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PubMed2004

Temporal control of differentiation by the insulin receptor/tor pathway in Drosophila.

Multicellular organisms must integrate growth and differentiation precisely to pattern complex tissues. Despite great progress in understanding how different cell fates are induced, it is poorly understood how differentiation decisions are temporally regulated. In a screen for patterning mutants, we isolated alleles of tsc1, a component of the insulin receptor (InR) growth control pathway. We find that loss of tsc1 disrupts patterning due to a loss of temporal control of differentiation. tsc1 controls the timing of differentiation downstream or in parallel to the RAS/MAPK pathway. Examination of InR, PI3K, PTEN, Tor, Rheb, and S6 kinase mutants demonstrates that increased InR signaling leads to precocious differentiation while decreased signaling leads to delays in differentiation. Importantly, cell fates are unchanged, but tissue organization is lost upon loss of developmental timing controls. These data suggest that intricate developmental decisions are coordinated with nutritional status and tissue growth by the InR signaling pathway.

Animals↗
PubMed2003

Gene expression profiling and functional proteomic analysis reveal perturbed kinase-mediated signaling in genetic stroke susceptibility.

The stroke-prone spontaneously hypertensive rat (SHRSP) is a model of heritable hypertension-associated cerebrovascular injury. This study sought to compare SHRSP to the stroke-resistant SHR strain to identify genes and protein pathways whose expression and/or function was significantly altered between the strains prior to the onset of stroke. Cerebral cortex gene expression profiles from male SHRSPs and matched SHRs were examined by Affymetrix microarray analysis. mRNAs encoding the brain-derived neurotrophic factor receptor (TrkB) and multiple kinases of the MAPK/AKT signaling pathways, including JNK2, AKT2, and PI3K, were differentially expressed between SHRSP and SHR. Because these data suggest altered function in pathways involving MAP and AKT kinase activity, we performed Western blot using phosphorylation state-specific antibodies to characterize activity of MAP kinase and PI3K/AKT pathways. Changes in the levels of the phosphorylated forms of these kinases paralleled the changes in transcript levels observed between the strains. Two-dimensional gel electrophoresis and peptide fragment mass fingerprinting were used to identify altered protein substrates of these kinases. Protein profiling of kinase substrates further supported the notion of perturbed kinase-mediated signaling in SHRSP and identified adenylyl cyclase associated protein 2, TOAD-64, propionyl CoA carboxylase, APG-1, and valosin-containing protein as kinase targets whose phosphorylation state is altered between these strains. Altered gene and protein expression patterns in SHRSP are consistent with increased vulnerability of this strain to cerebrovascular injury.

Animals↗
PubMed2004

In situ Akt phosphorylation in the nucleus tractus solitarii is involved in central control of blood pressure and heart rate.

BACKGROUND: Previously, we have shown that nitric oxide (NO) plays a significant role in central cardiovascular regulation and modulates the baroreflex in the nucleus tractus solitarii (NTS) of rats. NO production is mediated by activation of NO synthase (NOS). Insulin signaling was involved in controlling peripheral blood pressure via the activation of endothelial NOS. Here, we investigated whether the insulin signal transduction pathway is involved in controlling central cardiovascular effects. METHODS AND RESULTS: Insulin was injected into NTS of urethane-anesthetized male Wistar-Kyoto (WKY) rats. Unilateral microinjection (60 nL) of insulin (100 IU/mL) into the NTS produced prominent depressor and bradycardic effects in 8- and 16-week-old WKY rats. In addition, pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the NOS inhibitor L-NAME into the NTS caused attenuation of the cardiovascular response evoked by insulin in either 8- or 16-week-old WKY rats. Western blot analysis showed a significant increase (2.6+/-0.4-fold; P<0.05) in Akt phosphorylation after insulin injection, whereas LY294002 abolished the insulin-induced effects. In situ Akt phosphorylation was found in NTS by immunohistochemistry analysis after injection of insulin. This in situ Akt phosphorylation was abolished significantly after injection of LY294002. CONCLUSIONS: Take together, these results suggest that the insulin-PI3K-Akt-NOS signaling pathway may play a significant role in central cardiovascular regulation.

