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PubMedDate not supplied

The influence of Ras pathway signaling on tumor radiosensitivity.

Radiotherapy is used to treat approximately 60% of solid tumors in the US. The relative radiosensitivity of these tumors can have a significant impact upon local control. One factor that has been shown to contribute to the increased survival of tumor cells is the activation of signaling pathways in which oncogene products play a central role. The Ras oncoprotein family, comprised of H-, K-, and N-Ras are frequently activated by mutation in certain tumors such as pancreatic and non-small cell lung cancers and are activated by receptor tyrosine kinase activity in an even wider range of tumor types. The role of ras mutation and more recently Ras signaling has been an area of intense study in both radiobiology and tumor biology in general. In this review, we focus on findings from our lab and others that led to the current hypotheses relating to the role of Ras signaling in tumor radiation survival and the strategies used to block Ras activation. We will also point out new means of studying the contribution of Ras and Ras pathway components that could contribute to defining new targets for inhibition in the context of radiation therapy.

Animals↗

PubMed2005

Stress-activated protein kinase signaling pathways in dry eye and ocular surface disease.

Inflammation is recognized as a key component in the pathogenesis of dry eye and a variety of ocular surface diseases. Stress-activated protein kinases have been identified as pathways signaling ocular surface stresses, such as increased tear film osmolarity and ultraviolet light exposure. Activation of these stress pathways results in transcription of stress related genes, including inflammatory cytokines (e.g. interleukin-1 and tumor necrosis factor (TNF)-alpha and matrix metalloproteinases (MMPs), such as MMP-9. Treatment of osmo-stressed cultured corneal epithelia with inhibitors of the stress associated kinase c-jun N-terminal kinases was found to decrease production of MMPs by these cells. These findings suggest that SAPKs may be key therapeutic targets for dry eye and ocular surface diseases.

Journal Article↗

PubMed2006

ATM and ATR pathways signal alternative splicing of Drosophila TAF1 pre-mRNA in response to DNA damage.

Alternative pre-mRNA splicing is a major mechanism utilized by eukaryotic organisms to expand their protein-coding capacity. To examine the role of cell signaling in regulating alternative splicing, we analyzed the splicing of the Drosophila melanogaster TAF1 pre-mRNA. TAF1 encodes a subunit of TFIID, which is broadly required for RNA polymerase II transcription. We demonstrate that TAF1 alternative splicing generates four mRNAs, TAF1-1, TAF1-2, TAF1-3, and TAF1-4, of which TAF1-2 and TAF1-4 encode proteins that directly bind DNA through AT hooks. TAF1 alternative splicing was regulated in a tissue-specific manner and in response to DNA damage induced by ionizing radiation or camptothecin. Pharmacological inhibitors and RNA interference were used to demonstrate that ionizing-radiation-induced upregulation of TAF1-3 and TAF1-4 splicing in S2 cells was mediated by the ATM (ataxia-telangiectasia mutated) DNA damage response kinase and checkpoint kinase 2 (CHK2), a known ATM substrate. Similarly, camptothecin-induced upregulation of TAF1-3 and TAF1-4 splicing was mediated by ATR (ATM-RAD3 related) and CHK1. These findings suggest that inducible TAF1 alternative splicing is a mechanism to regulate transcription in response to developmental or DNA damage signals and provide the first evidence that the ATM/CHK2 and ATR/CHK1 signaling pathways control gene expression by regulating alternative splicing.

Alternative Splicing↗

PubMed1999

The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism.

