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PubMed2006

Gastrodia elata modulated activator protein 1 via c-Jun N-terminal kinase signaling pathway in kainic acid-induced epilepsy in rats.

Gastrodia elata (Orchidaceae) is a Chinese herb. Our previous study showed that Gastrodia elata is able to reduce epileptic seizures, oxygen free radicals, microglia activation, and apoptosis in kainic acid (KA)-treated rats. Activator protein 1 (AP-1) is involved in modulating the neuronal plasticity and apoptosis. Therefore, the aim of this study was to investigate the role of AP-1 in antiepileptic effect of Gastrodia elata. Gastrodia elata (0.5, 1.0g/kg) or valproic acid (VA, 250mg/kg) was administered orally in Sprague-Dawley rats for 1 week before and 2 weeks after intraperitoneal injection of KA. Protein levels of AP-1 were determined by measuring c-Jun and c-Fos proteins, and the mitogen-activated protein (MAP) kinases activations were determined by measuring the phosphorylations of extracellular signal-regulated kinases, p38, and c-Jun N-terminal kinases (JNKs) in the frontal cortex and the hippocampus of rat brain using Western blotting. These results indicated that pre-treatment with Gastrodia elata or VA activated JNK signal pathway and c-Jun expression, while post-treatment with Gastrodia elata or VA suppressed both the JNK signaling pathway and the c-Jun expression induced by KA. These findings suggested that Gastrodia elata regulated the AP-1 expression via the JNK signaling pathway in KA-induced epilepsy.

Animals↗
PubMed1997

Coupling signalling pathways to transcriptional control: nuclear factors responsive to cAMP.

Several endocrine and neuronal functions are governed by the cAMP-dependent signalling pathway. In eukaryotes, transcriptional regulation upon stimulation of the adenylyl cyclase signalling pathway is mediated by a family of cAMP-responsive nuclear factors. This family consists of a large number of members that may act as activators or repressors. These factors contain the basic domain/ leucine zipper motifs and bind as dimers to cAMP-response elements (CRE). The function of CRE-binding proteins (CREBs) is modulated by phosphorylation by several kinases. Direct activation of gene expression by CREB requires phosphorylation by the cAMP-dependent protein kinase A to the serine-133 residue. Among the repressors, ICER (Inducible cAMP Early Repressor) deserves special mention. ICER is generated from an alternative CREM promoter and constitutes the only inducible cAMP-responsive element binding protein. Furthermore, ICER negatively autoregulates the alternative promoter, thus generating a feedback loop. In contrast to the other members of the CRE-binding protein family, ICER expression is tissue specific and developmentally regulated. The kinetics of ICER expression are characteristic of an early response gene. Our results indicate that CREM plays a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis. We have previously shown that the transcriptional activator CREM is highly expressed in postmeiotic cells. Spermiogenesis is a complex process by which postmeiotic male germ cells differentiate into mature spermatozoa. This process involves remarkable structural and biochemical changes that are under the hormonal control of the hypothalamic-pituitary axis. We have addressed the specific role of CREM in spermiogenesis using CREM-mutant mice generated by homologous recombination. Analysis of the seminiferous epithelium from mutant male mice reveals that spermatogenesis stops at the first step of spermiogenesis. Late spermatids are completely absent, while there is a significant increase in apoptotic germ cells. A series of postmeiotic germ cell-specific genes are not expressed. Mutant male mice completely lack spermatozoa. This phenotype is reminiscent of cases of human infertility. We have shown that ICER is regulated in a circadian manner in the pineal gland, the site of the hormone melatonin production. This night-day oscillation is driven by the endogenous clock (located in the suprachiasmatic nucleus, SCN). The synthesis of melatonin is regulated by a rate-limiting enzyme, the serotonin N-acetyltransferase (NAT). By using the CREM-deficient mice and by analysis of the regulatory region of the gene encoding the serotonin NAT, we have established that ICER is responsible for the amplitude and rhythmicity of NAT and thus for the oscillation in the hormonal synthesis of melatonin.