Animals↗
PubMed2001

Modulation of the Ras/MAPK signalling pathway by the redox function of selenoproteins in Drosophila melanogaster.

Modulation of reactive oxygen species (ROS) plays a key role in signal transduction pathways. Selenoproteins act controlling the redox balance of the cell. We have studied how the alteration of the redox balance caused by patufet (selD(ptuf)), a null mutation in the Drosophila melanogaster selenophosphate synthetase 1 (sps1) gene, which codes for the SelD enzyme of the selenoprotein biosynthesis, affects the Ras/MAPK signalling pathway. The selD(ptuf) mutation dominantly suppresses the phenotypes in the eye and the wing caused by hyperactivation of the Ras/MAPK cassette and the activated forms of the Drosophila EGF receptor (DER) and Sevenless (Sev) receptor tyrosine kinases (RTKs), which signal in the eye and wing, respectively. No dominant interaction is observed with sensitized conditions in the Wnt, Notch, Insulin-Pi3K, and DPP signalling pathways. Our current hypothesis is that selenoproteins selectively modulate the Ras/MAPK signalling pathway through their antioxidant function. This is further supported by the fact that a selenoprotein-independent increase in ROS caused by the catalase amorphic Cat(n1) allele also reduces Ras/MAPK signalling. Here, we present the first evidence for the role of intracellular redox environment in signalling pathways in Drosophila as a whole organism.

Alleles↗
PubMed2025

Multi-context modeling of driver pathways reveals common and specific mechanisms across 23 cancer types.

Discovery of cancer driver pathways is essential for targeted therapies, since these pathways govern tumor progression and treatment resistance. However, their context-specific patterns across populations remain poorly understood. Leveraging pan-cancer genomic data, we apply our two models, EntCDP and ModSDP, to perform stratified analyses from four perspectives: region, tumor type, age group, and risk factors. Our results reveal the regional biases in perturbed pathways, such as PI3K-Akt in Chinese patients and GPCR in American patients with bladder cancer. Subtype comparisons highlight the mTOR signaling in lung adenocarcinoma and the FoxO signaling in lung squamous cell carcinoma. Pediatric-adult comparisons emphasize the enrichment of Ras signaling in pediatric acute myeloid leukemia and PAK signaling in pediatric glioblastoma, respectively. Risk factor associations further link Notch-mediated pathways to alcohol consumption and CDKN-regulated pathways to obesity-related cancers. Our findings demonstrate the utility of stratified driver pathway analysis in uncovering common and specific mechanisms, which can help prioritize context-aware therapeutic targets.

Humans↗
PubMed2007

The role of PI3Ks in the regulation of the neutrophil NADPH oxidase.

The NADPH oxidase complex of neutrophils and macrophages is an important weapon used by these cells to kill microbial pathogens. The regulation of this enzyme complex is necessarily complicated by the diverse receptor types that are needed to trigger its activation and also the tight control that is required to deliver this activation at the appropriate time and place. As such, several signalling pathways have been established to regulate the NADPH oxidase downstream of cell surface receptors. Central amongst these are PI3K- (phosphoinositide 3-kinase)-dependent pathways, blockade of which severely limits activation of the oxidase to several soluble and particulate stimuli. The precise roles of the phosphoinositide products of PI3K activity in regulating NADPH oxidase assembly and activation are still unclear, but there is emerging evidence that they play a key role via regulation of guanine nucleotide exchange on Rac, a key component in the oxidase complex. There is also very strong evidence that the PI3K products PtdIns(3,4)P2 and PtdIns3P can bind directly to the PX (Phox homology) domains of the core oxidase components p47phox and p40phox respectively. However, the significance of these interactions in terms of membrane localization or allosteric consequences for the oxidase complex remains to be established.

Animals↗
PubMed2006

Two signaling pathways regulate the expression and secretion of a neuropeptide required for long-term facilitation in Aplysia.

