Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin mainly acts on the hypothalamus in the brain, in which it regulates food intake and energy expenditure. However, the direct effects of leptin on adipocytes have been controversial in the cellular level. In this study, the effects of leptin on rosiglitazone-induced adipocyte differentiation were investigated in the primary preadipocytes prepared from subcutaneous fat tissues of C57BL/6-Lep(ob/ob) mouse. We found that acute and prolonged treatment of leptin on preadipocytes inhibited the rosiglitazone-induced transcription factor expression and adipocyte differentiation, respectively, accompanied with decreased expression of PPARgamma and aP2. Either PD98059, an ERK inhibitor or fludarabine, a STAT1 inhibitor restored leptin-inhibited PPARgamma expression and subsequent lipid accumulation, but inhibitors for PI-3K (LY294002) and for STAT3 (piceatannol) did not. Furthermore, leptin decreased PPARgamma expression also in fully differentiated adipocytes, which was reversed by either PD98059 or fludarabine. Taken together, these data suggest that leptin has a direct inhibitory effect on the rosiglitazone-induced adipocyte differentiation and PPARgamma expression, in which ERK1/2 MAP kinase and JAK/STAT1 signaling pathways are involved.
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PMID:Leptin inhibits rosiglitazone-induced adipogenesis in murine primary adipocytes. 1879 Jul 15

Insulin resistance and obesity are underlying causes of type 2 diabetes and therefore much interest is focused on the potential genes involved. A series of anthropometric and metabolic characteristic were measured in 240 MZ and 112 DZ twin pairs recruited from the East Flanders Prospective Twin Survey. Microsatellite markers located close to ABCC8, ADIPOQ, GCK, IGF1, IGFBP1, INSR, LEP, LEPR, PPARgamma and the RETN gene were genotyped. Univariate single point variance components linkage analyses were performed using two methods: (1) the standard method, only comprising the phenotypic and genotypic data of the DZ twin pairs and (2) the extended method, also incorporating the phenotypic data of the MZ twin pairs. Suggestive linkages (LOD > 1) were observed between the ABCC8 marker and waist-to-hip ratio and HDL-cholesterol levels. Both markers flanking ADIPOQ showed suggestive linkage with triglycerides levels, the upstream marker also with body mass and HDL-cholesterol levels. The IGFBP1 marker showed suggestive linkage with fat mass, fasting insulin and leptin levels and the LEP marker showed suggestive linkage with birth weight. This study suggests that DNA variants in ABCC8, ADIPOQ, IGFBP1 and LEP gene region may predispose to type 2 diabetes. In addition, the two methods used to perform linkage analyses yielded similar results. This was however not the case for birth weight where chorionicity seems to be an important confounder.
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PMID:Anthropometry, carbohydrate and lipid metabolism in the East Flanders Prospective Twin Survey: linkage of candidate genes using two sib-pair based variance components analyses. 1882 33

Retinoic acids (RAs) and also their analogs (synthetic retinoids and rexinoids) have been regarded as major therapeutic and/or chemopreventive agents and can regulate a number of diverse processes-such as immune system, hormonal systems. In this work we describe different effects of short-term treatment of Wistar male rats with 13-cis retinoic acid on the regulation of retinoic acid receptors (RARs), retinoid-X receptors (RXRs), thyroid hormone receptors (TRs), ERs, 5'-DI, EGFR and erb-B2/neu genes in liver and/or spleen. Using RT-PCR analysis we have found that administration of 13-cis retinoic acid enhanced expression of RARbeta and PPARgamma mRNA, and decreased expression of RARalpha, RARgamma, RXRbeta and TRbeta mRNA in liver. On the other hand, in spleen this treatment resulted in decreased expression of RARalpha, RARbeta, RARgamma, TRalpha and ERbeta mRNA. Our findings indicate distinct modulation of various signal pathways by short-term administration of 13cRA, which also differ in spleen when compared to liver. We suggest that even a short-term treatment of rats with 13cRA may affect a reasonable number of steps in retinoid signaling pathways, a number of which might be very likely extended by long-term treatment of mammals by 13-cis retinoic acid.
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PMID:Different mRNA expression profiling of nuclear retinoid, thyroid, estrogen and PPARgamma receptors, their coregulators and selected genes in rat liver and spleen in response to short-term in vivo administration of 13-cis retinoic acid. 1904 96

Well-differentiated thyroid carcinomas comprise two well-defined histological types: papillary and follicular (PTCs and FTCs, respectively). Despite being derived from the same cell (thyroid follicular cell), these two types of tumour accumulate distinct genetic abnormalities during progression. The molecular pathology of thyroid cancer is now better understood because of our ability to identify RET/PTC rearrangements and BRAF mutations in the aetiopathogenesis of the large majority of PTCs and the high prevalence of RAS mutations and PAX8/PPARgamma rearrangements in follicular patterned carcinomas (FTCs and follicular variant of PTCs). This review summarises most of the molecular alterations currently used as targets for new biological treatments and looks at some of the changes that are already occurring or may occur in the treatment of patients with thyroid cancer. For simplicity, the review is divided up according to the major genetic alterations identified in well-differentiated thyroid carcinomas (RET/PTC rearrangements, BRAF mutations, RAS mutations and mitochondrial DNA deletions and mutations) and their respective treatments.
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PMID:How molecular pathology is changing and will change the therapeutics of patients with follicular cell-derived thyroid cancer. 1914 28