Adenylyl Cyclases↗
PubMed2002

Calpain as an effector of the Gq signaling pathway for inhibition of Wnt/beta -catenin-regulated cell proliferation.

Signaling pathways interact to integrate and regulate information flow in evoking complex cellular responses. We have studied the mechanisms and consequences of interactions between the Gq and Wnt/beta-catenin pathways. In human colon carcinoma SW480 cells, activation of the Gq pathway inhibits beta-catenin signaling as determined by transcriptional reporter and cell proliferation assays. Ca(2+) release from internal stores results in nuclear export and calpain-mediated degradation of beta-catenin in the cytoplasm. Galphaq does not inhibit the effects of constitutively activated DeltaN-XTCF3-VP16 chimera in SW480 cells. Similarly, in HEK293 cells the Gq pathway suppresses beta-catenin-T cell factor/lymphocyte enhancer factor-1 transcriptional activity induced by Wnt/Frizzled interaction or glycogen synthase kinase-3beta-resistant beta-catenin, but not DeltaN-XTCF3-VP16. We conclude that Gq signaling promotes nuclear export and calpain-mediated degradation of beta-catenin, which therefore contributes to the inhibition of Wnt/beta-catenin pathway.

Calcium↗
PubMed2005

Methods of analysis for chemicals that disrupt cellular signaling pathways: risk assessment for potential endocrine disruptors.

Here we present a basic concept and several examples of methods of analysis for chemicals that disrupt cellular signaling pathways, in view of risk assessment for potential endocrine disrupting chemicals (EDCs). The key cellular signaling pathways include 1) ER/coactivator interaction, 2) AR translocation into the nucleus, 3) ER/NO/sGC/cGMP, 4) ER/Akt, 5) ER/Src, 6)ER/Src/Grb2, and 7) ER/Ca2+/CaM/CaMK pathways. These were visualized in relevant live cells using newly developed fluorescent and bioluminescent probes. Changes in cellular signals were thereby observed in nongenomic pathways of steroid hormones upon treatment of the target cells with steroid hormones and related chemicals. This method of analysis appears to be a rational approach to high-throughput prescreening (HTPS) of biohazardous chemicals, EDCs, in particular. Also described was the screening of gene expression by serial analysis of gene expression and gene chips upon applying EDCs to breast cancer cells, mouse livers, and human neuroblastoma NB-1 cells.

Animals↗
PubMed2004

Investigation of signaling pathways that mediate the inotropic effect of urotensin-II in human heart.

OBJECTIVE: This study investigated signaling pathways that may contribute to the potent positive inotropic effect of human urotensin-II (hU-II) in human isolated right atrial trabeculae obtained from patients with coronary artery disease. METHODS: Trabeculae were set up in tissue baths and stimulated to contract at 1 Hz. Tissues were incubated with 20 nM hU-II with or without phorbol 12-myristate 13-acetate (PMA, 10 microM) to desensitize PKC, the PKC inhibitor chelerythrine (10 microM), 10 microM 4alpha-phorbol that does not desensitize PKC, the myosin light chain kinase inhibitor wortmannin (50 nM, 10 microM), or the Rho kinase inhibitor Y-27632 (0.1-10 microM). Activated RhoA was determined by affinity immunoprecipitation, and phosphorylation of signaling proteins was determined by SDS-PAGE. RESULTS: hU-II caused a potent positive inotropic response in atrial trabeculae, and this was concomitant with increased phosphorylation of regulatory myosin light chain (MLC-2, 1.8+/-0.4-fold, P<0.05, n=6) and PKCalpha/betaII (1.4+/-0.2-fold compared to non-stimulated controls, P<0.05, n=7). Pretreatment of tissues with PMA caused a marked reduction in the inotropic effect of hU-II, but did not affect hU-II-mediated phosphorylation of MLC-2. The inotropic response was inhibited by chelerythrine, but not 4alpha-phorbol or wortmannin. Although Y-27632 also reduced the positive inotropic response to hU-II, this was associated with a marked reduction in basal force of contraction. RhoA.GTP was immunoprecipitated in tissues pretreated with or without hU-II, with findings showing no detectable activation of RhoA in the agonist stimulated tissues. CONCLUSIONS: The findings indicated that hU-II increased force of contraction in human heart via a PKC-dependent mechanism and increased phosphorylation of MLC-2, although this was independent of PKC. The positive inotropic effect was independent of myosin light chain kinase and RhoA-Rho kinase signaling pathways.