Stabilization of mRNAs contributes to the strong and rapid induction of genes in the inflammatory response. The signaling mechanisms involved were investigated using a tetracycline-controlled expression system to determine the half-lives of interleukin (IL)-6 and IL-8 mRNAs. Transcript stability was low in untreated HeLa cells, but increased in cells expressing a constitutively active form of the MAP kinase kinase kinase MEKK1. Destabilization and signal-induced stabilization was transferred to the stable beta-globin mRNA by a 161-nucleotide fragment of IL-8 mRNA which contains an AU-rich region, as well as by defined AU-rich elements (AREs) of the c-fos and GM-CSF mRNAs. Of the different MEKK1-activated signaling pathways, no significant effects on mRNA degradation were observed for the SAPK/JNK, extracellular regulated kinase and NF-kappaB pathways. Selective activation of the p38 MAP kinase (=SAPK2) pathway by MAP kinase kinase 6 induced mRNA stabilization. A dominant-negative mutant of p38 MAP kinase interfered with MEKK1 and also IL-1-induced stabilization. Furthermore, an active form of the p38 MAP kinase-activated protein kinase (MAPKAP K2 or MK2) induced mRNA stabilization, whereas a negative interfering MK2 mutant interfered with MAP kinase kinase 6-induced stabilization. These findings indicate that the p38 MAP kinase pathway contributes to cytokine/stress-induced gene expression by stabilizing mRNAs through an MK2-dependent, ARE-targeted mechanism.

3' Untranslated Regions↗

PubMed1999

Roles of Axin in the Wnt signalling pathway.

The Wnt signalling pathway is conserved in various species from worms to mammals, and plays important roles in development, cellular proliferation, and differentiation. The molecular mechanisms by which the Wnt signal regulates cellular functions are becoming increasingly well understood. Wnt stabilizes cytoplasmic beta-catenin, which stimulates the expression of genes including c-myc, c-jun, fra-1, and cyclin D1. Axin, newly recognized as a component of the Wnt signalling pathway, negatively regulates this pathway. Other components of the Wnt signalling pathway, including Dvl, glycogen synthase kinase-3beta, beta-catenin, and adenomatous polyposis coli, interact with Axin, and the phosphorylation and stability of beta-catenin are regulated in the Axin complex. Thus, Axin acts as a scaffold protein in the Wnt signalling pathway, thereby regulating cellular functions.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Functional roles of sphingosine, sphingosine 1-phosphate, and methylsphingosines: in regard to membrane sphingolipid signaling pathways.

The signaling roles of ceramide and sphingosine produced through the degrading processes of membrane sphingolipids are currently receiving hot attention in the biochemical and biomedical research fields. For these 9 years at the Biomembrane Institute in Seattle, we have studied functional roles of various sphingolipids such as ceramide, sphingosine, methylsphingosines, and sphingosine 1-phosphate in a variety of biomedical systems. In this article, first, the recent conceptual developments on sphingolipid signaling pathways is outlined. Next, our recent findings on the functional roles of sphingolipids are described focusing on (i) functional roles of sphingosine 1-phosphate in cell motility regulation and platelet activation (ii) involvement of sphingosine in cell signaling (iii) effects of methylsphingosines in cancer cell apoptosis induction and in the regulation of inflammatory processes. Based upon these findings from our studies and others, the perspective of future sphingosine research (sphingology or sphingophysiology) is briefly discussed.

Animals↗

PubMed2003

HES and HERP families: multiple effectors of the Notch signaling pathway.

Notch signaling dictates cell fate and critically influences cell proliferation, differentiation, and apoptosis in metazoans. Multiple factors at each step-ligands, receptors, signal transducers and effectors-play critical roles in executing the pleiotropic effects of Notch signaling. Ligand-binding results in proteolytic cleavage of Notch receptors to release the signal-transducing Notch intracellular domain (NICD). NICD migrates into the nucleus and associates with the nuclear proteins of the RBP-Jkappa family (also known as CSL or CBF1/Su(H)/Lag-1). RBP-Jkappa, when complexed with NICD, acts as a transcriptional activator, and the RBP-Jkappa-NICD complex activates expression of primary target genes of Notch signaling such as the HES and enhancer of split [E(spl)] families. HES/E(spl) is a basic helix-loop-helix (bHLH) type of transcriptional repressor, and suppresses expression of downstream target genes such as tissue-specific transcriptional activators. Thus, HES/E(spl) directly affects cell fate decisions as a primary Notch effector. HES/E(spl) had been the only known effector of Notch signaling until a recent discovery of a related but distinct bHLH protein family, termed HERP (HES-related repressor protein, also called Hey/Hesr/HRT/CHF/gridlock). In this review, we summarize the recent data supporting the idea of HERP being a new Notch effector, and provide an overview of the similarities and differences between HES and HERP in their biochemical properties as well as their tissue distribution. One key observation derived from identification of HERP is that HES and HERP form a heterodimer and cooperate for transcriptional repression. The identification of the HERP family as a Notch effector that cooperates with HES/E(spl) family has opened a new avenue to our understanding of the Notch signaling pathway.

