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Nitric oxide and cell signaling pathways in mitochondrial-dependent apoptosis.

Nitric oxide, generated by endogenous nitric oxide synthases or nitric oxide donors, can promote or prevent apoptosis induced by diverse pro-apoptotic stimuli in cell culture models. Both mitochondrial-dependent and -independent apoptotic signaling pathways mediate this dichotomous cellular response to nitric oxide. The molecular mechanisms behind these effects are complex and involve a number of nitrogen oxide-related species that are more reactive than nitric oxide itself. The local cellular environment plays a dynamic role in determining the nature and concentration of these species. Important components of the microenvironment include: the cellular redox state, glutathione, transition metals and the presence of other oxygen- and nitrogen-centered radicals. In particular, redox-sensitive nitrosating species are favorably generated under physiological conditions and capable of modifying multiple cell signaling pathways through reversible S-nitrosation reactions. Cytochrome c release from mitochondria is an important mechanism for the activation of caspase-3 and the initiation of cell death in response to 'intrinsic' pro-apoptotic stimuli, including oxidative and nitrosative stress. In turn, caspases and mitogen associated protein kinases may modulate cytochrome c release through their effects on the Bcl-2 family of proteins. This review will focus on (i) the importance of the cellular environment in determining the fate of nitric oxide and (ii) the ability of S-nitrosation to regulate mitochondrial-dependent apoptosis at the level of mitochondrial bioenergetics, cytochrome c release, caspases, mitogen associated protein kinases, and the Bcl-2 family of proteins.

Animals↗
PubMed2006

Retracted: Modulation of Stat3 activation by the cytosolic phospholipase A2alpha and cyclooxygenase-2-controlled prostaglandin E2 signaling pathway.

A variety of human cancers show constitutive activation of signal transducer and activator of transcription-3 (Stat3) and overexpression of cyclooxygenase-2 (COX-2). This study describes a novel cross-talk between the COX-2-controlled prostaglandin E(2) (PGE(2)) and Stat3 signaling pathways that coordinately regulate human cancer cell growth. COX-2-derived PGE(2) induces interleukin-6 production through activation of EP(4) receptor and subsequent phosphorylation of gp130/Stat3 in human cholangiocarcinoma cells. In parallel, activation of COX-2/PGE(2) signaling also enhances Stat3 phosphorylation and reporter activity through EP(1) receptor-induced activation of c-Src and EGFR in these cells. Moreover, the observations that EP(1) receptor is detected in the nucleus as well as in the Stat3.DNA binding complex and that activation of EP(1) receptor in the nuclei enhances Stat3 activation depicts a previously undescribed G protein-coupled receptor in the nucleus for Stat3 activation and tumor cell growth.

Cell Line, Tumor↗
PubMed2001

Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit: importance of kinins and influence on angiotensin II type 1 receptor signaling pathway.

BACKGROUND: The role of kinins in the cardioprotective effects of ACE inhibitors remains controversial. METHODS AND RESULTS: Right ventricular pressure overload in rabbits was produced by pulmonary artery banding for 21 days. Rabbits were untreated, or they received the ACE inhibitor ramipril with or without bradykinin B(1) and B(2) receptor blockers or the angiotensin (Ang) II type I (AT(1)) receptor blocker losartan. Pulmonary artery banding caused right ventricular hypertrophy, depressed papillary muscle contractility, and loss of Ang II contractile effects because of a signaling defect downstream of AT(1) receptors. Paradoxically, AT(1) receptor density and G protein alpha subunits alphaq and alphai1/2 increased. Inotropic responsiveness to the alpha-receptor agonist phenylephrine was normal. Ramipril preserved cardiac contractility, but this effect was attenuated by simultaneous use of kinin receptor blockers. Ramipril also maintained responsiveness to Ang II and prevented AT(1) receptor and G protein upregulation. The simultaneous use of a kinin receptor blocker attenuated but did not prevent upregulation in the AT(1) receptor and G protein. Losartan had no effect on baseline contractility, but it maintained cardiac inotropic responsiveness to Ang II, prevented upregulation of AT(1) receptors, but did not modify G protein upregulation. CONCLUSIONS: Pressure overload of the right ventricle decreases contractility, uncouples AT(1) receptors to downstream signaling pathways, and changes the expression of components of the AT(1) receptor signaling pathway. Ramipril attenuates these effects via kinins. Interventions that prevent local increases in Ang II or block AT(1) receptors also prevent decreased responsiveness of the AT(1) receptor in this model.

