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At least 199 records · Page 11Linked to original sources
PubMed2004

PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations.

Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase. Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling. This function of PS1 is unaffected by gamma-secretase inhibitors. Pharmacological and genetic evidence indicates that PS1 acts upstream of Akt, at or before PI3K kinase. PS1 forms complexes with the p85 subunit of PI3K and promotes cadherin/PI3K association. Furthermore, conditions that inhibit this association prevent the PS1-induced PI3K/Akt activation, indicating that PS1 stimulates PI3K/Akt signaling by promoting cadherin/PI3K association. By activating PI3K/Akt signaling, PS1 promotes phosphorylation/inactivation of glycogen synthase kinase-3 (GSK-3), suppresses GSK-3-dependent phosphorylation of tau at residues overphosphorylated in AD and prevents apoptosis of confluent cells. PS1 FAD mutations inhibit the PS1-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau overphosphorylation at AD-related residues. Our data raise the possibility that PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway.

Alzheimer Disease↗
PubMed2006

A PI3K activity-independent function of p85 regulatory subunit in control of mammalian cytokinesis.

Cytosolic division in mitotic cells involves the function of a number of cytoskeletal proteins, whose coordination in the spatio-temporal control of cytokinesis is poorly defined. We studied the role of p85/p110 phosphoinositide kinase (PI3K) in mammalian cytokinesis. Deletion of the p85alpha regulatory subunit induced cell accumulation in telophase and appearance of binucleated cells, whereas inhibition of PI3K activity did not affect cytokinesis. Moreover, reconstitution of p85alpha-deficient cells with a Deltap85alpha mutant, which does not bind the catalytic subunit, corrected the cytokinesis defects of p85alpha(-/-) cells. We analyzed the mechanism by which p85alpha regulates cytokinesis; p85alpha deletion reduced Cdc42 activation in the cleavage furrow and septin 2 accumulation at this site. As Cdc42 deletion also triggered septin 2 and cytokinesis defects, a mechanism by which p85 controls cytokinesis is by regulating the local activation of Cdc42 in the cleavage furrow and in turn septin 2 localization. We show that p85 acts as a scaffold to bind Cdc42 and septin 2 simultaneously. p85 is thus involved in the spatial control of cytosolic division through regulation of Cdc42 and septin 2, in a PI3K-activity independent manner.

Animals↗
PubMed2005

Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support.

Bone marrow stromal cells are essential for the differentiation, survival and proliferation of normal and leukemic human B-lineage cells. Leukemic cells require stromal cell support for optimal proliferation and apoptotic resistance. Stromal cell contact can promote resistance to chemotherapeutic agents. In this study, we have made use of small molecular weight inhibitors and an established stromal cell-dependent pre-B-ALL cell line, BLIN-2, to investigate the role of the MAP kinase, PI3K/Akt, JAK/STAT and mTOR pathways in the promotion of leukemic cell growth in the presence of stromal cell support. Treatment with PI3K+JAK, PI3K+MEK, or MEK+JAK inhibitor combinations resulted in an inhibition of proliferation as measured by DNA synthesis. However, only inhibition of both PI3K and MEK or both mTOR and MEK resulted in a dramatic increase in the number of annexinV(+)/PI(+) apoptotic events within a 24 h period. Our data suggest that stromal cell-mediated apoptotic protection in B-lineage ALL is mediated by PI3K/mTOR and MEK via a synergistic mechanism(s).

Apoptosis↗
PubMed2000

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation.