Activation of several signaling pathways contributes to long-term synaptic plasticity, but how brief stimuli produce coordinated activation of these pathways is not understood. In Aplysia, the long-term facilitation (LTF) of sensory neuron synapses by 5-hydroxytryptamine (serotonin; 5-HT) requires the activation of several kinases, including mitogen-activated protein kinase (MAPK). The 5-HT-enhanced secretion of the sensory neuron-specific neuropeptide sensorin mediates the activation of MAPK. We find that stimulus-induced activation of two signaling pathways, phosphoinositide 3-kinase (PI3K) and type II protein kinase A (PKA), regulate sensorin secretion and responses. Treatment with 5-HT produces a rapid increase in sensorin synthesis, especially at varicosities, which precedes the secretion of sensorin. PI3K inhibitor and rapamycin block LTF and the rapid synthesis of sensorin at varicosities even in the absence of sensory neuron cell bodies. Secretion of the newly synthesized sensorin from the varicosities and activation of the autocrine responses of sensorin to produce LTF require type II PKA interaction with AKAPs (A-kinase anchoring proteins). Thus, long-term synaptic plasticity is produced when multiple signaling pathways that are important for regulating distinct cellular functions are activated in a specific sequence and recruit the secretion of a neuropeptide to activate additional critical pathways.

Animals↗
PubMed2005

Hyperglycemia alters PI3k and Akt signaling and leads to endothelial cell proliferative dysfunction.

Diabetes mellitus is a major risk factor for the development of vascular complications. We hypothesized that hyperglycemia decreases endothelial cell (EC) proliferation and survival via phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathways. We cultured human umbilical vein ECs (HUVEC) in 5, 20, or 40 mM d-glucose. Cells grown in 5, 20, and 40 mM mannitol served as a control for osmotic effects. We measured EC proliferation for up to 15 days. We assessed apoptosis by annexin V and propidium iodide staining and flow cytometry, analyzed cell lysates obtained on culture day 8 for total and phosphorylated PI3k and Akt by Western blot analysis, and measured Akt kinase activity using a GSK fusion protein. HUVEC proliferation was also tested in the presence of pharmacological inhibitors of PI3k-Akt (wortmannin and LY294002) and after transfection with a constitutively active Akt mutant. ECs in media containing 5 mM d-glucose (control) exhibited log-phase growth on days 7-10. d-Glucose at 20 and 40 mM significantly decreased proliferation versus control (P < 0.05 for both), whereas mannitol did not impair EC proliferation. Apoptosis increased significantly in HUVEC exposed to 40 mM d-glucose. d-Glucose at 40 mM significantly decreased tyrosine-phosphorylated PI3k, threonine 308-phosphorylated-Akt, and Akt activity relative to control 5 mM d-glucose. Pharmacological inhibition of PI3k-Akt resulted in a dose-dependent decrease in EC proliferation. Transfection with a constitutively active Akt mutant protected ECs by enhancing proliferation when grown in 20 and 40 mM d-glucose. We conclude that d-glucose regulates Akt signaling through threonine phosphorylation of Akt and that hyperglycemia-impaired PI3k-Akt signaling may promote EC proliferative dysfunction in diabetes.

Cell Division↗
PubMed2000

Perturbation of EGF-activated MEK1 and PKB signal pathways by TGF-beta1 correlates with perturbation of EGF-induced cyclin D1 and DNA synthesis by TGF-beta1 in C3H 10T1/2 cells.