Angiotensin II↗
PubMed2002

Sphingosine-induced c-jun expression: differences between sphingosine- and C2-ceramide-mediated signaling pathways.

Sphingolipids such as ceramide and sphingosine are putative intracellular signal mediators in cell differentiation, growth inhibition and apoptosis. Previously, we reported that C2-ceramide induced c-jun expression in apoptosis of human leukemia HL-60 cells. Here we report that sphingosine also induced c-jun expression in apoptosis of HL-60 cells. Sphingosine-induced c-jun expression was stimulated by H-89, a protein kinase A inhibitor, whereas C2-ceramide-induced c-jun expression was inhibited by protein kinase C inhibitors. Furthermore, H-89 potentiated sphingosine-induced but not C2-ceramide-induced growth inhibition. These results suggest that sphingosine and C2-ceramide might induce c-jun expression and apoptosis in distinct signaling pathways.

Cell Division↗
PubMed2001

Stimulation of protein kinase C-dependent and -independent signaling pathways by bistratene A in intestinal epithelial cells.

The marine toxin bistratene A (BisA) potently induces cytostasis and differentiation in a variety of systems. Evidence that BisA is a selective activator of protein kinase C (PKC) delta implicates PKC delta signaling in the negative growth-regulatory effects of this agent. The current study further investigates the signaling pathways activated by BisA by comparing its effects with those of the PKC agonist phorbol 12-myristate 13-acetate (PMA) in the IEC-18 intestinal crypt cell line. Both BisA and PMA induced cell cycle arrest in these cells, albeit with different kinetics. While BisA produced sustained cell cycle arrest in G(0)/G(1) and G(2)/M, the effects of PMA were transient and involved mainly a G(0)/G(1) blockade. BisA also produced apoptosis in a proportion of the population, an effect not seen with PMA. Both agents induced membrane translocation/activation of PKC, with BisA translocating only PKC delta and PMA translocating PKC alpha, delta, and epsilon in these cells. Notably, while depletion of PKC alpha, delta, and epsilon abrogated the cell cycle-specific effects of PMA in IEC-18 cells, the absence of these PKC isozymes failed to inhibit BisA-induced G(0)/G(1) and G(2)/M arrest or apoptosis. The cell cycle inhibitory and apoptotic effects of BisA, therefore, appear to be PKC-independent in IEC-18 cells. On the other hand, BisA and PMA both promoted PKC-dependent activation of Erk 1 and 2 in this system. Thus, intestinal epithelial cells respond to BisA through activation of at least two signaling pathways: a PKC delta-dependent pathway, which leads to activation of mitogen-activated protein kinase and possibly cytostasis in the appropriate context, and a PKC-independent pathway, which induces both cell cycle arrest in G(0)/G(1) and G(2)/M and apoptosis through as yet unknown mechanisms.

Acetamides↗
PubMed2004

The role of the mitogen-activated protein kinase cellular signaling pathway in tumor cell survival and apoptosis.

A number of signaling pathways are important in the initiation and maintenance of tumor cell survival and growth. Mitogen activated protein kinases are a family of kinases of different lineages that are thought to be important in tumor growth and metastasis. These pathways provide insight into how tumor cells may escape killing by different agents. In addition, since these pathways are involved in tumor cell survival, several strategies to inhibit them are being tested for novel cancer therapies. This review summarizes the evidence for the role of these pathways in cancer and the current status of therapies.