Hormones are specialized mitogens that stimulate proliferation in their differentiated target cells. Thyrotropin (TSH), the physiologic regulator of thyroid cells, stimulates cAMP-mediated proliferation and thyroid-specific gene expression. The mitogenic effects of TSH require Ras, therefore Ras activation should be compatible with the maintenance of thyroid differentiation. However, expression of activated Ras extinguishes the differentiated phenotype of thyroid cells. One explanation for this apparent paradox is the selective utilization of Ras effector pathways. We tested the hypothesis that Ras signaling through PI3K mediates the mitogenic effects of TSH in cells which retain their differentiated character. Expression of a Ras effector mutant (RasV12S35) that signals preferentially through Raf-1, although sufficient to confer TSH-independent proliferation, abolished hormone-regulated expression of thyroglobulin and the sodium/iodide symporter. In contrast, expression of a Ras mutant (RasV12C40) that binds selectively to PI3K conferred TSH-independent proliferation without marked effects on thyroid-specific gene expression. Unlike the inhibitory effects of TSH on the proliferation of RasV12S35-expressing cells, TSH enhanced RasV12C40-stimulated proliferation by further increasing the activity of p70s6k, an important mediator of the mitogenic effects of TSH and RasV12C40. These results demonstrate that channeling Ras-dependent signals to PI3K confers TSH with the ability to stimulate proliferation in differentiated cells. Oncogene (2000) 19, 924 - 932.

Animals↗
PubMed2002

Oncogenic Ras/Her-2 mediate hyperproliferation of polarized epithelial cells in 3D cultures and rapid tumor growth via the PI3K pathway.

Carcinogenesis by oncogenic Ras and Her-2 involves enhanced proliferation of epithelial cells in vivo. However, hyperproliferation induced by these oncogenes, or their downstream pathways in vitro has mainly been studied in cultured, fibroblastic cell lines. Here, we demonstrate that oncogenic Ha-Ras or constitutively active Her-2 cause increased proliferation and cyclin D1 upregulation in fully polarized, mammary epithelial cells (EpH4), if cultivated as organotypic structures in three-dimensional collagen/matrigel matrices. Under standard culture conditions, however, these oncogenes failed to induce hyperproliferation. Using both specific low molecular weight inhibitors and Ras-effector-specific mutants, we dissected signaling pathways downstream of oncogenic Ras (PI3K, Mek1/MAPK) with respect to (i) hyperproliferation in collagen gels and tumorigenesis in mice and (ii) epithelial/mesenchymal transition (EMT). We show that the Ras-activated PI3K pathway is required to induce rapid tumor growth and enhanced proliferation of EpH4 cells in collagen gels, but fails to cause EMT in vitro and in vivo. On the other hand, Ras-dependent activation of the Mek1/MAPK pathway in EpH4 cells (previously shown to cause EMT and metastasis) did not induce hyperproliferation in collagen gels and caused only slow tumor growth. Our data thus indicate that Ras-dependent signaling through the PI3K- and MAPK pathways fulfil distinct, but complementary functions during carcinogenesis.

Animals↗
PubMed2003

Selective activation of the c-Jun N-terminal kinase (JNK) pathway fails to elicit Bax activation or apoptosis unless the phosphoinositide 3'-kinase (PI3K) pathway is inhibited.

c-Jun N-terminal kinase (JNK) is activated when cells are exposed to noxious stimuli. The role of JNK in apoptosis is subject to considerable debate; for example, JNK activation may promote or inhibit apoptosis depending on the cell type and stimulus involved. These conflicting results have arisen in part because few studies have successfully separated JNK activation from the primary stress-induced damage or from other stress-induced signalling pathways. Here we describe a conditional mutant, deltaMEKK1:ER*, which allows selective activation of the JNK cascade in the absence of any cellular stress. Activation of deltaMEKK1:ER* in CC139 fibroblasts resulted in the rapid and sustained activation of JNK without activating ERK or p38 or promoting IkappaBalpha phosphorylation. Activation of deltaMEKK1:ER* caused a reversible halt in cell growth but failed to induce apoptosis. In contrast, treatment of cells with LY294002, to inhibit phosphoinositide 3-kinase (PI3K), caused downregulation of Bcl-2 and Mcl-1 and allowed deltaMEKK1:ER* to elicit a robust apoptotic response characterized by activation of Bax and caspases. This PI3K-inhibitable, JNK-induced death response was not impeded, but actually accelerated, by cycloheximide. This suggests that JNK-induced activation of Bax and cell death does not require the upregulation of pro-death genes such as Bim or FasL, but rather proceeds through pre-existing components. However, if the PI3K cell survival pathway is not inhibited, even sustained activation of JNK exerts no overt proapoptotic effect in CC139 cells.