The successful demonstration that the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of breast cancer has stimulated great interest in using drugs to prevent breast cancer in high-risk women. In addition, recent results from breast cancer treatment trials suggest that aromatase inhibitors may be even more effective at preventing breast cancer than are SERMs. However, while SERMs and aromatase inhibitors do prevent the development of many estrogen-receptor (ER)-positive breast cancers, these drugs do not prevent the development of ER-negative breast cancer. Thus, there is an urgent need to identify agents that can prevent ER-negative breast cancer. We have studied the cancer preventative activity of several classes of drugs for their ability to prevent ER-negative breast cancer in preclinical models. Results from these studies demonstrate that rexinoids (analogs of retinoids that bind and activate RXR receptors), tyrosine kinase inhibitors (such as EGFR inhibitors and dual kinase inhibitors that block EGFR and HER2/neu signaling), and cyclo-oxygenase 2 (COX-2) inhibitors all prevent ER-negative breast cancer in transgenic mice that develop ER-negative breast cancer. Other promising agents now under investigation include vitamin D and vitamin D analogs, drugs that activate PPAR-gamma nuclear receptors, and statins. Many of these agents are now being tested in early phase cancer prevention clinical trials to determine whether they will show activity in breast tissue and whether they are safe for use in high-risk women without breast cancer. The current status of these studies will be reviewed. It is anticipated that in the future, drugs that effectively prevent ER-negative breast cancer will be used in combination with hormonal agents such SERMs or aromatase inhibitors to prevent all forms of breast cancer.
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PMID:Prevention of ER-negative breast cancer. 1921 64

Mesenchymal stem cells (MSCs) provide us an excellent cellular model to uncover the molecular mechanisms underlying adipogenic differentiation of adult stem cells. PPARgamma had been considered as an important molecular marker of cells undergoing adipogenic differentiation. Here, we demonstrated that expression and phosphorylation of PPARgamma could be found in bone marrow-derived MSCs cultured in expansion medium without any adipogenic additives (dexamethasone, IBMX, insulin or indomethacin). Then, PPARgamma was dephosphorylated in MSCs during the process of adipogenic differentiation. We then found that inhibition of MEK activation by specific inhibitor (PD98059) counteracted the PPARgamma expression and phosphorylation. However, expression and phosphorylation of PPARgamma did not present in MSCs cultured in medium with lower serum concentration. When these MSCs differentiated into adipocytes, no phosphorylation could be detected to accompany the expression of PPARgamma. Moreover, exposure of MSCs to higher concentration of serum induced stronger PPARgamma expression, and subsequently enhanced their adipogenesis. These data suggested that activation of the MEK/ERK signalling pathway by high serum concentration promoted PPARgamma expression and phosphorylation, and subsequently enhanced adipogenic differentiation of MSCs.
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PMID:Serum regulates adipogenesis of mesenchymal stem cells via MEK/ERK-dependent PPARgamma expression and phosphorylation. 1924 75

We examined the effects of troglitazone on expression of E-cadherin and claudin 4 in human pancreatic cancer cells. Troglitazone dose-dependently increased expression of E-cadherin and claudin 4 mRNA and protein in PK-1 cells. Snail, Slug and ZEB1, mRNAs were not changed by troglitazone, indicating that these three transcriptional repressors would not play a role in the induction of E-cadherin by troglitazone. GW9662, a PPARgamma antagonist, failed to block the increased expression of E-cadherin or claudin 4 mRNA, suggesting a PPARgamma-independent pathway. A MEK inhibitor, U0126, increased E-cadherin or claudin 4 mRNA and protein expression, and potently inhibited cell invasion. Because troglitazone down-regulates MEK-ERK signaling and inhibit cell invasion in PK-1 as shown in our previous study, these results suggest that troglitazone increases expression of E-cadherin and claudin 4 possibly through inhibition of MEK-ERK signaling in pancreatic cancer cells, which might be involved in the troglitazone-induced inhibition of cell invasive activity.
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PMID:Troglitazone increases expression of E-cadherin and claudin 4 in human pancreatic cancer cells. 1928 10

Peroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor superfamily of ligand-dependent transcription factors. Recent results have shown that agonists of PPARgamma, such as troglitazone (TGZ), can inhibit cell proliferation and promote cell differentiation independent of PPARgamma. In the present study, we provide evidence that TGZ may bind directly to EGFR and trigger its signaling and internalization independent of PPARgamma. Detailed studies revealed that prolonged incubation with TGZ effectively attenuated EGFR signaling by targeting the receptor to the endo-lysosomal degradation machinery. Although the extracellular signal-regulated kinase-signaling pathway was transiently activated by TGZ in EGFR overexpressing cancer cells, inhibition of EGF-induced Akt phosphorylation most likely accounted for the growth arrest of tumor cells caused by TGZ at pharmacologically achievable concentrations. Therefore, we have provided a new line of evidence indicating that TGZ inhibits cell proliferation by promoting EGFR degradation and attenuating Akt phosphorylation.
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PMID:Troglitazone inhibits cell proliferation by attenuation of epidermal growth factor receptor signaling independent of peroxisome proliferator-activated receptor gamma. 1948 32

Both estrogen receptor (ER) and peroxisome proliferator-activated receptor gamma (PPARgamma) regulate bone metabolism, and because steroid receptor coactivator (SRC)-2 (TIF-2) enhances ER and PPARgamma activity, we examined the consequences of deletion of SRC-2 on bone using SRC-2 knock out (KO) mice. Loss of SRC-2 resulted in increased bone mass, with SRC-2 KO mice having 80% higher trabecular bone volume as compared with wild type mice. SRC-2 KO mice also had a marked decrease (by 50%) in bone marrow adipocytes. These data suggested that marrow precursor cells in the SRC-2 KO mice may be resistant to the inhibitory effects of endogenous PPARgamma ligands on bone formation. Consistent with this, compared with cultures from wild type mice, marrow stromal cultures from SRC-2 KO mice formed significantly more mineralized nodules (by 3-fold) in the presence of the PPARgamma agonist, rosiglitazone. Using chromatin immunoprecipitation analysis, we demonstrated that in bone marrow stromal cells, loss of SRC-2 leads to destabilization of the transcription complex at the peroxisome proliferator response elements of a number of PPARgamma target genes, resulting in an overall decrease in the expression of adipocyte-related genes and a marked decrease in adipocyte development. Using ovariectomy with or without estrogen replacement, we also demonstrated that SRC-2 KO mice were partially resistant to the skeletal actions of estrogen. Collectively, these findings indicate that loss of SRC-2 leads to partial skeletal resistance to the ER and PPARgamma, but resistance to PPARgamma is dominant, leading to increased bone mass. Modulating SRC-2 action may, thus, represent a novel therapeutic target for osteoporosis.
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PMID:Skeletal consequences of deletion of steroid receptor coactivator-2/transcription intermediary factor-2. 1942 3

WNT5A is a cancer-associated gene involved in invasion and metastasis of melanoma, breast cancer, pancreatic cancer, and gastric cancer. WNT5A transduces signals through Frizzled, ROR1, ROR2 or RYK receptors to beta-catenin-TCF/LEF, DVL-RhoA-ROCK, DVL-RhoB-Rab4, DVL-Rac-JNK, DVL-aPKC, Calcineurin-NFAT, MAP3K7-NLK, MAP3K7-NF-kappaB, and DAG-PKC signaling cascades in a context-dependent manner. SNAI1 (Snail), CD44, G3BP2, and YAP1 are WNT5A target genes. We and other groups previously reported that IL6- or LIF-induced signaling through JAK-STAT3 signaling cascade is involved in WNT5A upregulation (STAT3-WNT5A signaling loop). Here, refined integrative genomic analyses of WNT5A were carried out to elucidate other mechanisms of WNT5A transcription. The WNT5A gene was found to encode two isoforms by using alternative first exons 1A and 1B. Quadruple Smad-binding elements (SBEs), single Sp1-binding site (GC-box), PPARgamma-binding site, C/EBP-binding site and bHLH-binding site within the promoter A region, 5'-adjacent to exon 1A, were conserved in human WNT5A, chimpanzee WNT5A, mouse Wnt5a, and rat Wnt5a. NF-kappaB-binding site, CUX1-binding site, double SBEs and double GC-boxes within the promoter B region, 5'-adjacent to exon 1B, were conserved in mammalian WNT5A orthologs. Quadruple FOX-binding sites and double SBEs within ultra-conserved intron 1 were also conserved in mammalian WNT5A orthologs. Conserved NF-kappaB-binding site within the WNT5A promoter B region elucidated the mechanisms that TNFalpha and toll-like receptor (TLR) signals upregulate WNT5A via MAP3K7. Quadruple FOX-binding sites rather than GLI-binding site revealed that Hedgehog signals induce WNT5A upregulation indirectly via FOX family members, such as FOXA2, FOXC2, FOXE1, FOXF1 and FOXL1. TGFbeta signals were found to upregulate WNT5A expression directly through the Smad complex, and also indirectly through Smad-induced CUX1 and MAP3K7-mediated NF-kappaB. Together these facts indicate that WNT5A is transcribed based on multiple mechanisms, such as NF-kappaB, Hedgehog, TGFbeta, and Notch signaling cascades.
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PMID:Transcriptional mechanisms of WNT5A based on NF-kappaB, Hedgehog, TGFbeta, and Notch signaling cascades. 1942 2


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