Alkaloids↗
PubMed2005

ERK and JNK signaling pathways are involved in the regulation of activator protein 1 and cell death elicited by three isothiocyanates in human prostate cancer PC-3 cells.

Many isothiocyanates (ITCs) such as sulforaphane (SFN), phenethyl isothiocyanate (PEITC) and allyl isothiocyanate (AITC) are highly effectively in chemoprevention or reduction of the risk of cancer and possess antitumor activities in vitro and in vivo. The activator protein 1 (AP-1) and MAPK signaling pathways are believed to play an important role in cancer chemoprevention and chemotherapy due to their involvement in tumor cell growth, proliferation, apoptosis and survival. In the present study, we determined the effects of SFN, PEITC and AITC on AP-1 activation, and investigated the roles of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways in the regulation of AP-1 activation and cell death elicited by these ITCs in human prostate cancer PC-3 cells. SFN, PEITC and AITC each induced AP-1 activity potently and caused a significant elevation in the phosphorylation of ERK1/2, JNK1/2, Elk-1 and c-Jun. Transfection with ERK2 and upstream kinase DNEE-MEK1 activated AP-1 activity, and transfection with dominant-negative mutant ERK2 (dnERK2) potently decreased AP-1 activation induced by SFN, PEITC and AITC. Transfection with JNK1 and upstream kinase MKK7 activated AP-1 activity, and transfection with dominant-negative mutant JNK1-APF significantly attenuated AP-1 activation induced by SFN, PEITC and AITC. Pretreatment with MEK1-ERK inhibitor U0126 and JNK inhibitor SP600125 substantially attenuated the decrease in cell viability induced by SFN, PEITC and AITC. Transfection with dnERK2 and JNK1-APF significantly reversed the decrease of Bcl-2 expression elicited by these ITCs. Furthermore, transfection with dnERK2 and JNK1-APF blocked the apoptosis induced by these ITCs in PC-3 cells. Taken together, our results indicate that the activation of the ERK and JNK signaling pathways is important for transcriptional activity of AP-1 and is involved in the regulation of cell death elicited by ITCs in PC-3 cells.

Anticarcinogenic Agents↗
PubMed2005

A genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway.

Members of the Hedgehog (Hh) family of signaling proteins are powerful regulators of developmental processes in many organisms and have been implicated in many human disease states. Here we report the results of a genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway. The screen identified hundreds of potential new regulators of Hh signaling, including many large protein complexes with pleiotropic effects, such as the coat protein complex I (COPI) complex, the ribosome and the proteasome. We identified the multimeric protein phosphatase 2A (PP2A) and two new kinases, the D. melanogaster orthologs of the vertebrate PITSLRE and cyclin-dependent kinase-9 (CDK9) kinases, as Hh regulators. We also identified a large group of constitutive and alternative splicing factors, two nucleoporins involved in mRNA export and several RNA-regulatory proteins as potent regulators of Hh signal transduction, indicating that splicing regulation and mRNA transport have a previously unrecognized role in Hh signaling. Finally, we showed that several of these genes have conserved roles in mammalian Hh signaling.

Animals↗
PubMedDate not supplied

Signalling pathways evoked by alpha1-adrenoceptors in human melanoma cells.