Animals↗

PubMed2003

Temporal computation by synaptic signaling pathways.

Synaptic signaling comprises a complex molecular network. Such networks carry out diverse operations such as molecular logic, signal amplification, memory and other aspects of cellular decision-making. The synapse in particular encounters complex input patterns that have different temporal sequences. Different input patterns to the synapse are known to give rise to a range of synaptic responses, including facilitation, depression and various forms of short and long-term potentiation. In many cases the stimuli that generate these disparate responses are tens of seconds or more in length, much greater than the typical time-courses of calcium dynamics. In this paper I propose that the synaptic signaling network can perform temporal computation operations such as tuning for stimulus duration or interval. Using simulation methods I show that the simple time-courses of individual signaling pathways combine in the network to give rise to different temporally selective responses. Downstream pathways that exhibit temporal integration or amplitude thresholding select different input patterns and thus perform temporal computation.

Algorithms↗

PubMed2006

A FRET analysis to unravel the role of cholesterol in Rac1 and PI 3-kinase activation in the InlB/Met signalling pathway.

The signalling pathway for the hepatocyte growth factor receptor, Met/HGF-R, is hijacked by the bacterial surface protein InlB to induce Listeria monocytogenes entry into non-phagocytic cells. We previously showed that Listeria invades host cells by interacting with specialized microdomains of the host plasma membrane called lipid rafts. In this study, we analysed in living cells signalling events that are crucial for Listeria entry using a fluorescence resonance energy transfer-based microscopic method. Phosphoinositide (PI) 3-kinase activity and Rac1 signalling induced by Listeria interacting with epithelial cells were monitored as well as signalling induced by soluble InlB and the Met natural ligand HGF. We found that InlB and HGF induced similar kinetics of PI 3-kinase and Rac1 activation. PI 3-kinase activation was upstream and independent of Rac1 activation. Cholesterol-depletion experiments were performed to address the role of lipid rafts in Met signalling. The amount of 3'-phosphoinositides produced by PI 3-kinase was not affected by cholesterol depletion, while their membrane dynamic was cholesterol-dependent. Rac1 activation, downstream from PI 3-kinase, was cholesterol-dependent suggesting that the spatial distribution of 3'-phosphoinositides within membrane microdomains is critical for Rac1 activation and consequently for F-actin assembly at bacterial entry site.

Animals↗

PubMed2006

Hedgehog signaling pathway and gastrointestinal stem cell signaling network (review).

Hedgehog, BMP/TGFbeta, FGF, WNT and Notch signaling pathways constitute the stem cell signaling network, which plays a key role in a variety of processes, such as embryogenesis, maintenance of adult tissue homeostasis, tissue repair during chronic persistent inflammation, and carcinogenesis. Sonic hedgehog (SHH), Indian hedgehog (IHH) and Desert hedgehog (DHH) bind to PTCH1/PTCH or PTCH2 receptor to release Smoothened (SMO) signal transducer from Patched-dependent suppression. SMO then activates STK36 serine/threonine kinase to stabilize GLI family members and to phosphorylate SUFU for nuclear accumulation of GLI. Hedgehog signaling activation leads to GLI-dependent transcriptional activation of target genes, such as GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1. GLI1-dependent positive feedback loop combined with PTCH1-dependent negative feedback loop gives rise to transient proliferation of Hedgehog target cells. Iguana homologs (DZIP1 and DZIP1L) and Costal-2 homologs (KIF7 and KIF27) are identified by comparative integromics. SHH-dependent parietal cell proliferation is implicated in gastric mucosal repair during chronic Helicobacter pylori infection. BMP-RUNX3 signaling induces IHH expression in surface differentiated epithelial cells of stomach and intestine. Hedgehog signals from epithelial cells then induces FOXL1-mediated BMP4 upregulation in mesenchymal cells. Hedgehog signaling is frequently activated in esophageal cancer, gastric cancer and pancreatic cancer due to transcriptional upregulation of Hedgehog ligands and epigenetic silencing of HHIP1/HHIP gene, encoding the Hedgehog inhibitor. However, Hedgehog signaling is rarely activated in colorectal cancer due to negative regulation by the canonical WNT signaling pathway. Hedgehog signaling molecules or targets, such as SHH, IHH, HHIP1, PTCH1 and GLI1, are applied as biomarkers for cancer diagnostics, prognostics and therapeutics. Small-molecule inhibitors for SMO or STK36 are suitable to be used for treatment of Hedgehog-dependent cancer.

