Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a ligand-binding inducible transcriptional factor linked to carcinogenesis. Important functions of PPARbeta/delta were demonstrated in series of human epithelial cancers; however, its role in lung cancer remains controversial. We investigated the differential expression level and localization of PPARbeta/delta in tumors and adjacent normal lung tissue, and the effect of PPARbeta/delta activation on lung cancer cell proliferation and apoptosis. PPARbeta/delta was expressed in all studied human non-small cell lung cancers, and strong PPARbeta/delta immunoreactivity was observed in epithelial cells of more than 75% of studied lung tumors. PPARbeta/delta expression was consistently limited to the cancer cells in tumor tissue, while in adjacent normal lung tissue it was limited predominantly to the mononuclear cells. We found that ligand-binding activation of PPARbeta/delta stimulates cell proliferation (an effect that was blocked by a dominant-negative construct of PPARbeta/delta), stimulates anchorage-independent cell growth, and inhibits apoptosis in lung cancer cell lines. Importantly, the activation of PPARbeta/delta induces Akt phosphorylation correlated with up-regulation of PDK1, down-regulation of PTEN, and increased expression of Bcl-xL and COX-2. These findings indicate that PPARbeta/delta exerts proliferative and anti-apoptotic effects via PI3K/Akt1 and COX-2 pathways. In conclusion, PPARbeta/delta is strongly expressed in the majority of lung cancers, and its activation induces proliferative and survival response in non-small cell lung cancer.
Am J Respir Cell Mol Biol 2008 Dec
PMID:Peroxisome proliferator-activated receptor beta/delta expression and activation in lung cancer. 1856 35

In order to understand the transcriptional mechanism that underlies cell protection to stress, we evaluated the role of CLP-1, a known inhibitor of the transcription elongation complex (pTEFb), in CLP-1 +/- mice hearts. Using the isolated heart model, we observed that the CLP-1 +/- hearts, when subjected to ischaemic stress and evaluated by haemodynamic measurements, exhibit significant cardioprotection. CLP-1 remains associated with the pTEFb complex in the heterozygous hearts, where as it is released in the wild-type hearts suggesting the involvement of pTEFb regulation in cell protection. There was a decrease in Cdk7 and Cdk9 kinase activity and consequently in phosphorylation of serine-5 and serine-2 of Pol II CTD in CLP-1 +/- hearts. However, the levels of mitochondrial proteins, PGC-1alpha and HIF-1alpha, which enhance mitochondrial activity and are implicated in cell survival, were increased in CLP-1 +/- hearts subjected to ischaemic stress compared to that in wild-type CLP-1 +/- hearts treated identically. There was also an increase in the expression of pyruvate dehydrogenase kinase (PDK-1), which facilitates cell adaptation to hypoxic stress. Taken together, our data suggest that regulation of the CLP-1 levels is critical to cellular adaptation of the survival program that protects cardiomyocytes against stress due collectively to a decrease in RNA Pol II phosphorylation but an increase in expression of target proteins that regulate mitochondrial function and metabolic adaptation to stress.
J Cell Mol Med 2009 Aug
PMID:Down-regulation of cardiac lineage protein (CLP-1) expression in CLP-1 +/- mice affords. 1862 53

Pressure overload (PO) first causes cardiac hypertrophy and then heart failure (HF), which are associated with sex differences in cardiac morphology and function. We aimed to identify genes that may cause HF-related sex differences. We used a transverse aortic constriction (TAC) mouse model leading to hypertrophy without sex differences in cardiac function after 2 weeks, but with sex differences in hypertrophy 6 and 9 weeks after TAC. Cardiac gene expression was analyzed 2 weeks after surgery. Deregulated genes were classified into functional gene ontology (GO) categories and used for pathway analysis. Classical marker genes of hypertrophy were similarly upregulated in both sexes (alpha-actin, ANP, BNP, CTGF). Thirty-five genes controlling mitochondrial function (PGC-1, cytochrome oxidase, carnitine palmitoyl transferase, acyl-CoA dehydrogenase, pyruvate dehydrogenase kinase) had lower expression in males compared to females after TAC. Genes encoding ribosomal proteins and genes associated with extracellular matrix remodeling exhibited relative higher expression in males (collagen 3, matrix metalloproteinase 2, TIMP2, and TGFbeta2, all about twofold) after TAC. We confirmed 87% of the gene expression by real-time polymerase chain reaction. By GO classification, female-specific genes were related to mitochondria and metabolism and males to matrix and biosynthesis. Promoter studies confirmed the upregulation of PGC-1 by E2. Less downregulation of metabolic genes in female hearts and increased protein synthesis capacity and deregulation of matrix remodeling in male hearts characterize the sex-specific early response to PO. These differences could contribute to subsequent sex differences in cardiac function and HF.
J Mol Med (Berl) 2008 Sep
PMID:Sex-specific pathways in early cardiac response to pressure overload in mice. 1866 44