In mouse C3H 10T1/2 cells, we previously reported that TGF-beta1 first delays and later potentiates EGF-induced DNA synthesis corresponding to an inhibition of EGF-induced cyclin D1 expression at t = 13 h. We report here that in accord with DNA synthesis kinetics, TGF-beta1 initially suppresses EGF-induced cyclin D1 expression then later releases the inhibition. Furthermore, TGF-beta1 also first decreases and later potentiates the levels of EGF-activated MEK1/MAPK and PKB, indicating the existence of cross talk between TGF-beta 1- and EGF-activated signal transduction pathways. PD98059, the specific inhibitor of MEK1, significantly blocks EGF-induced DNA synthesis, whereas wortmannin, the PI3K inhibitor, exerts a modest inhibitory effect, which suggests that the activation of MEK1-MAPK pathway plays a major role in EGF-induced DNA synthesis and the activation of PI3K-PKB pathway plays a minor role. Upon examination of mechanisms underlying the cross talk, it was discovered that application of TGF-beta1 triggers a rapid association between Raf-1 and catalytic subunits of PKA, which are reported to be able to inactivate Raf-1 upon activation. Therefore, TGF-beta1 may activate PKA to inhibit the EGF-activated MEK1-MAPK pathway. The wortmannin-sensitive phosphorylation at the thr(389) site is necessary for activation of p70s6K, an important kinase involved in mitogen-stimulated protein synthesis. Although we found that EGF-stimulated p70s6K phosphorylates through a MAPK-dependent and a MAPK-independent (wortmannin-sensitive) pathway, TGF-beta1 failed to block EGF-triggered phosphorylation of p70s6K at thr(389) and thr(421)/ser(424) sites, implying that PKB inhibition by TGF-beta1 may result from inhibition of PDK1 activity instead of inhibition of PI3K activity. These data also suggest that TGF-beta1 may selectively perturb certain EGF-activated MAPK pools.

Animals↗
PubMed2002

Role of cAMP, PKA and Rap1A in thyroid follicular cell survival.

Cyclic AMP (cAMP) rescues cells from apoptosis stimulated by diverse insults. We examined the role of cAMP as a survival factor, and the signaling pathways through which cAMP affords protection. Rat thyroid cells were selected for these studies given the predominant role of cAMP in thyrotropin (TSH)-stimulated proliferation and as an oncogene in thyroid cells. Wistar rat thyroid (WRT) cells perished via apoptosis following sodium nitroprusside (SNP) treatment. Elevations in cAMP following treatment with forskolin, 8BrcAMP or IBMX rescued cells from SNP-induced cell death. Notably, TSH prevented apoptosis, implicating an important role for this hormone as a survival factor. Cyclic AMP activates multiple signaling pathways including those mediated through PKA, PI3K, p70S6k and the Ras-related small G protein, Rap1. Intriguingly, multiple pathways modulate thyroid cell survival. Interference with cAMP-stimulated p70S6k, but not PI3K, activity abrogated cell survival. Treatment with PKA inhibitors was sufficient to stimulate apoptosis in hormone-deprived cells and markedly enhanced cell death in response to SNP. Cells expressing an activated Rap1A mutant exhibited an enhanced sensitivity to SNP-induced apoptosis, while those expressing dominant negative Rap1A were resistant to SNP-initiated cell death. Together, these findings establish an important role for PKA and Rap1 in the control of thyroid cell survival.

Animals↗
PubMed2003

Epidermal growth factor receptor-dependent, NF-kappaB-independent activation of the phosphatidylinositol 3-kinase/Akt pathway inhibits ultraviolet irradiation-induced caspases-3, -8, and -9 in human keratinocytes.

Both phosphatidylinositol 3-kinase (PI3K)/Akt and NF-kappaB pathways function to promote cellular survival following stress. Recent evidence indicates that the anti-apoptotic activity of these two pathways may be functionally dependent. Ultraviolet (UV) irradiation causes oxidative stress, which can lead to apoptotic cell death. Human skin cells (keratinocytes) are commonly exposed to UV irradiation from the sun. We have investigated activation of the PI3K/Akt and NF-kappaB pathways and their roles in protecting human keratinocytes (KCs) from UV irradiation-induced apoptosis. This activation of PI3K preceded increased levels (3-fold) of active/phosphorylated Akt. UV (50 mJ/cm2 from UVB source) irradiation caused rapid recruitment of PI3K to the epidermal growth factor receptor (EGFR). Pretreatment of KCs with EGFR inhibitor PD169540 abolished UV-induced Akt activation/phosphorylation, as did the PI3K inhibitors LY294002 or wortmannin. This inhibition of Akt activation was associated with a 3-4-fold increase of UV-induced apoptosis, as measured by flow cytometry and DNA fragmentation ELISA. In contrast to Akt, UV irradiation did not detectably increase nuclear localization of NF-kappaB, indicating that it was not strongly activated. Consistent with this observation, interference with NF-kappaB activation by adenovirus-mediated overexpression of dominant negative IKK-beta or IkappaB-alpha did not increase UV-induced apoptosis. However, adenovirus-mediated overexpression of constitutively active Akt completely blocked UV-induced apoptosis observed with PI3K inhibition by LY294002, whereas adenovirus mediated overexpression of dominant negative Akt increased UV-induced apoptosis by 2-fold. Inhibition of UV-induced activation of Akt increased release of mitochondrial cytochrome c 3.5-fold, and caused appearance of active forms of caspase-9, caspase-8, and caspase-3. Constitutively active Akt abolished UV-induced cytochrome c release and activation of caspases-9, -8, and -3. These data demonstrate that PI3K/Akt is essential for protecting human KCs against UV-induced apoptosis, whereas NF-kappaB pathway provides little, if any, protective role.