Animals↗
PubMed2005

Arachidonic acid epoxygenase metabolites stimulate endothelial cell growth and angiogenesis via mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways.

Cytochrome P450 arachidonic acid (AA) epoxygenase metabolites, the epoxyeicosatrienoic acids (EETs), dilate arteries via hyperpolarization of smooth muscle cells and also have nonvasodilatory effects within the vasculature. The present study investigated the angiogenic effects of endogenous and exogenous EETs and the relevant signaling mechanisms involved. Bovine aortic endothelial cells (BAECs) were incubated with synthetic EETs or infected with recombinant adeno-associated viruses (rAAVs) containing CYP2C11-NADPH-cytochrome P450 oxidoreductase (CYPOR), CYP2J2, or CYP102 F87V mutant to increase endogenous levels of EETs. The following endpoints were measured: BAEC proliferation, migration, capillary formation, and in vivo angiogenesis. The potential involvement of various signaling pathways was explored using selective inhibitors. The results showed that transfection with either rAAV-CYP2C11-CYPOR, rAAV-CYP2J2, or rAAV-CYP102 F87V, or incubation with EETs promoted BAEC proliferation, increased migration of BAECs as assessed by Transwell analysis and wound healing assays, and enhanced capillary tubule formation as determined by chicken embryo chorioallantoic membrane assays and tube formation tests on matrigel. The effects of EETs on proliferation, migration, and capillary tubule formation were attenuated by inhibitors of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 (PI3)-kinase/Akt pathways and partially attenuated by an endothelial nitric-oxide synthase (eNOS) inhibitor but not by a protein kinase C inhibitor. In a rat ischemic hind limb model, rAAV-mediated AA epoxygenase transfection induced angiogenesis. We conclude that AA epoxygenase metabolites can promote angiogenesis, which may provide protection to ischemic tissues. The results also suggest that the angiogenic effects of EETs involve the MAPK and PI3-kinase/Akt signaling pathways, and to some extent, the eNOS pathway.

Adenoviridae↗
PubMed2000

Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53.

Dickkopf-1 (Dkk-1), a secreted glycoprotein, has been found to be necessary and sufficient for inducing amphibian head formation. Interestingly, the mechanism by which Dkk-1 does this is the ability of Dkk-1 to antagonize the Wnt signaling pathway. Wnt, itself a proto-oncoprotein, can promote cell proliferation and transformation when mutated or overexpressed, leading to tumor formation. p53 is a tumor suppressor and loss of p53 function accelerates mammary tumorigenesis by Wnt. In this study, we found that Dkk-1 is induced by wild-type p53 but not mutant p53(R249S). In addition, DNA damage upregulates Dkk-1 in cell lines that harbor an endogenous wild-type p53 gene but not in cell lines that are p53-null or harbor an endogenous mutant p53 gene. We also found a potential p53 responsive element located approximately 2100 nucleotides upstream of the Dkk-1 transcription start site and we show that p53 binds specifically to this element both in vitro and in vivo. Furthermore, we have established several cell lines derived from H1299 lung carcinoma and U118 glioma cells that inducibly express Dkk-1 under a tetracycline-regulated promoter. We found that Dkk-1 has no effect on proliferation of cells that are not transformed by Wnt. Taken together, these results suggest that Dkk-1 may mediate p53 tumor suppression by antagonizing the Wnt signaling pathway.

Camptothecin↗
PubMed1999

Role of the PI3K/PKB signaling pathway in cAMP-mediated translocation of rat liver Ntcp.