The biological effects of catecholamines in mammalian pigment cells are poorly understood, but in poikilothermic vertebrates they regulate the translocation of pigment granules. We have previously demonstrated in SK-Mel 23-human melanoma cells the presence of low affinity alpha(1)-adrenoceptors, which mediate a decrease in cell proliferation and increase in tyrosinase activity, with no change of tyrosinase expression. In this report, we investigated the signalling pathways involved in these responses. Calcium mobilization in response to phenylephrine (PHE), an alpha(1)-adrenergic agonist, was investigated by confocal microscopy, and no change of fluorescence during the treatment was observed, suggesting that calcium is not involved in the signalling pathway activated by alpha(1)-adrenoceptors in SK-Mel 23 cells. cAMP levels, determined by enzyme-immunoassay, were significantly increased by PHE (10(-5)-10(-4)M), that could be blocked by the alpha(1)-adrenergic antagonist benoxathian (10(-5)-10(-4)M). Several biological assays were then performed with PHE, for 72 h, in the absence or presence of various signalling pathway inhibitors, in an attempt to determine the intracellular messengers involved in the responses of proliferation and tyrosinase activity. Our results suggest the participation of p38 and ERKs in PHE-induced decrease of proliferation, and possibly also of cAMP and protein kinase A. Regarding PHE-induced increase of tyrosinase activity, it is suggested that the following signalling components are involved: cAMP/PKA, PKC, PI3K, p38 and ERKs.

Adenine↗
PubMed2002

Apoptotic signaling pathways: caspases and stress-activated protein kinases.

Apoptotic cell death is an active process mediated by various signaling pathways, which include the caspase cascade and the stress-activated protein kinase pathways. The caspase cascade is activated by two distinct routes: one from cell surface and the other from mitochondria. Activation of the route from cell surface requires the cellular components that include membrane receptors, adaptor proteins such as TRADD and FADD, and caspase-8, while activation of the other from mitochondria requires Apaf-1, caspase-9, and cytosolic cytochrome c. On the other hand, persistent stimulation of the stress-activated protein kinase pathway is also shown to mediate apoptosis in many cell types. Gene-targeting studies with jnk- or jip-null mice, in particular, strongly suggest that this signaling pathway plays a pivotal role in the cellular machinery for apoptosis.

Animals↗
PubMed1998

Dendritic cell survival and maturation are regulated by different signaling pathways.

Although dendritic cell (DC) activation is a critical event for the induction of immune responses, the signaling pathways involved in this process have not been characterized. In this report, we show that DC activation induced by lipopolysaccharide (LPS) can be separated into two distinct processes: first, maturation, leading to upregulation of MHC and costimulatory molecules, and second, rescue from immediate apoptosis after withdrawal of growth factors (survival). Using a DC culture system that allowed us to propagate immature growth factor-dependent DCs, we have investigated the signaling pathways activated by LPS. We found that LPS induced nuclear translocation of the nuclear factor (NF)-kappaB transcription factor. Inhibition of NF-kappaB activation blocked maturation of DCs in terms of upregulation of major histocompatibility complex and costimulatory molecules. In addition, we found that LPS activated the extracellular signal-regulated kinase (ERK), and that specific inhibition of MEK1, the kinase which activates ERK, abrogated the ability of LPS to prevent apoptosis but did not inhibit DC maturation or NF-kappaB nuclear translocation. These results indicate that ERK and NF-kappaB regulate different aspects of LPS-induced DC activation: ERK regulates DC survival whereas NF-kappaB is responsible for DC maturation.

Animals↗
PubMed2003

Targeting RAS signalling pathways in cancer therapy.

The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. They are aberrant in most human tumours due to activating mutations in the RAS genes themselves or to alterations in upstream or downstream signalling components. Rational therapies that target the RAS pathways might inhibit tumour growth, survival and spread. Several of these new therapeutic agents are showing promise in the clinic and many more are being developed.

