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PubMedDate not supplied

Angiopoietin-1 inhibits doxorubicin-induced human umbilical vein endothelial cell death by modulating fas expression and via the PI3K/Akt pathway.

Angiopoietin-1 (Ang-1) is essential for the maturation of blood vessels during vasculogenesis. Besides angiogenesis, recent publications indicate that Ang-1 is also a potent survival factor for endothelial cells; however, the mechanisms by which pathways remain elusive. Doxorubicin (DOX) is a powerful anticancer drug, but its use is severely restricted by its cardiotoxicity. The authors report here that Ang-1 inhibits DOX-induced cell death in human umbilical vein endothelial cells (HUVECs). Interestingly, the DOX-induced up-regulation in Fas (CD95/APO-1) and Fas ligand expression could be blocked by Ang-1, indicating a pivotal role of Ang-1 in DOX-induced Fas and Fas ligand expression. In addition, the prevention of cell death in this model system seems to be dependent on the activation of phosphatidylinositol 3-kinase (PI3K)/Akt, as Ang-1 fails to inhibit DOX-induced cell death while PI3K/Akt pathway was blocked by the PI3K inhibitor LY294002. Moreover, Ang-1 inhibits DOX-induced up-regulation of p53 through PI3K/Akt. Therefore, Ang-1 is a potent inhibitor for DOX-induced cell death through Fas and PI3K/Akt-mediated pathways.

Angiopoietin-1↗
PubMed2006

EGF-induced cell migration is mediated by ERK and PI3K/AKT pathways in cultured human lens epithelial cells.

Cataract is considered as the most common cause of blindness, which is curable only by surgery. Postsurgery, however, many patients gradually develop the complication of posterior capsule opacification (PCO) or secondary cataract, arising from stimulated cell proliferation and cell migration within the lens capsule. The migration of human lens epithelial cells (HLECs) plays crucial roles in the remodeling of lens capsule and cataract formation, but less is known about the cell-signaling mechanism of migration. We observed that epithelial growth factor (EGF) induced cell migration in cultured human lens epithelial cells through the ERK and PI3K/AKT pathways. EGF induced cell migration in a dose-dependent manner; EGF-induced EGFR phosphorylation and downstream activation of c-Jun N-terminal protein kinase (JNK), p38 MAP kinase (p38), extracellular signal-regulated kinase (ERK1/2) and AKT, were inhibited by PD153035 (EGFR inhibitor), JNKi (JNK inhibitor), SB203580 (p38 inhibitor), U0126 (MEK/ERK inhibitor), and LY294002 (PI3K/AKT inhibitor), respectively. Furthermore, we found that EGF induced activity of matrix metalloproteinase-2 (MMP-2) in cultured HLECs. EGF-induced MMP-2 activity was significantly inhibited by treatment of PD153035, U0126, and LY294002, but not SB203580 and JNK inhibitor, suggesting that ERK and the phosphatidylinositol-3-kinase (PI3K)/AKT pathways selectively mediate EGF-stimulated MMP-2 activity and cell migration in cultured HLECs in vitro. Taken together, our results suggest that the cell-signaling pathways involved in EGF-stimulated cell migration may constitute potential therapeutic targets in the treatment of PCO.

Cell Line↗
PubMed2005

Nucleus pulposus cells upregulate PI3K/Akt and MEK/ERK signaling pathways under hypoxic conditions and resist apoptosis induced by serum withdrawal.

