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

---

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

Hepatocyte growth factor (HGF) and c-met proto-oncogene product (c-Met) have varied biological functions in different tissues and have been implicated in mitogenic, motogenic and morphogenic responses in both organ regeneration and carcinogenesis. Some studies have suggested that the overexpression of c-Met and epidermal growth factor receptor (EGFR) are associated with growth advantage, while transforming growth factor-beta receptor II (TGF beta R II) is associated with growth disadvantage of human prostatic adenocarcinoma. However, it is unclear if the expression of c-Met correlates with the expression of EGFR and TGF beta R II, and with the proliferative status of human prostatic adenocarcinoma. Using immunohistochemical staining with anti-c-Met (C-12), anti-EGFR (NCL-EGFR) and anti-TGF beta R II (L-21) antibodies, we determined the frequency of expression of c-MET, EGFR, and TGF beta R II respectively in a series of 134 radical prostatectomy specimens. We evaluated the relationship between the expression of these receptors and clinicopathological characteristics. Overall, c-Met immunostaining was detected in 54 of 134 (40.3%) cases, EGFR in 45 (33.6%) and TGF beta R II in 64 (48.4%). The overexpression of c-Met was significantly more common in poorly differentiated (P < 0.0001) and in the diffusely infiltrated specimens (P < 0.0005). In contrast, TGF beta R II was significantly overexpressed in the well differentiated specimens (P < 0.0001) and associated negatively with c-Met (P < 0.0001). Overall, these data suggest that c-Met/HGF receptor and TGF beta R II overexpression may be involved in the differentiation of human prostatic adenocarcinoma, c-Met with de-differentiation and TGF beta R II with differentiation.
...
PMID:Overexpression of c-Met/hepatocyte growth factor receptors in human prostatic adenocarcinoma. 987 67

Our previous data demonstrated that Ras activation was necessary and sufficient for transforming growth factor-beta (TGFbeta)-mediated Erk1 activation, and was required for TGFbeta up-regulation of the Cdk inhibitors (CKI's) p27(Kip1) and p21(Cip1) (KM Mulder and SL Morris, J. Biol. Chem., 267, 5029-5031, 1992; MT Hartsough and KM Mulder, J. Biol. Chem., 270, 7117-7124, 1995; MT Hartsough et al., J. Biol. Chem., 271, 22368-22375, 1996 and J Yue et al., Oncogene, 17, 47-55, 1998). Here we examined the role of Ras in TGFbeta-mediated effects on a rat homolog of Smad1 (termed RSmad1). We demonstrate that both TGFbeta and bone morphogenetic protein (BMP) can induce endogenous Smad1 phosphorylation in intestinal epithelial cells (IECs). The combination of transient expression of RSmad1 and TGFbeta treatment had an additive effect on induction of the TGFbeta-responsive reporter 3TP-lux. Either inactivation of Ras by stable, inducible expression of a dominant-negative mutant of Ras (RasN17) or addition of MAP and ERK kinase (MEK) inhibitor PD98059 to cells significantly decreased the ability of both TGFbeta and BMP to induce phosphorylation of endogenous Smad1 in IECs. Moreover, either inactivation of Ras or addition of PD98059 to IEC 4-1 cells inhibited the ability of RSmad1 to regulate 3TP luciferase activity in both the presence and absence of TGFbeta. Collectively, our data indicate that TGFbeta can regulate RSmad1 function in epithelial cells, and that the Ras/MEK pathway is partially required for TGFbeta-mediated regulation of RSmad1.
...
PMID:Cross-talk between the Smad1 and Ras/MEK signaling pathways for TGFbeta. 1020 26

Angiogenesis is the process by which new blood vessels are formed via proliferation of vascular endothelial cells. A variety of angiogenesis inhibitors that antagonize the effects of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have recently been identified. However, the mechanism by which these diverse angiogenesis inhibitors exert their common effects remains largely unknown. Caveolin-1 and -2 are known to be highly expressed in vascular endothelial cells both in vitro and in vivo. Here, we examine the potential role of caveolins in the angiogenic response. For this purpose, we used the well established human umbilical vein endothelial cell line, ECV 304. Treatment of ECV 304 cells with known angiogenic growth factors (VEGF, bFGF, or hepatocyte growth factor/scatter factor), resulted in a dramatic reduction in the expression of caveolin-1. This down-regulation event was selective for caveolin-1, as caveolin-2 levels remained constant under these conditions of growth factor stimulation. VEGF-induced down-regulation of caveolin-1 expression also resulted in the morphological loss of cell surface caveolae organelles as seen by transmission electron microscopy. A variety of well characterized angiogenesis inhibitors (including angiostatin, fumagillin, 2-methoxy estradiol, transforming growth factor-beta, and thalidomide) effectively blocked VEGF-induced down-regulation of caveolin-1 as seen by immunoblotting and immunofluorescence microscopy. However, treatment with angiogenesis inhibitors alone did not significantly affect the expression of caveolin-1. PD98059, a specific inhibitor of mitogen-activated protein kinase and a known angiogenesis inhibitor, also blocked the observed VEGF-induced down-regulation of caveolin-1. Furthermore, we show that caveolin-1 can function as a negative regulator of VEGF-R (KDR) signal transduction in vivo. Thus, down-regulation of caveolin-1 may be an important step along the pathway toward endothelial cell proliferation.
...
PMID:Angiogenesis activators and inhibitors differentially regulate caveolin-1 expression and caveolae formation in vascular endothelial cells. Angiogenesis inhibitors block vascular endothelial growth factor-induced down-regulation of caveolin-1. 1033 80