Animals↗
PubMed2006

[Involvement of epidermal growth factor receptor signaling pathway in tamoxifen resistance of MCF-7 cells].

BACKGROUND & OBJECTIVE: Tamoxifen (TAM) is an important endocrine therapeutic drug used in combined treatment for breast cancer. However the drug resistant effect of TAM has become a major concern in clinical use. Epidermal growth factor receptor (EGFR) is expressed in many tumors and the expression of EGFR in breast cancer tissues is associated with poor prognosis. This study was to investigate EGFR signaling pathway in the drug resistant effect of TAM in breast cancer cells. METHODS: An estrogen receptor (ER) positive breast cancer cell line, MCF-7 was incubated with TAM (10(-7) mol/L) for up to 6 months to produce drug resistant cells. mRNA and protein expression of EGFR signaling pathway related genes and ER gene was analyzed by fluorescent quantitation reverse transcription-polymerase chain reaction (fqRT-PCR) and Western blot. AG1478, an EGFR inhibitor, was also used to study the drug resistant effect of TAM. RESULTS: The proliferation of MCF-7 cells was inhibited in the early stage after TAM treatment. However the inhibitory effect vanished after continuous 6-month treatment and the cell proliferation rate returned back to normal. The tolerance of MCF-7 cells to TAM was confirmed by cell growth inhibitory test. In TAM resistant MCF-7 cells, the expression of EGFR mRNA was increased by 4.5 times and the protein expression of EGFR, phosphorylation-extracellular signal-regulated kinase (p-ERK1/2) was also increased dramatically (P<0.05). While ER protein expression remained unchanged. Moreover the drug resistant cells were identified more sensitive to AG1478. CONCLUSION: In endocrine therapy, TAM resistant breast cancer cells are likely to be generated by the activation of EGFR signaling pathway after long-term TAM treatment, and EGFR inhibitors might increase the therapeutic effects in breast cancer treatment.

Antineoplastic Agents, Hormonal↗
PubMed2004

Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazide.

AIM: We have previously demonstrated that advanced glycation end products (AGEs) stimulate bovine retinal endothelial cell (BREC) proliferation through induction of vascular endothelial growth factor (VEGF) production by these cells. We have also shown that gliclazide, a sulfonylurea which decreases oxidative stress, inhibits this effect. The aim of the present study was to characterize the signalling pathways involved in AGE-induced BREC proliferation and VEGF production and mediating the inhibitory effect of gliclazide on these biological events. METHODS: BRECs were treated or not treated with AGEs in the presence or absence of gliclazide, antioxidants, protein kinase C (PKC), mitogen-activated protein kinase (MAPK) or nuclear factor-kappaB (NF-kappaB) inhibitors. BREC proliferation was assessed by measuring [3H]-thymidine incorporation into DNA. Activation of PKC, MAPK and NF-kappaB signal transduction pathways and determination of VEGF expression were assessed by Western blot analysis using specific antibodies. MAPK activity was also determined by an in vitro kinase assay. RESULTS: Treatment of BRECs with AGEs significantly increased cell proliferation and VEGF expression. AGEs induced PKC-beta translocation, extracellular signal-regulated protein kinase 1/2 and NF-kappaB activation in these cells. Pharmacological inhibition of these signalling pathways abolished AGE effects on cell proliferation and VEGF expression. Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N-acetyl-l-cysteine resulted in a significant decrease in AGE-induced activation of PKC-, MAPK- and NF-kappaB-signalling pathways. CONCLUSIONS: Our results demonstrate the involvement of PKC, MAPK and NF-kappaB in AGE-induced BREC proliferation and VEGF expression. Gliclazide inhibits BREC proliferation by interfering with these intracellular signal transduction pathways.

Animals↗
PubMed2006

Ageing evokes an intrinsic pro-apoptotic signalling pathway in rat cochlea.