STUDY DESIGN: To examine the impact of hypoxia, rat nucleus pulposus cells were maintained in monolayer culture in 2% O2 and survival and signal transduction pathways identified. OBJECTIVE: To elucidate the signaling pathways that allow nucleus pulposus cells to adapt to low oxygen environment. SUMMARY OF BACKGROUND DATA: Mammalian cell function is critically dependent on a continuous supply of oxygen. Interestingly, some specialized cell types that include nucleus pulposus cells of the intervertebral disc reside in a hypoxic environment. However, the mechanism of their adaptation to this low oxygen environment is not known. METHODS: Rat nucleus pulposus cells were harvested from explant cultures and grown to confluence in monolayer. Cells from passage 3-7 were maintained under hypoxia (2% O2) and normoxia (20% O2) for various time periods in complete or serum-free medium. Cells were also treated with pharmacologic agents that block PI3K and MAPK signaling pathways. Cell survival was assessed by MTT assay, annexinV-PI dual-color flow cytometry, and the TUNEL procedure. Expression of signaling proteins was evaluated by Western blot analysis. Cell phenotype was studied by semiquantitative RT-PCR. RESULTS: Under hypoxic conditions, rat nucleus pulposus cells were resistant to apoptosis induced by serum starvation. Protection was also observed after treatment of the nucleus cells by desferrioxamine, a compound that mimics many of the effects of hypoxia. Cell survival in hypoxia was related to activation of phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways. Induction of Akt activation and ERK1/2 activationunder hypoxic condition was detected at 12 hours and correlated with inactivation of glycogen synthase kinase-3beta (GSK-3beta), an effector protein involved in regulation of apoptosis. Finally, inhibition of PI3K/Akt and MEK/ERK pathway using the inhibitors LY294002 and PD98059, respectively, impaired cell survival. CONCLUSION: It is concluded that under hypoxic conditions, rat nucleus pulposus cells are adapted for survival by regulation of expression of critical genes, downregulation of apoptosis through activation of the PI3K/Akt and MAPK survival pathways.

Animals↗
PubMed2006

Regulation of vascular endothelial growth factor expression and vascularization in the myocardium by insulin receptor and PI3K/Akt pathways in insulin resistance and ischemia.

OBJECTIVE: This study characterized the role of insulin receptors and resistance on vascular endothelial growth factor (VEGF) expression and myocardial vascularization in physiological conditions and after ischemia. METHODS AND RESULTS: Cardiac microvascular density was reduced by 30% in insulin-resistant Zucker fatty rats versus lean controls. This was associated with a parallel 40% inhibition of insulin-stimulated activation of both Akt and VEGF expression in the myocardium and cardiomyocytes. In contrast, the activation of Erk1/2 by insulin remained unchanged. In cultured cardiomyocytes, insulin or insulin-like growth factor (IGF)-1 increased VEGF mRNA and protein expression by 2-fold. Inhibition of PI3K/Akt, especially Akt2-mediated cascades but not the Ras/MEK/Erk pathway, using chemical inhibitors, dominant negative adenoviral constructs, or siRNA approaches suppressed VEGF mRNA expression by insulin. Ventricular tissues from muscle insulin receptor knockout (MIRKO) mice, which lack insulin receptors in the myocardium, have significant reductions in insulin but not IGF-1 signaling, VEGF expression, and vascular density before and after ischemia versus controls. CONCLUSIONS: Insulin regulates VEGF gene expression and vascularization in the myocardium specifically via insulin receptors and the activation of PI3K/Akt pathway. Selective inhibition of this pathway may lead to the decreases in VEGF expression and capillary density in the myocardium of patients with insulin resistance.

Androstadienes↗
PubMed2004

Ability of the activated PI3K/Akt oncoproteins to synergize with MEK1 and induce cell cycle progression and abrogate the cytokine-dependence of hematopoietic cells.

Multiple signal transduction pathways, including the Raf/MEK/ERK and PI3K/Akt kinase cascades, play critical roles in transducing growth signals from activated cell surface receptors. Using conditionally and constitutively-active forms of MEK1 and either PI3K or Akt, we demonstrate synergy between these kinases in relieving cytokine-dependence of the FDC-P1 hematopoietic cell line. Cytokine-independent cells were obtained from DeltaMEK1:ER-infected cells at a frequency of 5 x 10(-5) indicating that low frequency of cells expressing beta-estradiol-regulated DeltaMEK1:ER became factor-independent, while activated PI3K or Akt by themselves did not relieve cytokine-dependence. In contrast, cytokine-independent cells were recovered approximately 25 to 250-fold more frequently from DeltaMEK1:ER infected cells also infected with either activated PI3K or Akt. MEK/PI3K and MEK/Akt-responsive cells could be maintained long-term as long as either beta-estradiol or the estrogen receptor antagonist 4-hydroxy-tamoxifen (4HT) were provided. The MEK/PI3K/Akt responsive cells were sensitive to both MEK and PI3K/Akt/p70S6K inhibitors. Synergy was observed when inhibitors which targeted both pathways were added together. These results indicate that there is synergy between the Raf/MEK/ERK and PI3K/Akt pathways in terms of abrogation of cytokine-dependence of hematopoietic cells. Likewise, suppression of multiple signal transduction pathways is a more effective means to inhibit cell cycle progression and induce apoptosis in leukemic cells.