Animals↗

PubMed1999

Caveolin interacts with Trk A and p75(NTR) and regulates neurotrophin signaling pathways.

Neurotrophins signal through Trk tyrosine kinase receptors and the low-affinity neurotrophin receptor p75(NTR). We have shown previously that activation of Trk A tyrosine kinase activity can inhibit p75(NTR)-dependent sphingomyelin hydrolysis, that caveolae are a localized site for p75(NTR) signaling, and that caveolin can directly interact with p75(NTR). The ability of caveolin to also interact with tyrosine kinase receptors and inhibit their activity led us to hypothesize that caveolin expression may modulate interactions between neurotrophin signaling pathways. PC12 cells were transfected with caveolin that was expressed efficiently and targeted to the appropriate membrane domains. Upon exposure to nerve growth factor (NGF), caveolin-PC12 cells were unable to develop extensive neuritic processes. Caveolin expression in PC12 cells was found to diminish the magnitude and duration of Trk A activation in vivo. This inhibition may be due to a direct interaction of caveolin with Trk A, because Trk A co-immunoprecipitated with caveolin from Cav-Trk A-PC12 cells, and a glutathione S-transferase-caveolin fusion protein bound to Trk A and inhibited NGF-induced autophosphorylation in vitro. Furthermore, the in vivo kinetics of the inhibition of Trk A tyrosine kinase activity by caveolin expression correlated with an increased ability of NGF to induce sphingomyelin hydrolysis through p75(NTR). In summary, our results suggest that the interaction of caveolin with neurotrophin receptors may have functional consequences in regulating signaling through p75(NTR) and Trk A in neuronal and glial cell populations.

3T3 Cells↗

PubMed1996

The concept of multiple vitamin D signaling pathways.

Nuclear signaling by 1 alpha, 25-dihydroxyvitamin D3 (VD) is mediated by its nuclear receptor (VDR). It is widely accepted that VDR forms heterodimers with retinoid X receptors (RXRs) that bind in 5'-RXR-VDR-3' polarity to response elements formed by direct repeats of hexameric core binding motifs spaced by three nucleotides. This model, however, might be too simple to explain the multiplicity of nuclear signaling by VD. Recently, it was reported that VDR forms homodimers and heterodimers with the nuclear receptors for all-trans retinoic acid and thyroid hormone. All four different VDR complexes bind not only to direct repeats, but also to inverted palindromes; moreover, in heterodimeric complexes VDR can also take the 5' position. Taken together, this discriminates at least seven different types of VDR complexes binding each to two types of response elements. For half of these 14 cases, representative natural VD response elements have already been identified, which demonstrates that nature takes advantage of this concept of diversity. It is our hypothesis that the different physiological functions of VD can be related to different VD signaling pathways. Therefore, the identification of VD analogs that specifically trigger these pathways is the goal of our present and future investigations.

Animals↗

PubMed1989

Growth factors, signaling pathways, and the regulation of proliferation and differentiation in BC3H1 muscle cells. II. Two signaling pathways distinguished by pertussis toxin and a potential role for the ras oncogene.