cAMP stimulates Na(+)-taurocholate (TC) cotransport by translocating the Na(+)-TC-cotransporting peptide (Ntcp) to the plasma membrane. The present study was undertaken to determine whether the phosphatidylinositol-3-kinase (PI3K)-signaling pathway is involved in cAMP-mediated translocation of Ntcp. The ability of cAMP to stimulate TC uptake declined significantly when hepatocytes were pretreated with PI3K inhibitors wortmannin or LY-294002. Wortmannin inhibited cAMP-mediated translocation of Ntcp to the plasma membrane. cAMP stimulated protein kinase B (PKB) activity by twofold within 5 min, an effect inhibited by wortmannin. Neither basal mitogen-activated protein kinase (MAPK) activity nor cAMP-mediated inhibition of MAPK activity was affected by wortmannin. cAMP also stimulated p70(S6K) activity. However, rapamycin, an inhibitor of p70(S6K), failed to inhibit cAMP-mediated stimulation of TC uptake, indicating that the effect of cAMP is not mediated via p70(S6K). Cytochalasin D, an inhibitor of actin filament formation, inhibited the ability of cAMP to stimulate TC uptake and Ntcp translocation. Together, these results suggest that the stimulation of TC uptake and Ntcp translocation by cAMP may be mediated via the PI3K/PKB signaling pathway and requires intact actin filaments.

Androstadienes↗
PubMed1999

Insulin regulates expression of metabolic genes through divergent signaling pathways.

The regulation of metabolic gene expression is a major mechanism by which insulin modulates glucose homeostasis. Defective transcription factors or signal transduction molecules that are required for insulin regulated gene expression could contribute to insulin resistance. The phosphoenolpyruvate carboxykinase (PEPCK) and hexokinase II (HKII) genes are involved in metabolic processes that represent opposing facets of glucose homeostasis, namely gluconeogenesis and glucose utilization. The regulation of the PEPCK and HKII genes by insulin has been studied in great detail at the level of both transcription and signal transduction. Recent work on the insulin signaling pathways that lead to down-regulation of PEPCK gene expression and upregulation of HKII gene expression has shown that they both require activation of phosphatidylinositol 3-kinase (PI3K) for the transmission of the insulin signal. However, the pathways diverge after PI3K and lead to activation of different downstream effectors. In this paper we review the results of studies on the transcriptional regulation of these genes by insulin and the signal transduction pathways that mediate these responses.

Animals↗
PubMed1997

TGF-beta1 selectively suppresses PDGF receptor signaling pathways in MG-63 human osteosarcoma cell.

We previously found that TGF-beta1 inhibits PDGF mitogenicity in MG-63 cells and the inhibition is correlated with a suppression of the PDGF-induced receptor autophosphorylation. In this study, we analyze if all the PDGF receptor signaling pathways are similarly affected by the TGF-beta1 pretreatment. We show that TGF-beta1 suppresses PDGF-stimulated tyrosine phosphorylation of PLC-gamma1, and the phosphorylation of Erk. In contrast, the tyrosine phosphorylation of PI3-kinase is not affected. Thus, TGF-beta1 selectively suppresses two out of three PDGF receptor signaling pathways despite of its prominent inhibition of the PDGF-induced receptor autophosphorylation. The results also indicate that activation of the PI3-kinase pathway alone by PDGF is not sufficient in supporting the optimum growth of MG-63 cells under the culture conditions employed.

Humans↗
PubMed2000

Perturbation of myelination by activation of distinct signaling pathways: an in vitro study in a myelinating culture derived from fetal rat brain.

An in vitro myelinating mouse-derived model system has been adapted and optimized for fetal rat brain. In these mixed brain cell (MBC) cultures, myelinogenesis was studied by examining the effect of signaling pathways that are involved in the timing of oligodendrocyte differentiation. When PMA, a protein kinase C (PKC) activator, was kept present during development, the early myelin protein, CNP, was expressed in oligodendrocytes as promptly as in control MBC cultures. In contrast, continuous activation of signaling pathways triggered by FGF-2 caused a delay in the expression of CNP. The expression of the late myelin proteins MBP and PLP in oligodendrocytes was impeded by both PMA- and FGF-2-treatment, and, as a consequence, also myelin formation. Surprisingly, the continuous presence of PDGF during development also prevented myelin formation, even though all myelin-specific proteins were significantly expressed. Taken together, the data indicate that this in vitro myelinating culture system represents an excellent system to study signaling events necessary for the onset of myelination. Moreover, the present results demonstrate that oligodendrocyte differentiation in the presence of neurons and astrocytes can be manipulated both by extracellular and intracellular signaling factors. Importantly, differentiation per se is not necessarily culminating into myelination.