Animals↗
PubMed2004

Ang II attenuates IGF-1-stimulated Na+, K(+)-ATPase activity via PI3K/Akt pathway in vascular smooth muscle cells.

We have investigated the role of phosphatidylinositol 3-kinase (PI3K) and serine/threonine protein kinase B (Akt) in mediating vascular smooth muscle cells (VSMC) sodium pump (Na+, K(+)-ATPase) regulatory interactions between insulin-like growth factor-1 (IGF-1) and angiotensin II (Ang II). Treatment with IGF-1 (100 nM) for 30 min or Ang II (100 nM) for 10 min increased sodium pump activity. Pretreatment with Ang II for 10 min, abolished IGF-1 increased sodium pump activity. Given separately for 6 h, Ang II and IGF-1 stimulated alpha1 mRNA accumulation. Phosphorylation on Ser473 of Akt was increased after treatment with both IGF-1 and Ang II. Pretreatment with 100 nM of PI3K inhibitor Wortmannin (WT) for 30 min decreased: IGF-1 and Ang II-stimulated pump activity, phosphorylation of Akt and PI3K protein expression. Pretreatment with Ang II attenuated IGF-1-stimulated sodium pump activity, phosphorylation of Akt and PI3K protein expression. IGF-1 increased the association between IRS-1 and p85, and Ang II as well as PI3K inhibition decreased this IGF-1 effect. These results suggest that Ang II, which increases pump activity alone, reduces the IGF-1 stimulation of sodium pump activity by attenuating PI3K/Akt signaling. These results implicate PI3K/Akt pathways in Ang II/IGF-1 regulation of the sodium pump in VSMC.

Androstadienes↗
PubMed2002

Inhibition of dystroglycan binding to laminin disrupts the PI3K/AKT pathway and survival signaling in muscle cells.

Dystroglycan is a component of the dystrophin-glycoprotein complex (DGC) in muscle and a cell surface receptor for laminin. Numerous muscular dystrophies are the result of disruption of proteins comprising the DGC, but the underlying pathogenetic mechanisms are unknown. Because apoptosis is an early feature of muscular dystrophy in vivo, and perturbation of cell-extracellular matrix associations is known to induce apoptosis, we investigated the role of dystroglycan-laminin interactions in the propagation and maintenance of cell survival signals in muscle cells. We found that disrupting the interaction between alpha-dystroglycan and the extracellular matrix protein laminin induces apoptosis in muscle cells. This increase in apoptosis is mediated in part by caspase activation and can be blocked by a caspase-3 inhibitor. We demonstrate a role for the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in muscle cell-survival signaling using a pharmacological inhibitor of PI3K. Treatment with this inhibitor resulted in decreased phosphorylation of AKT and its downstream effector glycogen synthase kinase (GSK)-3beta and induced apoptosis in muscle cell cultures. Disruption of dystroglycan-laminin interactions resulted in decreased phosphorylation of AKT and GSK-3beta. Furthermore, activation of AKT prior to the disruption of dystroglycan-laminin protected the muscle cells from the induction of apoptosis. These results support a role for the PI3K/AKT pathway in the propagation of cell-survival signals mediated by the DGC and provide new insight into the molecular pathogenesis associated with the development of muscular dystrophies.

Animals↗
PubMed1999

The beta4 integrin subunit rescues A431 cells from apoptosis through a PI3K/Akt kinase signaling pathway.