Fusion of tumorigenic HeLa cells with human skin fibroblasts results in chromosomally stable hybrids that are nontumorigenic and no longer express the HeLa tumor-associated marker intestinal alkaline phosphatase (IAP). Previous studies of spontaneous tumorigenic segregants from the nontumorigenic hybrids implicated the loss of one copy of human fibroblast chromosome 11 in the concomitant reexpression of tumorigenicity. In an attempt to identify genes involved in the control of tumorigenic expression, we performed differential display screening of nontumorigenic hybrid cells and tumorigenic segregants. Subsequent northern blot analyses reproducibly showed 17 differentially expressed genes, eight of which were expressed differentially in the nontumorigenic hybrids and nine of which were expressed differentially in the tumorigenic hybrids. The former were genes for 80K-L protein (a substrate of protein kinase C), AXL/UFO (a receptor tyrosine kinase), insulin-like growth factor binding protein 3, apolipoprotein AI regulatory protein, collagen type I alpha-2 chain, transforming growth factor-beta-induced gene product 3 (BIGH3), pregnancy-specific beta-1-glycoprotein, and fibroblast activation protein alpha. The latter nine genes were genes for serum/glucocorticoid-regulated kinase (SGK; a serine/threonine protein kinase), PTPCAAX1 (a tyrosine phosphatase), CXCR-4 (a G-protein-coupled membrane receptor), L-kynurenine hydrolase, beta-1, 4-galactosyltransferase, keratin 8, keratin 17, and H19 and a novel gene. The differential expression of these genes provided several interesting candidates for regulation of tumorigenic expression, including those involved in signal transduction and the extracellular matrix, cytoskeletal proteins, cell-surface enzyme, and the H19 gene.
...
PMID:Differential gene expression in tumorigenic and nontumorigenic HeLa x normal human fibroblast hybrid cells. 1056 6

The RET proto-oncogene encodes a receptor tyrosine kinase for transforming growth factor-beta-related neurotrophic factors, which include GDNF and neurturin. The expression of RET proto-oncogene was detected in several tissues, such as spleen, thymus, lymph nodes, salivary gland, and spinal cord, and in several neural crest-derived cell lines. RET expression in the thyroid gland was reported to be restricted to neural crest-derived C cells. The presence of RET mRNA or protein has not yet been reported in thyroid follicular cells. We previously demonstrated the expression of oncogenic rearranged versions of RET in papillary thyroid carcinomas: tumors derived from thyroid follicular cells. To assess the expression of the normal RET proto-oncogene in follicular cells, we analyzed its expression in a panel of neoplasias originating from thyroid follicular epithelial cells: papillary carcinomas and both follicular adenomas and carcinomas. We also demonstrated the presence of RET normal transcripts in two follicular thyroid carcinoma lymph node metastases. Moreover, we found the presence of the RET/ELE1 transcript, the reciprocal complementary form of the oncogenic fusion transcript ELE1/RET, in a papillary thyroid carcinoma specimen expressing the RET/PTC3 oncogene, thus demonstrating that the RET promoter is active in those cells after rearrangement. Finally, we show that in a papillary carcinoma-derived cell line expressing the proto-RET receptor and the related GFRalpha2 co-receptor, GDNF treatment induced RET tyrosine phosphorylation and subsequent signal transduction pathway, indicating that RET could be active in thyroid follicular cells.
...
PMID:RET receptor expression in thyroid follicular epithelial cell-derived tumors. 1085 Apr 26

Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal vascular fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-alpha(2) chain promoter [procolalpha(2)(I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procolalpha(2)(I) activity in freshly isolated aortas and renal cortical slices (P:<0. 01) followed by similar increase in procolalpha(2)(I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway (SB202190) and blockade of the release of the transcription factor NFkappaB (PDTC) did not have any effect in the Ang II-induced activation of the collagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c-fos proto-oncogene. This increase of c-fos mRNA expression was blocked by PD98059; in addition, curcumin, a blocker of the transcriptional factor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-beta (TGF-beta), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-beta-induced activation of procolalpha(2)(I). These data indicate that the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require activation of both the MAPK/ERK and TGF-beta signaling pathways.
...
PMID:Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. 1098 60