Acrylamides↗
PubMed2001

An SH2-domain-containing kinase negatively regulates the phosphatidylinositol-3 kinase pathway.

SHK1 is a novel dual-specificity kinase that contains an SH2 domain in its C-terminal region. We demonstrate that SHK1 is required for proper chemotaxis and phagocytosis. Mutant shk1 null cells lack polarity, move very slowly, and exhibit an elevated and temporally extended chemoattractant-mediated activation of the kinase Akt/PKB. GFP fusions of the PH domain of Akt/PKB or the PH-domain-containing protein CRAC, which become transiently associated with the plasma membrane after a global stimulation with a chemoattractant, remain associated with the plasma membrane for an extended period of time in shk1 null cells. These results suggest that SHK1 is a negative regulator of the PI3K (phosphatidylinositol-3 kinase) pathway. Furthermore, when a chemoattractant gradient is applied to a wild-type cell, these PH-domain-containing proteins and the F-actin-binding protein coronin localize to its leading edge, but in an shk1 null cell they become randomly associated with the plasma membrane and cortex, irrespective of the direction of the chemoattractant gradient, suggesting that SHK1 is required for the proper spatiotemporal control of F-actin levels in chemotaxing cells. Consistent with such functions, SHK1 is localized at the plasma membrane/cortex, and we show that its SH2 domain is required for this localization and the proper function of SHK1.

Actins↗
PubMed2005

The 1,4,5-inositol trisphosphate pathway is a key component in Fas-mediated hypertrophy in neonatal rat ventricular myocytes.

OBJECTIVE: Cardiac hypertrophy is a compensatory response to increased mechanical load. Since Fas receptor activation is an important component in hypertrophy induced by pressure- and volume-overload, deciphering the underlying signaling pathways is of prime importance. Based on our previous work showing that in mice and rats ventricular myocytes the electrophysiological disturbances and diastolic [Ca2+]i-rise caused by 3 h of Fas activation are dependent on the Fas-->phospholipase C (PLC)-->1,4,5-inositol trisphosphate (1,4,5-IP3)-->sarcoplasmic reticulum (SR) [Ca2+]i release pathway, we tested the hypothesis that this pathway is also critical for Fas-mediated hypertrophy. METHODS: The effects of 24 h Fas activation in cultured neonatal rat ventricular myocytes (NRVM) were analyzed by means of RT-PCR, Western blot, immunofluorescence and fura-2 fluorescence. RESULTS: Fas activation increased nuclei surface area, atrial natriuretic peptide and connexin43 (Cx43) mRNA, the protein levels of total Cx43 and non-phosphorylated Cx43, and sarcomeric actin, all indicating hypertrophy. Concomitantly, Fas activation decreased mRNA of SERCA2a, the ryanodine receptor (RyR) and nuclear IP3R3. Further, Fas activation caused NFAT nuclear translocation. The hypertrophy was abolished by U73122, xestospongin C (blockers of the 1,4,5-IP3 pathway), genistein and by the PI3K blocker LY294002. CONCLUSIONS: Fas-mediated hypertrophy is dependent on the 1,4,5-IP3 pathway, which is functionally inter-connected to the PI3K/AKT/GSK3beta pathway. Both pathways act in concert to cause NFAT nuclear translocation and subsequent hypertrophy.