To study whether alpha6beta4 integrin regulates apoptosis, human A431 cells were plated on bacteria plates in the presence or absence of mAb beta4. In the absence of mAb beta4, A431 cells demonstrated morphological characteristics of apoptosis by 24 h and most cells died by 48 h. In contrast, in the presence of mAb beta4, cells remained viable, and at the end of 48 h, 70-80% of cells survived. Treatment of A431 cells with mAb beta4 resulted in tyrosine phosphorylation of the p85 subunit of PI3 kinase; PI3 kinase activity increased within 15 min and peaked at 60 min. Stimulation of beta4 in A431 cells resulted in a time-dependent phosphorylation of Akt with a concomitant and parallel phosphorylation of Bad. Inactivation of PI3 kinase with inhibitors blocked the anti-apoptotic effect induced by mAb beta4. These are the first results to suggest that ligation of alpha6beta4 integrin protects cells from apoptosis through a PI3K/Akt kinase signaling pathway.

Antigens, CD↗
PubMed2006

Low dose leflunomide activates PI3K/Akt signalling in erythroleukemia cells and reduces apoptosis induced by anticancer agents.

Rheumatoid arthritis (RA) is characterized by persistent joint synovial tissue inflammation. Leflunomide is an immunomodulatory agent that has been approved for treatment of active RA. In the past few years, uses other than RA treatment have appeared. Leflunomide has been reported to show antitumor potential through inhibition of cancer cell proliferation. We thus tested the antiproliferative potential of leflunomide on HEL and K562 erythroleukemia cells. The findings summarized in this report demonstrate for the first time that low dose leflunomide prolonged survival and reduced apoptosis induced by several anticancer agents in erythroleukemia cells. We showed that in treated cells, leflunomide reduced the signalling pathways involved in promoting apoptosis by reducing p38 MAPK and JNK basal activity. On the other hand, leflunomide transiently activated the ERK signalling pathway and induced a sustained activation of Akt. We also showed that leflunomide reduced caspase-3 activity and DNA fragmentation induced by anticancer agents. By using an inhibitory strategy, we showed that inhibition of Akt activation but not ERK abolished the protective effect of leflunomide. Thus our findings suggested that leflunomide reduced apoptosis induced by anticancer agents through PI3K/Akt signalling activation.

Antineoplastic Agents↗
PubMed2006

A conjugate of camptothecin and a somatostatin analog against prostate cancer cell invasion via a possible signaling pathway involving PI3K/Akt, alphaVbeta3/alphaVbeta5 and MMP-2/-9.

Camptothecin (CPT) was conjugated to the N-terminal of a somatostatin analog (SSA) directly via a carbamate group and a basic N-terminal linking motif, D-Lys-D-Tyr-Lys-D-Tyr-D-Lys. This new CPT-SSA conjugate termed JF-10-81 was evaluated as a receptor-specific delivery system for its anti-invasive and anti-angiogenic activities. It was found that, in addition to blocking migration and invasion of highly invasive prostate cancer PC-3 cells, this conjugate also inhibited in vitro capillary-like tube formation of endothelial cells and in vivo angiogenesis in C57B1/6N female mice. JF-10-81 was found to block PC-3 cell attachment to various extracellular matrix components, mainly to vitronectin, the ligand of cell surface receptors integrin alphaVbeta3 and alphaVbeta5. Additionally, JF-10-81 reduced expression of integrins alphaVbeta3 and alphaVbeta5 on PC-3 cell surfaces, without effects on beta1 or any alphabeta1 heterodimers. This conjugate also inactivated phosphorylation of protein kinase B (PKB/Akt), down-regulated the expression of latent matrix metalloproteinase (MMP) -2 and MMP-9, but had little effect on MMP-3/-10. Meanwhile, membrane type-1 matrix metalloproteinase (MT1-MMP) and the tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) were not detectable in PC-3 cells. alphaVbeta3/alphaVbeta5 and MMP-2/-9 are known to be highly expressed in many tumor cells and play an important role in tumor progression. Our results support that this conjugate could possibly inhibit prostate cancer PC-3 cell invasion through a signaling pathway involving PI3K/Akt, alphaVbeta3/alphaVbeta5 and MMP-2/-9, and this SSA could be used as an efficient vector to deliver CPT or other cytotoxic agents to target sites for cancer therapy.

Amino Acid Sequence↗
PubMed2005

The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells.