Animals↗
PubMed2005

Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway.

Epidermal growth factor receptor (EGFR) is expressed, albeit at low or intermediate levels, in human melanomas at the different stages of tumor progression. Coexpression of EGFR with its ligand TGFalpha indicates their role in paracrine and autocrine growth regulation of melanomas. As it was previously observed for several types of cancer, specific inhibitors of EGFR-mediated signaling may reduce antiapoptotic properties of cancer cells and sensitize them to cytotoxic drugs. We recently reported that arsenite, particularly in combination with inhibitors of the PI3K-AKT and mitogen-activated protein kinase (MAPK) kinase (MEK)-extracellular signal-regulated kinase (ERK) pathways, induces high levels of apoptosis in different melanomas. Since EGFR signaling operates via activation of the PI3K-AKT and MEK-ERK pathways, we suggested that the combination of arsenite and EGFR inhibitors might also effectively induce apoptosis in melanoma. Here, we demonstrate that a moderate concentration of arsenite (5-10 muM) indeed upregulates apoptosis induced by EGFR inhibitors in EGFR-positive melanomas. In contrast, induction of apoptosis in melanomas with negligible surface expression of EGFR or with defective EGFR signaling requires direct suppression of the PI3K-AKT and MAPK pathways by specific pharmacological inhibitors in the presence of arsenite. Under these conditions, metastatic melanoma cell lines undergo TNF-related apoptosis-inducing ligand (TRAIL)- and tumor necrosis factor alpha (TNFalpha)-mediated apoptosis. Taken together, these data provide additional approaches in sensitizing melanomas to the cytotoxic effects of specific inhibitors of survival pathways.

Apoptosis↗
PubMed2007

p56lck, LFA-1 and PI3K but not SHP-2 interact with GM1- or GM3-enriched microdomains in a CD4-p56lck association-dependent manner.

We previously showed that the association of CD4 and G(M3) ganglioside induced by CD4 ligand binding was required for the down-regulation of adhesion and that aggregation of ganglioside-enriched domains was accompanied by transient co-localization of LFA-1 (lymphocyte function-associated antigen-1), PI3K (phosphoinositide 3-kinase) and CD4. We also showed that these proteins co-localized with the G(M1) ganglioside that partially co-localized with G(M3) in these domains. In the present study, we show that CD4-p56(lck) association in CD4 signalling is required for the redistribution of p56(lck), PI3K and LFA-1 in ganglioside-enriched domains, since ganglioside aggregation and recruitment of these proteins were not observed in a T-cell line (A201) expressing the mutant form of CD4 that does not bind p56(lck). In addition, we show that although these proteins associated in different ways with G(M1) and G(M3), all of the associations were dependent on CD4-p56(lck) association. Gangliosides could associate with these proteins that differ in affinity binding and could be modified following CD4 signalling. Our results suggest that through these associations, gangliosides transiently sequestrate these proteins and consequently inhibit LFA-1-dependent adhesion. Furthermore, while structural diversity of gangliosides may allow association with distinct proteins, we show that the tyrosine phosphatase SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase 2), also required for the down-regulation of LFA-1-dependent adhesion, transiently and partially co-localized with PI3K and p56(lck) in detergent-insoluble membranes without association with G(M1) or G(M3). We propose that CD4 ligation and binding with p56(lck) and their interaction with G(M3) and/or G(M1) gangliosides induce recruitment of distinct proteins important for CD4 signalling to form a multimolecular signalling complex.

Antibodies↗
PubMed2002

Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes.