Animals↗
PubMed2003

Targeting of mitogen-activated protein kinases and phosphatidylinositol 3 kinase inhibits hepatocyte growth factor/scatter factor-induced angiogenesis.

BACKGROUND: Hepatocyte growth factor/scatter factor (HGF/SF) can sufficiently and independently induce pathophysiological angiogenesis. However, the treatment strategies have mostly been unsuccessful. The present study is the first to evaluate the possible targeting of downstream signals for the inhibition of HGF/SF-induced angiogenesis. METHODS AND RESULTS: In a multichannel scratch assay with human endothelial cells (ECs), HGF/SF induced a strong and prolonged activation of MAPK and cell proliferation that was inhibited by PD98059 and LY294002/wortmannin, selective inhibitors of MAPK and PI3K signaling modules, respectively. Western blotting demonstrated a temporal relation between the activation of the two pathways. Chemical inhibition of the PI3K and MAPK signals inhibited HGF/SF-induced chemoinvasion of ECs in vitro and blocked the HGF/SF-induced neovascularization into a polymer scaffold in vivo, as quantified by vessel counts and the clearance of radioactive 133Xe. CONCLUSIONS: These data indicate that MEK and PI3K inhibitors represent a promising approach to the clinical management of pathological conditions characterized by overt HGF/SF-induced angiogenesis.

Androstadienes↗
PubMed2005

Isorhapontigenin, a new resveratrol analog, attenuates cardiac hypertrophy via blocking signaling transduction pathways.

Cardiac hypertrophy is a major cause of morbidity and mortality worldwide. The hypertrophic process is mediated, in part, by oxidative stress-mediated signaling pathways. We hypothesized that isorhapontigenin (ISO), a new resveratrol analog, inhibits cardiac hypertrophy by blocking oxidative stress and oxidative stress-mediated signaling pathways. We treated cardiomyocytes with angiotensin II (Ang II) with or without ISO and found that ISO inhibited Ang II-induced cardiac hypertrophy. These effects were associated with a decrease in the levels of reactive oxygen species and H2O2 and the content of intracellular malonaldehyde and an increase in the activities of superoxide dismutase and glutathione peroxidase. Ang II induced the phosphorylation of PKC, Erk1/2, JNK, and p38 in cardiomyocytes and such phosphorylation was inhibited by ISO. ISO also blocked the PKC-dependent PI3K-Akt-GSK3beta/p70S6K pathway. These effects lead to direct or indirect inhibition of NF-kappaB and AP-1 activation. Our results revealed that pretreatment with ISO significantly inhibited Ang II-mediated NF-kappaB through affecting the degradation and phosphorylation of IkappaBalpha and the activity of IKKbeta and AP-1 activation by influencing the expression of c-Fos and c-Jun proteins. In addition, we also established the molecular link between activation of PKC and MAPKs and activation of NF-kappaB and AP-1 in cardiomyocytes. We also found that ISO treatment significantly attenuated heart weight/body weight ratio by approximately 25%, decreased posterior wall thickness and left ventricle diastolic and systolic diameters, and increased 10% fractional shortening in an aortic-banded rat model. Furthermore, treatment with ISO significantly decreased cardiac myocyte size and systolic blood pressure. These findings suggest that ISO prevents the development of cardiac hypertrophy through an antioxidant mechanism involving inhibition of different intracellular signaling transduction pathways.

Angiotensin II↗
PubMed1996

ARIA/HRG regulates AChR epsilon subunit gene expression at the neuromuscular synapse via activation of phosphatidylinositol 3-kinase and Ras/MAPK pathway.