CONCLUSIONS: These findings support the hypothesis that age-related apoptosis evokes an intrinsic pathway of pro-apoptotic signalling within the rat cochlea. OBJECTIVES: The aim of this study was to explore the effects of ageing on cochlear apoptosis in rats, as well as the different signalling pathways involved. MATERIALS AND METHODS: Female Sprague Dawley rats of different ages were used (mean age 7.72+/-1.93 months, n=100). Luciferase assays were used to determine the different caspase activities and ATP levels in rat cochlear protein extracts. Protein and gene expression was examined by Western blotting and real-time RT-PCR assays, respectively. RESULTS: Caspase-3/7 activity, as well as caspase-3 gene expression, were statistically higher in early-mature rats (EM, 276,139+/-13 669 RLUs (relative light units), p<0.001; and 390+/-50 arbitrary units, p=0.0017, respectively) or in aged-mature rats (AM, 371,020+/-26,457, p<0.0001; and 1510+/-90, p<0.0001, respectively) than younger rats (YR 147,129+/-8485 and 0.14+/-0.004, respectively). An increased caspase-9 activity with ageing was also observed (YR 49,932+/-2046 RLUs vs EM 260,890+/-5939, p<0.0001 or AM 118,241+/-12,423, p<0.0001). Caspase-8 activity was not affected significantly by age. Bax protein expression also increased by age (YR 38,200+/-1790 arbitrary units vs EM 76,549+/-5450, p<0.05), in contrast to Bcl-xL protein expression (YR 27,000+/-5000 arbitrary units vs EM 10,200+/-5000, p<0.005).

Aging↗
PubMed2007

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: it's inhibition leads to growth suppression and apoptosis.

The hedgehog (Hh) signal pathway has recently been shown to be activated in human malignancies. However, little is known about its role in the development or patient prognosis of epithelial ovarian carcinoma. In the present study, we examined in vivo and in vitro the expression and functional role of Hh signal molecules in epithelial ovarian tumors and normal ovarian surface epithelial (OSE) cells. The expression of Shh, Dhh, Ptch, Smo and Gli1 proteins was not observed in normal OSE, but was increased stepwise in benign, borderline and malignant neoplasms. In addition, immunoreactivity for Shh, Dhh, Ptch, Smo and Gli1 was highly correlated with cell proliferation assessed by Ki-67. Blocking the Hh signal using either the Hh pathway inhibitor cyclopamine or Gli1 siRNA led to remarkably decreased cell proliferation in ovarian carcinoma cells. Treatment with cyclopamine induced not only G, arrest but also apoptosis along with the downregulation of cyclin A and cyclin D1, and the upregulation of p21 and p27. Among the Hh signal molecules, Dhh expression was correlated with poor prognosis of ovarian carcinoma patients. These findings suggest that the Hh signal pathway plays an important role in ovarian tumorigenesis as well as in the activation of cell proliferation in ovarian carcinomas. Thus, the Hh signal pathway is a possible molecular target of new treatment strategies for ovarian carcinoma.

Apoptosis↗
PubMed2006

Differential caspase-9-dependent signaling pathway between tumor necrosis factor receptor- and Fas-mediated hepatocyte apoptosis in mice.