The mechanisms by which bile acids induce apoptosis in hepatocytes and the signaling pathways involved in the control of cell death are not understood fully. Here, we examined the impact of mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3-kinase (PI3K) signaling on the survival of primary hepatocytes exposed to bile acids. Treatment of hepatocytes with deoxycholic acid (DCA), chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA) caused sustained MAPK activation that was dependent on activation of the epidermal growth factor receptor (EGFR). Activation of MAPK was partially blocked by inhibitors of PI3K. Inhibition of DCA-, CDCA-, and UDCA-stimulated MAPK activation resulted in approximately 20%, approximately 35%, and approximately 55% apoptosis, respectively. The potentiation of DCA- and CDCA-induced apoptosis by MEK1/2 inhibitors correlated with cleavage of procaspase 3, which was blocked by inhibitors of caspase 8 (ile-Glu-Thr-Asp-p-nitroanilide [IETD]) and caspase 3 (DEVD). In contrast, the potentiation of UDCA-induced apoptosis weakly correlated with procaspase 3 cleavage, yet this effect was also blocked by IETD and DEVD. Incubation of hepatocytes with the serine protease inhibitor AEBSF reduced the death response of cells treated with UDCA and MEK1/2 inhibitor to that observed for DCA and MEK1/2 inhibitor. The apoptotic response was FAS receptor- and neutral sphingomyelinase-dependent and independent of FAS ligand expression, and neither chelation of intracellular and extracellular Ca(2+) nor down-regulation of PKC expression altered the apoptotic effects of bile acids. In conclusion, bile acid apoptosis is dependent on the production of ceramide and is counteracted by activation of the MAPK and PI3K pathways.

Animals↗
PubMed2000

Role of the PI3K regulatory subunit in the control of actin organization and cell migration.

Cell migration represents an important cellular response that utilizes cytoskeletal reorganization as its driving force. Here, we describe a new signaling cascade linking PDGF receptor stimulation to actin rearrangements and cell migration. We demonstrate that PDGF activates Cdc42 and its downstream effector N-WASP to mediate filopodia formation, actin stress fiber disassembly, and a reduction in focal adhesion complexes. Induction of the Cdc42 pathway is independent of phosphoinositide 3-kinase (PI3K) enzymatic activity, but it is dependent on the p85alpha regulatory subunit of PI3K. Finally, data are provided showing that activation of this pathway is required for PDGF-induced cell migration on collagen. These observations show the essential role of the PI3K regulatory subunit p85alpha in controlling PDGF receptor-induced cytoskeletal changes and cell migration, illustrating a novel signaling pathway that links receptor stimulation at the cell membrane with actin dynamics.

3T3 Cells↗
PubMed2005

Involvement of PI3K and MAPK signaling in bcl-2-induced vascular endothelial growth factor expression in melanoma cells.

We have previously demonstrated that bcl-2 overexpression in tumor cells exposed to hypoxia increases the expression of vascular endothelial growth factor (VEGF) gene through the hypoxia-inducible factor-1 (HIF-1). In this article, we demonstrate that exposure of bcl-2 overexpressing melanoma cells to hypoxia induced phosphorylation of AKT and extracellular signal-regulated kinase (ERK)1/2 proteins. On the contrary, no modulation of these pathways by bcl-2 was observed under normoxic conditions. When HIF-1alpha expression was reduced by RNA interference, AKT and ERK1/2 phosphorylation were still induced by bcl-2. Pharmacological inhibition of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways reduced the induction of VEGF and HIF-1 in response to bcl-2 overexpression in hypoxia. No differences were observed between control and bcl-2-overexpressing cells in normoxia, in terms of VEGF protein secretion and in response to PI3K and MAPK inhibitors. We also demonstrated that RNA interference-mediated down-regulation of bcl-2 expression resulted in a decrease in the ERK1/2 phosphorylation and VEGF secretion only in bcl-2-overexpressing cell exposed to hypoxia but not in control cells. In conclusion, our results indicate, for the first time, that bcl-2 synergizes with hypoxia to promote expression of angiogenesis factors in melanoma cells through both PI3K- and MAPK-dependent pathways.

Apoptosis↗
PubMed2006

JNK and PI3K differentially regulate MMP-2 and MT1-MMP mRNA and protein in response to actin cytoskeleton reorganization in endothelial cells.