In the preceding report (Kelvin, D.J., G. Simard, H.H. Tai, T.P. Yamaguchi, and J.A. Connolly. 1989. J. Cell Biol. 108:159-167) we demonstrated that pertussis toxin (PT) blocked proliferation and induced differentiation in BC3H1 muscle cells. In the present study, we have used PT to examine specific growth factor signaling pathways that may regulate these processes. Inhibition of [3H]thymidine by PT in 20% FBS was reversed in a dose-dependent fashion by purified fibroblast growth factor (FGF). In 0.5% FBS, the normally induced increase in creatine kinase (CK) activity was blocked by FGF in both the presence and absence of PT. Similar results were obtained with purified epidermal growth factor (EGF). We subsequently examined the effect of a family of growth factors linked to inositol lipid hydrolysis and found that thrombin, like FGF, would increase [3H]thymidine incorporation and block CK synthesis. However, PT blocked thymidine incorporation induced by thrombin, and blocked the inhibition of CK turn-on in 0.5% FBS by thrombin. The ras oncogene, a G protein homologue, has previously been shown to block muscle cell differentiation in C2 muscle cells (Olson, E.N., G. Spizz, and M.A. Tainsky. 1987. Mol. Cell. Biol. 7:2104-2111); we have characterized a BC3H1 cell line, BCT31, which we transfected with the val12 oncogenic Harvey ras gene. This cell line did not express CK in response to serum deprivation. Whereas [3H]thymidine incorporation was inhibited by 70-80% by increasing doses of PT in control cells, BCT31 cells were only inhibited by 15-20%. ADP ribosylation studies indicate this PT-insensitivity is not because of the lack of a PT substrate in this cell line. Furthermore, PT could not induce CK expression in BCT31 cells as it did in parental cells. We conclude that there are at least two distinct growth factor pathways that play a key role in regulating proliferation and differentiation in BC3H1 muscle cells, one of which is PT sensitive, and postulate that a G protein is involved in transducing signals from the thrombin receptor. We believe that ras functions in the transduction of growth factor signals in the nonPT-sensitive pathway or downstream from the PT substrate in the second pathway.

Animals↗

PubMed2003

Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways.

Notch receptor signaling regulates cell growth and differentiation, and core components of Notch signaling pathways are conserved from Drosophila to humans. Fringe glycosyltransferases are crucial modulators of Notch signaling that act on epidermal growth factor (EGF)-like repeats in the Notch receptor extracellular domain. The substrate of Fringe is EGF-O-fucose and the transfer of fucose to Notch by protein O-fucosyltransferase 1 is necessary for Fringe to function. O-fucose also occurs on Cripto and on Notch ligands. Here we show that mouse embryos lacking protein O-fucosyltransferase 1 die at midgestation with severe defects in somitogenesis, vasculogenesis, cardiogenesis, and neurogenesis. The phenotype is similar to that of embryos lacking downstream effectors of all Notch signaling pathways such as presenilins or RBP-J kappa, and is different from Cripto, Notch receptor, Notch ligand, or Fringe null phenotypes. Protein O-fucosyltransferase 1 is therefore an essential core member of Notch signaling pathways in mammals.

Animals↗

PubMed1993

Activation of MCP-1 gene expression is mediated through multiple signaling pathways.

Multiple signal transduction pathways including protein kinase C, tyrosine phosphorylation, and an independent third signaling mechanism are involved in the activation of monocyte chemotactic protein-1 gene. Northern blot analysis showed that the incubation of endothelial cell with dioctanoylglycerol induced maximum level of monocyte chemotactic protein-1 transcripts. The TPA-induced monocyte chemotactic protein-1 expression was abolished by treating the cells with both staurosporine and genistein; however, only a portion of the LPS-induced expression was inhibited by staurosporine/genistein. This is in accordance with the observation that LPS induced the expression of monocyte chemotactic protein-1 in desensitized cells. Thus, a third signal transduction pathway other than protein kinase C or tyrosine kinase is involved in the LPS-induced monocyte chemotactic protein-1 expression in human endothelial cell.