The angiogenic effects of vascular endothelial growth factor are mediated predominantly by the FLK-1/KDR receptor. An understanding of the transcriptional control mechanisms underlying flk-1/KDR expression should provide insight into the molecular basis of angiogenesis. In this study, we show that transforming growth factor-beta(1) (TGF-beta(1)) down-regulates expression of the endogenous flk-1/KDR gene in endothelial cells. In transient transfection assays, this effect was mapped to a palindromic GATA site in the 5'-untranslated region. In electrophoretic mobility shift assays, the palindromic GATA site was shown to bind to two molecules of GATA protein. Moreover, DNA-GATA interactions were inhibited by TGF-beta(1). Finally, in cotransfection assays, transactivation of the flk-1/KDR promoter by GATA-1 or GATA-2 was attenuated in TGF-beta(1)-treated cells. Taken together, these results suggest that the TGF-beta-1-mediated inhibition of the flk-1/KDR gene is mediated by a 5'-untranslated region palindromic GATA site.
...
PMID:Transforming growth factor-beta 1-mediated inhibition of the flk-1/KDR gene is mediated by a 5'-untranslated region palindromic GATA site. 1109 56

We performed an immunohistochemical study on 5 normal marrow samples and 3 fibrotic marrow samples to investigate the cellular distribution of various isoforms of platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), and their corresponding receptors. Immature hematopoietic precursors strongly expressed PDGF-B, all the TGF-beta isoforms, PDGFRbeta, TGFbetaRI and II, and FGFR1, 3, and 4. Megakaryocytes stained primarily for PDGF-B, TGF-beta2-3, and PDGFRbeta. Histiocytes displayed intense TGF-beta1, bFGF, and FGFR2 expression. Fibroblasts and endothelial cells carried receptors for all the aforementioned cytokines. The last 2 cell types also expressed the ligand cytokines to varied degrees.
...
PMID:Cellular distribution of platelet-derived growth factor, transforming growth factor-beta, basic fibroblast growth factor, and their receptors in normal bone marrow. 1127 3

Bone morphogenetic protein (BMP)-2, a member of the transforming growth factor-beta (TGF-beta) superfamily, is able to induce osteoblastic differentiation of C2C12 cells. Both Smad and mitogen-activated protein kinase (MAPK) pathways are essential components of the TGF-beta superfamily signaling machinery. Although Smads have been demonstrated to participate in the BMP-2-induced osteoblastic differentiation of C2C12 cells, the role of MAPK has not been addressed. This report shows that BMP-2 activates ERK and p38, but not JNK, in C2C12 cells. Pretreatment of cells with the p38 inhibitor, SB203580, dramatically reduced BMP-2-induced expression of the osteoblast markers alkaline phosphatase (ALP) and osteocalcin (OC). Nevertheless, overexpression of MKK3, a protein kinase that phosphorylates and activates p38, failed to induce ALP or OC expression in the absence of BMP-2, indicating that p38 activation is necessary but not sufficient for the acquisition of the osteoblast phenotype by these cells. Although ALP induction was increased slightly in the presence of PD-98059, a selective inhibitor of the ERK cascade, this compound significantly inhibited both steady-state and BMP-2-induced OC RNA levels. Our results indicate that p38 and ERK cascades play a crucial role in the osteoblast differentiation of C2C12 cells mediated by BMP-2.
...
PMID:Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells. 1134 48

The loss of growth-inhibitory responses to transforming growth factor-beta (TGF-beta) is a frequent consequence of malignant transformation. Smad2, Smad3, and Smad4 proteins are important mediators of the antiproliferative responses to TGF-beta and may become inactivated in some human cancers. Epithelial cells harboring oncogenic Ras mutations often exhibit a loss of TGF-beta antiproliferative responses. To further investigate the effect of oncogenic Ras in TGF-beta signaling, we used an isopropyl-1-thio-beta-d-galactopyranoside-inducible expression system to express Ha-Ras(Val-12) in intestinal epithelial cells. Induction of Ha-Ras(Val-12) caused a decrease in the level of Smad4 expression, inhibited TGF-beta-induced complex formation between Smad2/Smad3 and Smad4, blocked Smad4 nuclear translocation, inhibited the TGF-beta-mediated decrease in [(3)H]thymidine incorporation, and repressed TGF-beta-activated transcriptional responses. The withdrawal of isopropyl-1-thio-beta-d-galactopyranoside or the addition of an inhibitor of the ubiquitin-proteasome pathway restored the Smad4 level and TGF-beta-induced Smad complex formation. Forced expression of Smad4 resulted in partial recovery of the TGF-beta-mediated growth inhibition and transcriptional responses in the presence of oncogenic Ras. Further, PD98059, a specific inhibitor of the MEK/ERK/mitogen-activated protein kinase pathway prevented the Ras-induced decrease in Smad4 expression and complex formation. Our results suggest a novel mechanism by which oncogenic Ras represses TGF-beta signaling by mitogen-activated protein kinase-dependent down-regulation of Smad4, thereby subverting the tumor suppressor function of TGF-beta.
...
PMID:Oncogenic ras represses transforming growth factor-beta /Smad signaling by degrading tumor suppressor Smad4. 1137 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---