Animals↗
PubMed2001

Bone morphogenetic protein-2 promotes osteoblast apoptosis through a Smad-independent, protein kinase C-dependent signaling pathway.

Bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-beta (TGF-beta) family, regulates osteoblast differentiation and bone formation. Here we show a novel function of BMP-2 in human osteoblasts and identify a signaling pathway involved in this function. BMP-2 promotes apoptosis in primary human calvaria osteoblasts and in immortalized human neonatal calvaria osteoblasts, as shown by terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. In contrast, TGF-beta 2 inhibits apoptosis in human osteoblasts. Studies of the mechanisms of action showed that BMP-2 increases the Bax/Bcl-2 ratio, whereas TG beta-2 has a negative effect. Moreover, BMP-2 increases the release of mitochondrial cytochrome c to the cytosol. Consistent with these results, BMP-2 increases caspase-9 and caspase-3, -6, and -7 activity, and an anti-caspase-9 agent suppresses BMP-2-induced apoptosis. Overexpression of dominant-negative Smad1 effectively blocks BMP-2-induced expression of the osteoblast transcription factor Runx2 but not the activation of caspases or apoptosis induced by BMP-2, indicating that the Smad1 signaling pathway is not involved in the BMP-2-induced apoptosis. The proapoptotic effect of BMP-2 is PKC-dependent, because BMP-2 increases PKC activity, and the selective PKC inhibitor calphostin C blocks the BMP-2-induced increased Bax/Bcl-2, caspase activity, and apoptosis. In contrast, the cAMP-dependent protein kinase A inhibitor H89, the p38 MAPK inhibitor SB203580, and the MEK inhibitor PD-98059 have no effect. The results show that BMP-2 uses a Smad-independent, PKC-dependent pathway to promote apoptosis via a Bax/Bcl-2 and cytochrome c-caspase-9-caspase-3, -6, -7 cascade in human osteoblasts.

Apoptosis↗
PubMed1997

Two intracellular signaling pathways for activation of protein kinase C are involved in oxidized low-density lipoprotein-induced macrophage growth.

Recent studies demonstrated that oxidized LDL (Ox-LDL) induces macrophage growth in vitro. The present study was undertaken to elucidate the intracellular signaling pathways for macrophage growth. Ox-LDL initiated a rapid and transient rise in intracellular free calcium ion and induced activation of membrane protein kinase C (PKC). Pertussis toxin completely inhibited the Ox-LDL-induced rise in free calcium ion and significantly inhibited macrophage growth by 50%. Moreover, PKC inhibitors calphostin C and H-7 significantly inhibited Ox-LDL-induced macrophage growth by 80%. On the other hand, phospholipase A2-treated acetylated LDL did not induce a rise in calcium but significantly activated PKC and led to significant macrophage growth that was significantly inhibited by calphostin C by 90%. These results suggest the presence of two intracellular signaling pathways for activation of PKC, a rise in calcium that was mediated by pertussis toxin-sensitive G protein and the internalization of lysophosphatidylcholine through the scavenger receptors. These two pathways may play an important role in Ox-LDL-induced macrophage growth.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2001

Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway.

To understand how the Wnt coreceptor LRP-5 is involved in transducing the canonical Wnt signals, we identified Axin as a protein that interacts with the intracellular domain of LRP-5. LRP-5, when expressed in fibroblast cells, showed no effect on the canonical Wnt signaling pathway by itself, but acted synergistically with Wnt. In contrast, LRP-5 mutants lacking the extracellular domain functioned as constitutively active forms that bind Axin and that induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin. Addition of Wnt caused the translocation of Axin to the membrane and enhanced the interaction between Axin and LRP-5. In addition, the LRP-5 sequences involved in interactions with Axin are required for LEF-1 activation. Thus, we conclude that the binding of Axin to LRP-5 is an important part of the Wnt signal transduction pathway.