Increased production and activation of matrix metalloproteinase-2 (MMP-2) are critical events in skeletal muscle angiogenesis and are known to occur in response to mechanical stresses. We hypothesized that reorganization of the actin cytoskeleton would increase endothelial cell production and activation of MMP-2 and that this increase would require a MAPK-dependent signaling pathway in endothelial cells. The pharmacological actin depolymerization agent cytochalasin D increased expression of MMP-2 and membrane type 1-matrix metalloproteinase (MT1-MMP) mRNA, and this was reduced significantly in the presence of the JNK inhibitor SP600125. Activation of JNK by anisomycin was sufficient to induce expression of both MMP-2 and MT1-MMP mRNA in quiescent cells. Downregulation of c-Jun, a downstream target of JNK, with small interference (si)RNA inhibited MMP-2 expression in response to anisomycin. Inhibition of phosphoinositide 3-kinase (PI3K), but not JNK, significantly decreased the amount of active MMP-2 following cytochalasin D stimulation with a concurrent decrease in MT1-MMP protein. Physiological reorganization of actin occurs during VEGF stimulation. VEGF-induced MMP-2 protein production and activation, as well as MT1-MMP protein production, depended on PI3K activity. VEGF-induced MMP-2 mRNA expression was reduced by inhibition of JNK or by treatment with c-Jun siRNA. In summary, our results provide novel insight into the signaling cascades initiated in the early stages of angiogenesis through the reorganization of the actin cytoskeleton and demonstrate a critical role for JNK in regulating MMP-2 and MT1-MMP mRNA expression, whereas PI3K regulates protein levels of both MMP-2 and MT1-MMP.

Actins↗
PubMed2002

PI3K signaling is required for prostaglandin-induced mucosal recovery in ischemia-injured porcine ileum.

We have previously shown that PGE(2) and PGI(2) induce recovery of transepithelial resistance (TER) in ischemia-injured porcine ileal mucosa, associated with initial increases in Cl(-) secretion. We believe that the latter generates an osmotic gradient that stimulates resealing of tight junctions. Because of evidence implicating phosphatidylinositol 3-kinase (PI3K) in regulating tight junction assembly, we postulated that this signaling pathway is involved in PG-induced mucosal recovery. Porcine ileum was subjected to 45 min of ischemia, after which TER was monitored for a 180-min recovery period. Endogenous PG production was inhibited with indomethacin (5 microM). PGE(2) (1 microM) and PGI(2) (1 microM) stimulated recovery of TER, which was inhibited by serosal application of the osmotic agent urea (300 mosmol/kgH(2)O). The PI3K inhibitor wortmannin (10 nM) blocked recovery of TER in response to PGs or mucosal urea. Immunofluorescence imaging of recovering epithelium revealed that PGs restored occludin and zonula occludens-1 distribution to interepithelial junctions, and this pattern was disrupted by pretreatment with wortmannin. These experiments suggest that PGs stimulate recovery of paracellular resistance via a mechanism involving transepithelial osmotic gradients and PI3K-dependent restoration of tight junction protein distribution.

16,16-Dimethylprostaglandin E2↗
PubMed2004

Met5-enkephalin-induced cardioprotection occurs via transactivation of EGFR and activation of PI3K.