Tumor cells with mutated PTEN proliferate in an EGFR-independent manner. Induction of PTEN sensitizes cells to EGFR inhibition, and the combination causes synergistic apoptosis. Synergy is due to inhibition of two parallel pathways that phosphorylate the proapoptotic protein BAD at distinct sites. Serine 112 phosphorylation is EGFR/MEK/MAPK dependent, whereas serine 136 phosphorylation is PI3K/Akt dependent. Either phosphorylation is sufficient to sequester BAD to 14-3-3. BAD is released and apoptosis is induced only if both serines are dephosphorylated in response to inhibition of both pathways. Reduction of BAD expression by RNA interference prevents apoptosis in response to pathway inhibition. Thus, BAD integrates the antiapoptotic effects of both pathways. Combined inhibition of EGFR and PI3K signaling may be a useful therapeutic strategy.

Animals↗
PubMed2005

Catalase induced expression of inflammatory mediators via activation of NF-kappaB, PI3K/AKT, p70S6K, and JNKs in BV2 microglia.

Catalase induces COX-2 or iNOS expression in some type of cells, but the mechanism remains unclear. Here we investigated the effect of catalase on COX-2 and iNOS expression in BV2 microglia and the inductive mechanism associated. Exposure of catalase to BV2 microglia induced expression of COX-2 and iNOS that was related with transcriptional up-regulation. Importantly, catalase-induced COX-2 and iNOS expression needed activations of NF-kappaB, PI3K/AKT, and JNKs, which were important for the transcriptional up-regulation of COX-2 and iNOS. Notably, rapamycin inhibition of p70S6K led to down-regulation of COX-2 and iNOS protein expression, but not steady-state mRNA expression and transcription, induced by catalase, suggesting that p70S6K is involved in increased COX-2 and iNOS mRNA translation by catalase. Interestingly, there was PI3K-dependent activation of AKT, p70S6K, JNKs, and NF-kappaB in response to catalase. These data collectively suggest catalase-induced COX-2 and iNOS expression in BV2 microglia is, in part at least, mediated through activation of multiple signaling proteins.

Animals↗
PubMed2005

The hyaluronan-binding protease upregulates ERK1/2 and PI3K/Akt signalling pathways in fibroblasts and stimulates cell proliferation and migration.

The hyaluronan-binding protease (HABP) is a serine protease in human plasma which is structurally related to plasminogen activators, coagulation factor XII and hepathocyte growth factor activator. It can in vitro activate the coagulation factor FVII, kininogen and plasminogen activators. The present study was initiated to gain a more complete picture of the cell-associated activities of this fibrinolysis-related protease. Treatment of lung fibroblasts with HABP lead to a rapid activation of signalling pathways, including the mitogen-activated protein kinase (MAPK) pathway with c-Raf, MEK and ERK1/2. Additionally the activation of the PI3K/Akt pathway and of several translation-related proteins was found. Proliferation assays confirmed the assumption of a strong growth-stimulating effect of HABP on human lung and skin fibroblasts. Intracellular signalling and growth stimulation were strongly dependent on the proteolytic activity of HABP. Stimulation of signalling and proliferation by HABP involved the fibroblast growth factor receptor 1 (FGFR-1). HABP-stimulated proliferation of lung fibroblasts MRC-5 was accompanied by a significant intracellular increase in basic fibroblast growth factor (bFGF), the major ligand of FGFR-1; bFGF could however not be identified in the supernatant of HABP-treated cells. Though, the conditioned medium from HABP-treated cells showed a strong growth-promoting activity on quiescent fibroblasts, indicating the release of a yet unknown growth factor amplifying the initial growth stimulus. In a two-dimensional wound model HABP stimulated the invasion of fibroblasts into a scratch area, adding a strong pro-migratory activity to this plasma protease. In summary, HABP exhibits a significant growth factor-like activity on quiescent human lung and dermal fibroblasts. Our findings suggest that this fibrinolysis-related plasma protease may participate in physiologic or pathologic processes where cell proliferation and migration are pivotal, like tissue repair, vascular remodelling, wound healing or tumor development.

Androstadienes↗
PubMed2006

Signal transduction of MEK/ERK and PI3K/Akt activation by hypoxia/reoxygenation in renal epithelial cells.