3T3 Cells↗
PubMed2006

Stat1 expression is not sufficient to regulate the interferon signaling pathway in cellular immortalization.

DNA hypermethylation in gene promoters is an epigenetic mechanism regulating gene expression in cellular immortalization, an important step in carcinogenesis. Previously, we studied the genes dysregulated during immortalization using spontaneously immortalized fibroblasts from patients with Li-Fraumeni syndrome (LFS), who carry a germline mutation in the tumor suppressor gene p53. We found that multiple interferon (IFN) signaling pathway genes were regulated by epigenetic silencing. In this study we focused on a key regulator of that pathway, the signal transducer and transcription activator 1 (Stat1) gene. Although Stat1 is downregulated after cellular immortalization and upregulated in immortal MDAH041 cells after 5-aza-2'-deoxycytidine (5-aza-dC) treatment, we detected no methylation of the Stat1 promoter region in these cells before or after immortalization. To analyze the function of Stat1 in immortalization, we expressed Stat1 in immortal MDAH041 cells by stable infection, expecting to induce IFN-regulated genes or cellular senescence or both. However, the overexpression of Stat1 alone was not sufficient to repress the proliferation rate of immortal MDAH041 cells or induce senescence in immortal MDAH041 cells. We concluded that factor(s) additional to Stat1 (whether IFN dependent or not) are required for the immortalization of LFS fibroblasts.

Animals↗
PubMed2001

Regulation of Cyr61 gene expression by mechanical stretch through multiple signaling pathways.

The cysteine-rich protein 61 (Cyr61) is a signaling molecule with functions in cell migration, adhesion, and proliferation. This protein is encoded by an immediate early gene whose expression is mainly induced by serum growth factors. Here we show that Cyr61 mRNA levels increase sharply in response to cyclic mechanical stretch applied to cultured bladder smooth muscle cells. Stretch-induced changes of Cyr61 transcripts were transient and accompanied by an increase of the encoded protein that localized mainly to the cytoplasm and nucleus of the cells. With the use of pharmacological agents that interfere with known signaling pathways, we show that transduction mechanisms involving protein kinase C and phosphatidylinositol 3-kinase activation partly blocked stretch-induced Cyr61 gene expression. Selective inhibition of Rho kinase pathways altered this stretch effect as well. Meanwhile, using inhibitors of the actin cytoskeleton, we show that Cyr61 gene expression is sensitive to mechanisms that sense actin dynamics. These results establish the regulation of Cyr61 gene by mechanical stretch and provide clues to the key signaling molecules involved in this process.

Animals↗
PubMed1999

Corticotropin-releasing factor and vasoactive intestinal polypeptide activate gene transcription through the cAMP signaling pathway in a catecholaminergic immortalized neuron.

Corticotropin-releasing factor (CRF) and vasoactive intestinal polypeptide (VIP) are neuropeptides displaying a variety of short-term effects in the nervous system. It is shown here in transfection experiments of an immortalized noradrenergic locus coeruleus-like cell line that both CRF and VIP also trigger a signaling cascade capable of activating gene transcription. To elucidate the signaling pathway leading to transcriptional induction, cells were transfected with an inhibitor for cAMP-dependent protein kinase, targeted to the nucleus via a nuclear-localization signal. Transcriptional induction of a reporter gene by CRF and VIP was blocked in these cells, indicating that the cAMP-dependent protein kinase is required for transducing CRF and VIP generated signals into the nucleus. Additionally, transfection experiments with a reporter gene containing cAMP response elements in its regulatory region demonstrate that CRF and VIP receptor activation induce transcription through this genetic regulatory element. We conclude that long-term effects of CRF and VIP in neurons are likely to be mediated by the transcriptional regulation of CRF and VIP-responsive genes via the cAMP signaling pathway.

Animals↗