Our previous studies indicated that opioid-induced cardioprotection occurs via activation of mitochondrial ATP-sensitive K(+) (K(ATP)) channels. However, other elements of the Met(5)-enkephalin (ME) cardioprotection pathway are not fully characterized. In the present study, we investigated the role of tyrosine kinase, MAPK, and phosphatidylinositol 3-kinase (PI3K) signaling in ME-induced protection. Ca(2+)-tolerant, adult rabbit cardiomyocytes were isolated by collagenase digestion and subjected to simulated ischemia for 180 min. ME was administered 15 min before the 180 min of simulated ischemia; blockers were administered 15 min before ME. Cell death was assessed by trypan blue as a function of time. The epidermal growth factor receptor (EGFR) kinase inhibitor AG-1478 (250 nM) blocked ME-induced protection, but the inactive analog AG-9 (100 microM) did not. Treatment with herbimycin (1 microM) completely eliminated ME-induced protection. To verify that ME activates EGFR and to determine the involvement of Src, Western blotting of EGFR was performed after ME administration with and without herbimycin A. ME resulted in herbimycin-sensitive robust phosphorylation of EGFR at Tyr(992) and Tyr(1068). Administration of the selective MAPK inhibitor PD-98059 (10 nM) and the specific MEK1/2 inhibitor U-0126 (10 microM) also inhibited ME-induced cardioprotection. ME-induced ERK1/2 phosphorylation was significantly reduced by PD-98059, the EGFR kinase inhibitor PD-153035 (10 microM), and chelerythrine (2 microM). The PI3K inhibitor LY-294002 (20 microM) abrogated ME-induced protection, and ME-induced Akt phosphorylation at Ser(473) was suppressed by LY-294002, PD-153035, and chelerythrine. We conclude that ME-induced cardioprotection is mediated via Src-dependent EGFR transactivation and activation of the PI3K and MAPK pathways.

Animals↗
PubMed1998

ATP-stimulated smooth muscle cell proliferation requires independent ERK and PI3K signaling pathways.

Vascular smooth muscle cells respond to the purinergic agonist ATP by increasing intracellular calcium concentration and increasing the rate of cell proliferation. In many cells the extracellular signal-regulated kinase (ERK) cascade plays an important role in cellular proliferation. We have studied the effect of extracellular ATP on ERK activation and cell proliferation. ATP binding to a UTP-sensitive P2Y nucleotide receptor activates ERK1/ERK2 in a time- and dose-dependent manner in coronary artery smooth muscle cells (CASMC). ATP-induced activation of ERK1/ERK2 is dependent on the dual-specificity kinase mitogen-activated protein kinase/ERK kinase (i.e., MEK) but independent of phosphatidylinositol 3-kinase (PI3K) activity. We provide evidence that both ERK1/ERK2 and PI3K activities are required for CASMC proliferation. Thus ATP-stimulation of CASMC proliferation requires independent activation of both the ERK and PI3K signaling pathways.

Adenosine Triphosphate↗
PubMed1999

Participation of PI3K and atypical PKC in Na+-K+-pump stimulation by IGF-I in VSMC.

The activity of the Na+-K+-pump is intricately linked to the maintenance of vascular tone. Here we demonstrate that insulin-like growth factor I (IGF-I) increases Na+-K+-pump activity in the vascular smooth muscle cell (VSMC) clone A7r5 in a time- and dose-dependent manner. This stimulatory effect of IGF-I was prevented by the tyrosine kinase inhibitor genistein (5 microM) and by the specific phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin (100 nM) and LY-294002 (25 microM). IGF-I activated a wortmannin-sensitive PI3K and its purported effector, the atypical protein kinase C (PKC)-zeta. Stimulation of PKC-zeta was prevented by the generic PKC inhibitor GF109203x (bisindolylmaleimide, 10 microM). Downregulation of diacylglycerol-sensitive (conventional and novel) PKCs by 24-h pretreatment with 1 microM phorbol 12-myristate 13-acetate had no effect on IGF-I-stimulated Na+-K+-pump activity. Similarly, inhibition of only conventional and novel PKCs with GF109203x (1 microM) had no effect on IGF-I-stimulated Na+-K+-pump activity. In contrast, a concentration of GF109203x (10 microM) that also inhibits the atypical PKCs abolished Na+-K+-pump stimulation by IGF-I. Neither the Na+-K+-2Cl- cotransporter inhibitor bumetanide (100 microM) nor the Na+/H+ exchanger inhibitor HOE-694 (5 microM) affected the Na+-K+-pump stimulation by IGF-I, suggesting that a rise in intracellular Na+ concentration is not necessary for increased Na+-K+-pump activity. These results suggest that IGF-I directly stimulates the Na+-K+ pump via a signaling pathway involving PI3K and atypical PKC (zeta).