Cells, Cultured↗

PubMed2002

Resistance of cultivated tomato to cell content-feeding herbivores is regulated by the octadecanoid-signaling pathway.

The octadecanoid signaling pathway has been shown to play an important role in plant defense against various chewing insects and some pathogenic fungi. Here, we examined the interaction of a cell-content feeding arachnid herbivore, the two-spotted spider mite (Tetranychus urticae Koch), with cultivated tomato (Lycopersicon esculentum) and an isogenic mutant line (defenseless-1 [def-1]) that is deficient in the biosynthesis of the octadecanoid pathway-derived signal, jasmonic acid (JA). Spider mite feeding and fecundity on def-1 plants was significantly greater than on wild-type plants. Decreased resistance of def-1 plants was correlated with reduced JA accumulation and expression of defensive proteinase inhibitor (PI) genes, which were induced in mite-damaged wild-type leaves. Treatment of def-1 plants with methyl-JA restored resistance to spider mite feeding and reduced the fecundity of female mites. Plants expressing a 35S::prosystemin transgene that constitutively activates the octadecanoid pathway in a Def-1-dependent manner were highly resistant to attack by spider mites and western flower thrips (Frankliniella occidentalis), another cell-content feeder of economic importance. These findings indicate that activation of the octadecanoid signaling pathway promotes resistance of tomato to a broad spectrum of herbivores. The techniques of amplified fragment length polymorphism (AFLP) and bulk segregant analysis were used to map the Def-1 gene to a region on the long arm of chromosome 3 that is genetically separable from the map position of known JA biosynthetic genes. Tight linkage of Def-1 to a T-DNA insertion harboring the maize (Zea mays) Dissociation transposable element suggests a strategy for directed transposon tagging of the gene.

Acetates↗

PubMed2002

Mechanisms for temporal tuning and filtering by postsynaptic signaling pathways.

Networks of signaling pathways perform complex temporal decoding functions in diverse biological systems, including the synapse, development, and bacterial chemotaxis. This paper examines temporal filtering and tuning properties of synaptic signaling pathways as a possible substrate for emergent temporal decoding. A mass action kinetic model of 16 synaptic signaling pathways was used to dissect out the contribution of these pathways in linear cascades and when coupled to form a network. The model predicts two primary mechanisms of temporal tuning of pathways: a weighted summation of responses of pathways with different timings and the presence of biochemical feedback loop(s) with emergent dynamics. Regulatory inputs act differently on these two tuning mechanisms. In the first case, regulators act like a gain-control on pathways with different intrinsic tuning. In the case of feedback loops, the temporal properties of the loop itself are changed. These basic tuning mechanisms may underlie specialized temporal tuning functions in more complex signaling systems in biology.

Animals↗

PubMed2003

The Drosophila IgC2 domain protein Friend-of-Echinoid, a paralogue of Echinoid, limits the number of sensory organ precursors in the wing disc and interacts with the Notch signaling pathway.

The Notch signaling pathway is critical in cell fate specification throughout development. In the developing wing disc, single sensory organ precursors (SOPs) are selected from proneural clusters via a process of lateral inhibition mediated by the Notch signaling pathway. The epidermal growth factor receptor (EGFR) pathway has also been implicated in SOP formation. Here, we describe the Drosophila melanogaster gene friend of echinoid (fred), a paralogue of echinoid (ed), a gene recently identified as a negative regulator of the EGFR pathway. fred function was examined in transgenic flies by using inducible RNA interference (RNAi). Suppression of fred in developing wing discs results in specification of ectopic SOPs, additional microchaeta, and cell death. In eye-antennal discs, fred suppression causes a rough eye phenotype. These phenotypes are suppressed by overexpression of Notch, Suppressor of Hairless [Su(H)], and Enhancer of split m7. In contrast, overexpression of Hairless, a negative regulator of the Notch pathway, and decreased Su(H) activity enhance these phenotypes. Thus, fred acts in close concert with the Notch signaling pathway. Dosage-sensitive genetic interaction also suggests a close relationship between fred and ed.

Amino Acid Sequence↗