Intraneuronal beta-amyloid (Abeta(i)) accumulates early in Alzheimer's disease (AD) and inclusion body myositis. Several organelles, receptor molecules, homeostatic processes, and signal transduction components have been identified as sensitive to Abeta. Although prior studies implicate the insulin-PI3K-Akt signaling cascade, a specific step within this or any essential metabolic or survival pathway has not emerged as a molecular target. We tested the effect of Abeta42 on each component of this cascade. In AD brain, the association between PDK and Akt, phospho-Akt levels and its activity were all decreased relative to control. In cell culture, Abeta(i) expression inhibited both insulin-induced Akt phosphorylation and activity. In vitro experiments identified that beta-amyloid (Abeta), especially oligomer preparations, specifically interrupted the PDK-dependent activation of Akt. Abeta(i) also blocked the association between PDK and Akt in cell-based and in vitro experiments. Importantly, Abeta did not interrupt Akt or PI3K activities (once stimulated) nor did it affect more proximal signal events. These results offer a novel therapeutic strategy to neutralize Abeta-induced energy failure and neuronal death.
Mol Biol Cell 2009 Mar
PMID:The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. 1914 26

The phosphoinositide 3-kinase (PI3K)/phosphoinositide dependent kinase 1 (PDK1) signaling pathway exerts cardioprotective effects in the myocardium through activation of key proteins including Akt. Activated Akt accumulates in nuclei of cardiomyocytes suggesting that biologically relevant targets are located in that subcellular compartment. Nuclear Akt activity could be potentiated in both intensity and duration by the presence of a nuclear-associated PI3K/PDK1 signaling cascade as has been described in other non-myocyte cell types. PI3K/PDK1 distribution was determined in vitro and in vivo by immunostaining and nuclear extraction of cultured rat neonatal cardiomyocytes or transgenic mouse hearts. Results show that PI3K and PDK1 are present at a basal level in cardiomyocytes nuclei and that cardioprotective stimulation with atrial natriuretic peptide (ANP) increases their nuclear localization. In comparison, overexpression of nuclear-targeted Akt does not mediate increased translocation of either PI3K or PDK1 indicating that accumulation of Akt does not drive PI3K or PDK1 into the nuclear compartment. Furthermore, PI3K and phospho-Akt(473) show parallel temporal accumulation in the nucleus following (MI) infarction challenge. These findings demonstrate the presence of a dynamically regulated nuclear-associated signaling cascade involving PI3K and PDK that presumably influences nuclear Akt activation.
J Mol Cell Cardiol 2009 Jul
PMID:Cardioprotective stimuli mediate phosphoinositide 3-kinase and phosphoinositide dependent kinase 1 nuclear accumulation in cardiomyocytes. 1926 95

Grb14 belongs to the Grb7 family of molecular adapters and was identified as an inhibitor of insulin signaling. Grb14 binds to activated insulin receptors (IR) and inhibits their catalytic activity. To gain more insight into the Grb14 molecular mechanism of action, we generated various mutants and studied the Grb14-IR interaction using coimmunoprecipitation and bioluminescence resonance energy transfer (BRET) experiments. Biological activity was further analyzed using the Xenopus oocyte model and a functional complementation assay measuring cellular proliferation rate in Grb14 knockout mouse embryonic fibroblasts. These studies identified two important interaction sites, Grb14 L404-IR L1038 and Grb14 R385-IR K1168, involving the IR alphaC-helix and activation loop, respectively. Interestingly, the former involves residues that are likely to be crucial for the specificity of IR binding with regard to other members of the Grb7 family. In addition, mutation of the Grb14-S370 residue suggested that its phosphorylation status controlled the biological activity of the protein. We further demonstrated that insulin-induced Grb14-PDK1 interaction is required in addition to Grb14-IR binding to mediate maximal inhibition of insulin signaling. This study provides important insights into the molecular determinants of Grb14 action by demonstrating that Grb14 regulates insulin action at two levels, through IR binding and by interfering with downstream pathways. Indeed, a precise knowledge of the molecular mechanism of insulin signaling inhibition by Grb14 is a prerequisite for the development of insulin-sensitizing molecules to treat pathophysiological states such as obesity or type 2 diabetes.
Mol Endocrinol 2009 Jul
PMID:Molecular determinants of Grb14-mediated inhibition of insulin signaling. 1935 42

Oxidative stress and inflammation are implicated in the pathogenesis of many age-related diseases. We have demonstrated previously that oxidative inactivation of the proteasome is a molecular link between oxidative stress and overexpression of interleukin (IL)-8. Here, we elucidated a novel signaling cascade that leads to up-regulation of IL-8 in response to proteasome inactivation. The sequence of events in this cascade includes proteasome inactivation, activation of mitogen-activated protein kinase kinase (MKK)3/MKK6, activation of p38 mitogen-activated protein kinase (MAPK), epidermal growth factor receptor phosphorylation, phosphatidylinositol 3-kinase (PI3K) activation and increased IL-8 expression. Blocking any of these signaling pathways abolished the up-regulation of IL-8 induced by proteasome inhibition. Although Akt is also activated in response to proteasome inactivation, we found that the PI3K-dependent up-regulation of IL-8 is independent of 3-phosphoinositide-dependent protein kinase (PDK)1 and Akt. Inhibition of PDK1 and Akt with chemical inhibitors or expression of constitutive active Akt had little effects on IL-8 expression in response to proteasome inactivation. In contrast, inhibition of interleukin 2-inducible T cell kinase, a kinase downstream of PI3K, significantly reduced the expression and secretion of IL-8 in response to proteasome inactivation. Together, these data elucidate a novel signaling network that leads to increased IL-8 production in response to proteasome inactivation.
Mol Biol Cell 2009 Aug
PMID:Proteasome inactivation promotes p38 mitogen-activated protein kinase-dependent phosphatidylinositol 3-kinase activation and increases interleukin-8 production in retinal pigment epithelial cells. 1957 Sep 15