AChR-inducing activity (ARIA)/heregulin, a ligand for erbB receptor tyrosine kinases (RTKs), is likely to be one nerve-supplied signal that induces expression of acetylcholine receptor (AChR) genes at the developing neuromuscular junction. Since some RTKs act through Ras and phosphatidylinositol 3-kinase (PI3K), we investigated the role of these pathways in ARIA signaling. Expression of activated Ras or Raf mimicked ARIA-induction of AChR epsilon subunit genes in muscle cells; whereas dominant negative Ras or Raf blocked the effect of ARIA. ARIA rapidly activated erk1 and erk2 and inhibition of both erks also abolished the effect of ARIA. ARIA stimulated association of PI3K with erbB3, expression of an activated PI3K led to ARIA-independent AChR epsilon subunit expression, and inhibition of PI3K abolished the action of ARIA. Thus, synaptic induction of AChR genes requires activation of both Ras/MAPK and PI3K signal transduction pathways.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2003

Cyclic AMP-dependent protein kinase A and CREB are involved in neuregulin-induced synapse-specific expression of acetylcholine receptor gene.

Neuregulin is reported to stimulate synapse-specific transcription of acetylcholine receptor (AChR) genes in the skeletal muscle fiber by multiple signaling pathways such as ERK, PI3K, and JNK. The co-localization of PKA mRNA with AChR and ErbBs, receptors for neuregulin, at the confined region of synapse implicates the putative role of PKA in neuregulin-induced AChR gene expression. In the present study, we found that mRNA and protein of a regulatory subunit of PKA (PKARIalpha) were concentrated at synaptic sites of the rat sternomastoid muscle fiber, while those of ERK and PI3K were uniformly distributed throughout the muscle fiber. Neuregulin (100 ng/ml) increased both PKA activity in the nucleus and AChRdelta subunit gene transcription in cultured Sol8 myotubes. These increases were significantly blocked by a specific PKA inhibitor H-89 (100 nM) and an adenylcyclase inhibitor SQ 22536 (200 microM) (72.5% and 60.1%, respectively). Furthermore, neuregulin phosphorylated CREB, a well-known down-stream transcription factor of PKA. While H-89 inhibited CREB phosphorylation, H-89 and PD098059 (50 microM), a specific MEK1/2 inhibitor, did not inhibit the phosphorylation of ERK and CREB, respectively, suggesting no cross-talk between PKA and ERK pathways. In conclusion, neuregulin increases AChRdelta subunit gene transcription, in part, by the activation of PKA/CREB, an alternative route to the previously reported ERK signaling pathway.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2002

Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells.

Indole-3-carbinol (I3C) is a bioactive compound present in Brassica vegetables that shows an antitumor activity in experimental animals and inhibits the growth of human cancer cells in vitro. In recent years, studies on prostate cancer (PCa) chemoprevention have been intensified, because there is a long latency for the development of clinical PCa, which makes the PCa a better target for chemoprevention. We have shown previously that I3C induces cell growth inhibition by G(1) cell cycle arrest and induces apoptosis in a dose- and time-dependent manner in PC-3 PCa cells; however, the mechanism(s) by which I3C induces apoptosis in PC-3 cells is still not clear. A cell survival pathway involving phosphatidylinositol 3'-kinase (PI3K) and Akt is known to play an important role in inhibiting apoptosis in response to growth factor signaling, which prompted us to investigate whether this pathway plays any role in I3C-induced apoptosis in PCa cells. Here we report that I3C inhibits the phosphorylation and subsequent activation of Akt kinase. In addition, I3C abrogated epidermal growth factor (EGF)-induced activation of Akt in PC-3 cells. Western blot analyses of EGF receptor showed that I3C down-regulates the EGF receptor levels and its autophosphorylation. This was also accompanied by the inhibition of EGF-induced phosphorylation of PI3K by I3C treatment. Furthermore, the known downstream modulators of the Akt/PI3K cell survival pathway, Bcl-x(L), and BAD proteins showed decreased expression after I3C treatment. From these results, we conclude that I3C-induced apoptosis is partly mediated by the inhibition of Akt activation, resulting in the alterations in the downstream regulatory molecules of Akt activation in PC-3 cells. However, further in-depth investigation is needed to establish a cause-and-effect relationship between Akt pathway and I3C effect.

Apoptosis↗