The extracellular signal-regulated kinase (ERK) and Akt have been reported to be activated by ischemia/reperfusion in vivo. However, the signaling pathways involved in activation of these kinases and their potential roles were not fully understood in the postischemic kidney. In the present study, we observed that these kinases are activated by hypoxia/reoxygenation (H/R), an in vitro model of ischemia/reperfusion, in opossum kidney (OK) cells and elucidated the signaling pathways of these kinases. ERK and Akt were transiently activated during the early phase of reoxygenation following 4-12h of hypoxia. The ERK activation was inhibited by U0126, a specific inhibitor of ERK upstream MAPK/ERK kinase (MEK), but not by LY294002, a specific inhibitor of phosphoinositide 3-kinase (PI3K), whereas Akt activation was blocked by LY294002, but not by U0126. Inhibitors of epidermal growth factor receptor (EGFR) (AG 1478), Ras and Raf, as well as antioxidants inhibited activation of ERK and Akt, while the Src inhibitor PP2 had no effect. PI3K/Akt activation was shown to be associated with up-regulation of X chromosome-linked inhibitor of apoptosis (XIAP), but not survivin. Reoxygenation following 4-h hypoxia-stimulated cell proliferation, which was dependent on ERK and Akt activation and was also inhibited by antioxidants and AG 1478. Taken together, these results suggest that H/R induces activation of MEK/ERK and PI3K/Akt/XIAP survival signaling pathways through the reactive oxygen species-dependent EGFR/Ras/Raf cascade. Activation of these kinases may be involved in the repair process during ischemia/reperfusion.

Animals↗
PubMed2007

Induction of matrix metalloproteinases (MMP3, MMP12 and MMP13) expression in the microglia by amyloid-beta stimulation via the PI3K/Akt pathway.

Alzheimer's disease is characterized by the presence of senile plaques in the brain composed primarily of amyloid-beta peptide. Microglia have been reported to surround these Abeta plaques, which have opposite roles, provoking a microglia-mediated inflammatory response that contributes to neuronal cell loss or the removal of Abeta and damaged neurons. We herein analyzed the process of expression of Matrix metalloproteinases induced by Abeta stimulation. We found that Abeta1-42 induces a high level of MMP3, MMP12 and MMP13 in the microglia. The signal transduction pathway for the expression of these MMPs mRNA induced by Abeta1-42 depends on PI3K/Akt.

Alzheimer Disease↗
PubMed2005

Critical roles of Raf/MEK/ERK and PI3K/AKT signaling and inactivation of p38 MAP kinase in the differentiation and survival of monocyte-derived immature dendritic cells.

OBJECTIVE: The aim of this study is to investigate the signaling pathways and their roles in the differentiation of immature monocyte-derived dendritic cells (MoDCs). METHODS: MoDCs were generated from peripheral blood monocytes (PBMCs) using the standard protocols. Various kinase inhibitors, including SB203580, PD98059, and LY294002 and Wortmannin, or p38 activator were added at the beginning of the cultures. After 7 days of culture, immature MoDCs were harvested and analyzed for their surface expression of relevant molecules and the fraction of apoptotic cells by flow cytometry. Western blots were used to analyze mitogen-activated protein kinase (MAPK), NF-kappaB, Raf, mitogen-induced extracellular kinase (MEK), and AKT expression by cultured cells. NF-kappaB was also analyzed by electrophoretic mobility shift assay. Allogeneic MLR was used to examine the capacity of MoDCs to activate allogeneic T cells. RESULTS: The present study shows that the differentiation of immature MoDCs was accompanied by phosphorylation of AKT, Raf, MEK, extracellular signal-related kinase (ERK), and NF-kappaB activity. Inhibiting PI3K or MEK retarded the differentiation of immature MoDCs and induced apoptosis in 10 to 30% of the cultured cells, while inhibiting both PI3K and MEK resulted in apoptosis in 70% of the cells. Surprisingly, inhibiting p38 enhanced the phosphorylation of ERK and NF-kappaB activity and led to an enhanced upregulation, compared with control cells, of expression of dendritic cell (DC)-related adhesion and costimulatory molecules and antigen presentation capacity. CONCLUSIONS: Our results indicate that the Raf/MEK/ERK and PI3K/AKT signaling pathways play critical roles in the differentiation and survival of immature MoDCs. Moreover, this study also demonstrates that activated p38 is detrimental to the differentiation of immature MoDCs.