Akt (PKB) is a critical kinase in cell-survival pathways. Its activity depends on the phosphorylation of Thr308 and Ser473, by PDK1 and mTORC2, respectively. We found that Akt can be further stimulated through phosphorylation of Ser129 by another kinase, CK2. Here we show that phosphorylation of Akt at Ser129 also facilitates its association with Hsp90 chaperone, thus preventing Thr308 dephosphorylation. This is supported by the following observations: (1) phospho-Thr308 decreases when Ser129 is mutated to alanine, (2) this decrease is abolished by cell treatment with okadaic acid (to inactivate PP2A) or geldanamycin (to inactivate Hsp90), (3) phosphorylation of Ser129 neither enhances the activity of PDK1 nor hampers the in vitro activity of PP2A on Thr308, but increases the Hsp90 association to Akt. These data support the view that the antiapoptotic potential of CK2 is at least in part mediated by its ability to maintain Akt in its active form.
Cell Mol Life Sci 2009 Oct
PMID:Dephosphorylation and inactivation of Akt/PKB is counteracted by protein kinase CK2 in HEK 293T cells. 1966 98

Atk can be activated by two independent phosphorylation events. Growth factor-dependent phosphorylation of threonine 308 (Akt-308) by phosphatidylinositol 3-kinase-dependent PDK1 leads to activation of mammalian target of rapamycin (mTor) complex 1 (TORC1) and stimulation of protein synthesis. Phosphorylation on serine 473 (Akt-473) is catalyzed by mTor in a second complex (TORC2), and Akt-473 phosphorylates Foxo3a to inhibit apoptosis. Accumulation of both phosphorylated forms of Akt is frequent in cancer, and TORC2 activity is required for progression to prostate cancer with Pten mutation. Here, we link Akt-473 to the Rb1 pathway and show that mTor is overexpressed with loss of the Rb1 family pathway. This leads to constitutive Akt-473 and, in turn, phosphorylation of Foxo3a and resistance to cell adhesion-dependent apoptosis (anoikis). Additionally, Akt-473 accumulation blocks c-Raf activation, thereby preventing downstream Erk activation. This block cannot be overcome by constitutively active Ras, and it also prevents induction of the Arf tumor suppressor by Ras. These studies link inactivation of the Rb1 pathway, a hallmark of cancer, to accumulation of Akt-473, resistance to anoikis, and a block in c-Raf/Erk activation.
Mol Cell Biol 2009 Nov
PMID:Mutation of the Rb1 pathway leads to overexpression of mTor, constitutive phosphorylation of Akt on serine 473, resistance to anoikis, and a block in c-Raf activation. 1970 98

It is well known that free fatty acids (FFAs) play a key role in implementing insulin resistance and type 2 diabetes. Resources of chemical compounds that intervene the derogatory effect of FFAs are indeed very limited. We have isolated mahanine, a carbazole alkaloid, from the leaves of Murraya koenegii that prevented palmitate-induced inhibition of insulin-stimulated phosphorylation of IRbeta, PI3K, PDK1, and Akt in L6 myotubes. This was also reflected in the palmitate-induced inhibition of insulin-stimulated [(3)H] 2-DOG uptake by L6 myotubes, where palmitate adverse effect was significantly blocked by mahanine. Previous reports indicated that one of the major targets of lipid-induced damage in insulin signaling pathway resulting impairment of insulin sensitivity is insulin receptor (IR). Here, we have observed that palmitate significantly increased pPKCepsilon in both cytosol and nuclear region of L6 myotubes in comparison to control. Translocation of pPKCepsilon to the nucleus was associated with the impairment of HMGA1, the architectural transcription factor of IR gene and all these were reversed by mahanine. Palmitate-induced activation of IKK/IkappaBeta/NF-kappaBeta pathway was also attenuated by mahanine. Taken together, mahanine showed encouraging possibility to deal with lipid induced insulin resistance. In order to examine it further, mahanine was administered on nutritionally induced type 2 diabetic golden hamsters; it significantly improved hyperglycemia in all the treated animals. Our results, therefore, suggest that mahanine acts on two important sites of lipid induced insulin resistance (i) impairment of IR gene expression and (ii) activation of NF-kappaBeta pathway, thus, showing promise for its therapeutic choice for type 2 diabetes.
Mol Cell Biochem 2010 Mar
PMID:Insulin resistance due to lipid-induced signaling defects could be prevented by mahanine. 1982 69


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