BACKGROUND/AIMS: Two apoptosis signaling pathways, which are used by different cell types, are identified. The activation of caspases is critical for the apoptosis process. The aim of this study was to investigate the effects of the caspase-9 inhibitor Ac-LEHD-CHO on tumor necrosis factor receptor (TNFR)- and Fas-mediated hepatocyte apoptosis in vivo, in order to evaluate the similarities and distinctions between TNFR- and Fas-mediated signaling pathways. METHODS: BALB/c mice were intravenously injected with d-galactosamine (GalN, 20 mg/mouse)/tumor necrosis factor-alpha (TNF-alpha, 0.5 microg/mouse), or alphaFas (10 microg/mouse) 30 min after treatment with the caspase-9 inhibitor Ac-LEHD-CHO or pan-caspase inhibitor Z-VAD-fmk. Liver injury was assessed biochemically and histologically. Cytochrome c release and processing of procaspases in the liver were analyzed by Western blotting. Activities of caspases were measured using a fluorogenic peptide substrate. RESULTS: Pretreatment with Z-VAD-fmk prevented liver injury and hepatocyte apoptosis induced by either GalN/TNF-alpha or alphaFas. On the other hand, pretreatment with Ac-LEHD-CHO prevented GalN/TNF-alpha-induced hepatotoxicity and hepatocyte apoptosis but not alphaFas-induced liver injury and apoptosis. Both inhibitors reduced the activities of caspase-9 and -3 in the livers of mice administered by GalN/TNF-alpha. However, unlike Z-VAD-fmk, Ac-LEHD-CHO did not inhibit caspase-3 activation in alphaFas-treated mice, although this inhibitor attenuated caspase-9. CONCLUSION: Fas may rely on both caspase-8 activation (extrinsic pathway) and mitochondria (intrinsic pathway) to activate caspase-3. If the mitochondria-dependent pathway is blocked, the other pathway can compensate. In contrast, TNFR may mediate hepatocellular apoptosis mainly through the mitochondria-mediated caspase-9 activation pathway alone.

Amino Acid Chloromethyl Ketones↗
PubMed2006

The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways.

Few things can be considered to be more important to a cell than its threshold for apoptotic cell death, which can be modulated up or down, but rarely in both directions, by a single enzyme. Therefore, it came as quite a surprise to find that one enzyme, glycogen synthase kinase-3 (GSK3), has the perplexing capacity to either increase or decrease the apoptotic threshold. These apparently paradoxical effects now are known to be due to GSK3 oppositely regulating the two major apoptotic signaling pathways. GSK3 promotes cell death caused by the mitochondrial intrinsic apoptotic pathway, but inhibits the death receptor-mediated extrinsic apoptotic signaling pathway. Intrinsic apoptotic signaling, activated by cell damage, is promoted by GSK3 by facilitation of signals that cause disruption of mitochondria and by regulation of transcription factors that control the expression of anti- or pro-apoptotic proteins. The extrinsic apoptotic pathway entails extracellular ligands stimulating cell-surface death receptors that initiate apoptosis by activating caspase-8, and this early step in extrinsic apoptotic signaling is inhibited by GSK3. Thus, GSK3 modulates key steps in each of the two major pathways of apoptosis, but in opposite directions. Consequently, inhibitors of GSK3 provide protection from intrinsic apoptosis signaling but potentiate extrinsic apoptosis signaling. Studies of this eccentric ability of GSK3 to oppositely influence two types of apoptotic signaling have shed light on important regulatory mechanisms in apoptosis and provide the foundation for designing the rational use of GSK3 inhibitors for therapeutic interventions.

Animals↗
PubMed2006

Involvement of HDAC1 and the PI3K/PKC signaling pathways in NF-kappaB activation by the HDAC inhibitor apicidin.

Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-kappaB as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-kappaB activation in response to the HDAC inhibitor apicidin. Treatment of HeLa cells with apicidin leads to an increase in transcriptional activity of NF-kappaB and the expression of its target genes, IL-8 and TNF-alpha. TNF-alpha expression by apicidin is induced at earlier time points than NF-kappaB activation or IL-8 expression. In addition, our data show that the early expression of TNF-alpha does not lead to activation of NF-kappaB, because disruption of TNF-alpha activity by a neutralizing antibody does not affect nuclear translocation of NF-kappaB, IkappaBalpha degradation or reporter gene activation by apicidin. However, this activation of NF-kappaB requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, apicidin activation of NF-kappaB seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-kappaB reporter gene activity. Collectively, our results suggest that activation of NF-kappaB signaling by apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of apicidin.

Androstadienes↗