgenic mouse model through the downregulation of PGE2 release.28Most recent studies have tried to elucidate the role of glial cells in neurotoxicity using TDP-43-ALS models, which are considered to be helpful for better understanding the disease mechanisms.47, 48, 49, 50, 51 Although the contribution of glial cells to TDP-43-mediated motor neuron degeneration is now well supported, this model does not fully suggest an astrocyte-based non-cell autonomous mechanism. For example, recent studies have shown that TDP-43-mutant astrocytes do not affect the survival of motor neurons,50, 51 indicating a previously unrecognized non-cell autonomous TDP-43 proteinopathy that associates with cell types other than astrocytes.Given that the role of glial cell types other than astrocytes in TDP-43-mediated neuroinflammation is still not fully understood, we aim to compare the contribution of microglia and astrocytes to neurotoxicity in a TDP-43 loss-of-function model. Here, we show that TDP-43 has a dominant role in promoting COX-2-PGE2 production through the MAPK/ERK pathway in primary cultured microglia, but not in primary cultured astrocytes. Our study suggests that overproduction of PGE2 in microglia is a novel molecular mechanism underlying neurotoxicity in TDP-43-linked ALS. Moreover, our data identify celecoxib as a new potential effective treatment of TDP-43-linked ALS and possibly other types of ALS. 相似文献
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In the central nervous system (CNS), hyperglycemia leads to neuronal damage and cognitive decline. Recent research has focused on revealing alterations in the brain in hyperglycemia and finding therapeutic solutions for alleviating the hyperglycemia-induced cognitive dysfunction. Adiponectin is a protein hormone with a major regulatory role in diabetes and obesity; however, its role in the CNS has not been studied yet. Although the presence of adiponectin receptors has been reported in the CNS, adiponectin receptor-mediated signaling in the CNS has not been investigated. In the present study, we investigated adiponectin receptor (AdipoR)-mediated signaling in vivo using a high-fat diet and in vitro using neural stem cells (NSCs). We showed that AdipoR1 protects cell damage and synaptic dysfunction in the mouse brain in hyperglycemia. At high glucose concentrations in vitro, AdipoR1 regulated the survival of NSCs through the p53/p21 pathway and the proliferation- and differentiation-related factors of NSCs via tailless (TLX). Hence, we suggest that further investigations are necessary to understand the cerebral AdipoR1-mediated signaling in hyperglycemic conditions, because the modulation of AdipoR1 might alleviate hyperglycemia-induced neuropathogenesis.Adiponectin secreted by the adipose tissue1, 2 exists in either a full-length or globular form.3, 4, 5, 6 Adiponectin can cross the blood–brain barrier, and various forms of adiponectin are found in the cerebrospinal fluid.7, 8, 9, 10, 11 Adiponectin exerts its effect by binding to the adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2)12, 13 that have different affinities for the various circulating adiponectins.12, 14, 15, 16, 17 Several studies reported that both receptor subtypes are expressed in the central nervous system (CNS).7, 12, 18 As adiponectin modulates insulin sensitivity and inflammation,19 its deficiency induces insulin resistance and glucose intolerance in animals fed a high-fat diet (HFD).19, 20, 21 In addition, adiponectin can ameliorate the glucose homeostasis and increase insulin sensitivity.22, 23, 24 Adiponectin, which is the most well-known adipokine, acts mainly as an anti-inflammatory regulator,25, 26 and is associated with the onset of neurological disorders.27 In addition, a recent study reported that adiponectin promotes the proliferation of hippocampal neural stem cells (NSCs).28 Considering that adiponectin acts by binding to the adiponectin receptors, investigation of the adiponectin receptor-mediated signaling in the brain is crucial to understand the cerebral effects of adiponectin and the underlying cellular mechanisms.The prevalence of type II diabetes mellitus (DM2) and Alzheimer''s disease increases with aging.29 According to a cross-sectional study, in people with DM2, the risk of dementia is 2.5 times higher than that in the normal population.30, 31 A study performed between 1980 and 2002 suggested that an elevated blood glucose level is associated with a greater risk for dementia in elderly patients with DM2.32 In addition, according to a 9-year-long longitudinal cohort study, the risk of developing Alzheimer''s disease was 65% higher in people with diabetes than in control subjects.33 A community-based cohort study also reported that higher plasma glucose concentrations are associated with an increased risk for dementia, because the higher glucose level has detrimental effects on the brain.31 High blood glucose level causes mitochondria-dependent apoptosis,34, 35, 36 and aggravates diverse neurological functions.37, 38 Inflammation and oxidative stress, which are commonly observed in people with diabetes, inhibit neurogenesis.39, 40, 41 Similarly, neurogenesis is decreased in mice and rats with genetically induced type I diabetes.42, 43 In addition, diabetic rodents have a decreased proliferation rate of neural progenitors.43, 44 Furthermore, several studies suggested that an HFD leads to neuroinflammation, the impairment of synaptic plasticity, and cognitive decline.45, 46Here, we investigated whether AdipoR1-mediated signaling is associated with cell death in the brain of mice on a HFD, and whether high glucose level modifies the proliferation and differentiation capacity of NSCs in vitro. Our study provides novel findings about the role of AdipoR1-mediated signaling in hyperglycemia-induced neuropathogenesis. 相似文献
19.
J D Leverson H Zhang J Chen S K Tahir D C Phillips J Xue P Nimmer S Jin M Smith Y Xiao P Kovar A Tanaka M Bruncko G S Sheppard L Wang S Gierke L Kategaya D J Anderson C Wong J Eastham-Anderson M J C Ludlam D Sampath W J Fairbrother I Wertz S H Rosenberg C Tse S W Elmore A J Souers 《Cell death & disease》2015,6(1):e1590