Cell Line↗
PubMed2006

Mitochondrial aldehyde dehydrogenase attenuates hyperoxia-induced cell death through activation of ERK/MAPK and PI3K-Akt pathways in lung epithelial cells.

Oxygen toxicity is one of the major risk factors in the development of the chronic lung disease or bronchopulmonary dysplasia in premature infants. Using proteomic analysis, we discovered that mitochondrial aldehyde dehydrogenase (mtALDH or ALDH2) was downregulated in neonatal rat lung after hyperoxic exposure. To study the role of mtALDH in hyperoxic lung injury, we overexpressed mtALDH in human lung epithelial cells (A549) and found that mtALDH significantly reduced hyperoxia-induced cell death. Compared with control cells (Neo-A549), the necrotic cell death in mtALDH-overexpressing cells (mtALDH-A549) decreased from 25.3 to 6.5%, 50.5 to 9.1%, and 52.4 to 15.1% after 24-, 48-, and 72-h hyperoxic exposure, respectively. The levels of intracellular and mitochondria-derived reactive oxygen species (ROS) in mtALDH-A549 cells after hyperoxic exposure were significantly lowered compared with Neo-A549 cells. mtALDH overexpression significantly stimulated extracellular signal-regulated kinase (ERK) phosphorylation under normoxic and hyperoxic conditions. Inhibition of ERK phosphorylation partially eliminated the protective effect of mtALDH in hyperoxia-induced cell death, suggesting ERK activation by mtALDH conferred cellular resistance to hyperoxia. mtALDH overexpression augmented Akt phosphorylation and maintained the total Akt level in mtALDH-A549 cells under normoxic and hyperoxic conditions. Inhibition of phosphatidylinositol 3-kinase (PI3K) activation by LY294002 in mtALDH-A549 cells significantly increased necrotic cell death after hyperoxic exposure, indicating that PI3K-Akt activation by mtALDH played an important role in cell survival after hyperoxia. Taken together, these data demonstrate that mtALDH overexpression attenuates hyperoxia-induced cell death in lung epithelial cells through reduction of ROS, activation of ERK/MAPK, and PI3K-Akt cell survival signaling pathways.

Aldehyde Dehydrogenase↗
PubMed2006

Regulation of vascular endothelial growth factor expression by EMMPRIN via the PI3K-Akt signaling pathway.

Extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN) is a cell surface glycoprotein overexpressed in many solid tumors. In addition to its ability to stimulate stromal MMP expression, tumor-associated EMMPRIN also induces vascular endothelial growth factor (VEGF) expression. To explore the underlying signaling pathways used by EMMPRIN, we studied the involvement of phosphoinositide 3-kinase (PI3K)-Akt, mitogen-activated protein kinase (MAPK), JUN, and p38 kinases in EMMPRIN-mediated VEGF regulation. Overexpression of EMMPRIN in MDA-MB-231 breast cancer cells stimulated the phosphorylation of only Akt and MAPKs but not that of JUN and p38 kinases. Conversely, inhibition of EMMPRIN expression resulted in suppressed Akt and MAPK phosphorylation. Furthermore, the PI3K-specific inhibitor LY294002 inhibited VEGF production by EMMPRIN-overexpressing cells in a dose- and time-dependent manner. On the other hand, the MAPK inhibitor U0126 did not affect VEGF production. In vivo, EMMPRIN-overexpressing tumors with elevated VEGF expression had a high level of phosphorylation of Akt and MAPK. Finally, when fibroblast cells were treated with recombinant EMMPRIN, Akt kinase but not MAPK was phosphorylated concomitant with an increase in VEGF production. Both the activation of Akt kinase and the induction of VEGF were specifically inhibited with a neutralizing antibody to EMMPRIN. Our results show that in both tumor and fibroblast cells EMMPRIN regulates VEGF production via the PI3K-Akt pathway but not via the MAPK, JUN, or p38 kinase pathways.

Animals↗