Anisomycin↗
PubMed2004

Overexpression of transglutaminase 2 accelerates the erythroid differentiation of human chronic myelogenous leukemia K562 cell line through PI3K/Akt signaling pathway.

Transglutaminase 2 (TG2) is a GTP-binding protein with transglutaminase activity. Despite advances in the characterization of TG2 functions and their impact on cellular processes, the role of TG2 in Human chronic myelogenous leukemia K562 cell line is still poorly understood. To understand the biological significance of TG2 during the differentiation of K562 cells, we established and characterized K562 cells that specifically express TG2. Non-transfected K562 cells showed the increase of membrane-bound-TG2 level after 3 days in the response to Hemin and all trans-retinoic acid (tRA), indicating that membrane recruitment of TG2 is occurred during the erythroid differentiation. However, membrane recruitment of TG2 in TG2-transfected cells revealed within earlier time period, compared with that in vector-transfected cells. The ability of membrane-bound-TG2 to be photoaffinity-labeled with [alpha-32P]GTP was also increased in TG2-transfected cells. TG2-transfected cells activated Akt phosphorylation and inactivated ERK1/2 phosphorylation, compared with vector-transfected cells. Furthermore, phosphorylation of CREB, one of the Akt substrates, was increased in TG2-transfected cells and this phenomenon was confirmed by RT-PCR analysis of several marker genes related with erythroid lineage in the absence of PI3K specific inhibitor, Wortmannin, indicating that PI3K/Akt signaling pathway also involved in the differentiation of the cell. Finally, as results of benzidine positive staining as well as hemoglobinization analysis, overexpression of TG2 revealed acceleration of the erythroid differentiation of K562 cells. Taken together, there was no increased TG2 expression level in the response of Hemin/tRA and delayed differentiation in vector transfected cells than in TG2-transfected cells, suggesting that suppression of TG2 expression may retard the erythroid differentiation of K562 cells. Therefore, our study may give a new insight for another aspect of the development of this disease.

Androstadienes↗
PubMed2005

HB-EGF enhances restitution after intestinal ischemia/reperfusion via PI3K/Akt and MEK/ERK1/2 activation.

BACKGROUND & AIMS: Early recovery of intestinal function after injury occurs by restitution, a complex process with a poorly understood molecular basis. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a potent chemotactic factor that is induced during ischemia/reperfusion in vivo and intestinal wounding in vitro. The role of HB-EGF in intestinal restitution and the underlying intracellular signaling pathways involved were investigated. METHODS: Adult rats were subjected to intestinal ischemia, with histologic and biochemical damage assessed during the first 3 hours of reperfusion. The effect of recombinant HB-EGF (rHB-EGF) on structural and functional recovery of the intestine by restitution was evaluated in vivo. Scrape wounding of intestinal epithelial cell monolayers was used to elucidate the mechanisms of intrinsic and rHB-EGF-induced restitution. RESULTS: Early structural recovery occurred within 3 hours of reperfusion and was attributed to restitution rather than proliferation. HB-EGF treatment significantly improved structural recovery and accelerated functional recovery of the gut barrier. In vivo restitution was preceded by activation of Akt and extracellular signal-regulated kinase (ERK) 1/2, which were accelerated and enhanced by HB-EGF treatment. Blocking of ErbB-1, phosphatidylinositol 3-kinase (PI3K)/Akt, or mitogen-activated protein kinase/ERK kinase (MEK)/ERK activity resulted in significant reduction in intrinsic and HB-EGF-induced restitution in vitro. Endogenous HB-EGF was shown to play an essential role in wound-induced ErbB-1 and ERK1/2 activation and in intrinsic restitution. CONCLUSIONS: Endogenous HB-EGF, ErbB-1, PI3K/Akt, and MEK/ERK are involved in intrinsic restitution. rHB-EGF enhances restitution in vivo and in vitro in a PI3K/Akt- and MEK/ERK1/2-dependent fashion.

Animals↗