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)

Multiple hereditary exostoses (MHE) is an autosomal dominant skeletal disorder caused by mutations in one of the two EXT genes and characterized by multiple osteochondromas that generally arise near the ends of growing long bones. Defective endochondral ossification is likely to be involved in the formation of osteochondromas. In order to investigate potential changes in chondrocyte proliferation and/or differentiation during this process, osteochondroma samples from MHE patients were obtained and used for genetic, morphological, immunohistological, and in situ hybridization studies. The expression patterns of IHH (Indian hedgehog) and FGFR3 (Fibroblast Growth Factor Receptor 3) were similar with transcripts expressed throughout osteochondromas. Expression of PTHR1 (Parathyroid Hormone Receptor 1) transcripts was restricted to a narrow zone of prehypertrophic chondrocytes. Numerous cells forming osteochondromas although resembling prehypertrophic chondrocytes, stained positively with an anti-proliferating cell nuclear antigen (PCNA) antibody. In addition, ectopic expression of collagen type I and abnormal presence of osteocalcin (OC), osteopontin (OP), and bone sialoprotein (BSP) were observed in the cartilaginous osteochondromas. These data indicate that most chondrocytes involved in the growth of osteochondromas can proliferate, and that some of them exhibit bone-forming cell characteristics. We conclude that in MHE, defective heparan sulfate biosynthesis caused by EXT mutations maintains the proliferative capacity of chondrocytes and promotes phenotypic modification to bone-forming cells.
...
PMID:Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients. 1647 76

Urothelial carcinoma (UC), the common histological subtype of bladder cancer, presents as a papillary tumor or as an invasive, often lethal form. To study UC molecular biology, candidate gene and genome-wide approaches have been followed. Here, it is argued that a 'cancer pathway' perspective is useful to integrate findings from both approaches. According to this view, papillary cancers typically exhibit activation of the MAPK pathway, as a consequence of oncogenic mutations in FGFR3 or HRAS, with increased Cyclin D1 expression. In contrast, invasive UC are characterized by severe disturbances in proximate cell cycle regulators, e.g. RB1 and CDKN2A/p16(INK4A), which decrease dependency on mitogenic signaling. In addition, these disturbances permit, promote and are in turn exacerbated by chromosomal instability, which is further enhanced by loss of TP53 function. In another vicious cycle, defective cell cycle regulation interacts with DNA methylation alterations. The transition toward invasive UC may require concomitant and interacting defects in cell cycle regulation and the control of genomic stability. Intriguingly, neither canonical WNT/beta-Catenin nor hedgehog signaling appear to play major roles in UC. This may reflect its origin from more differentiated urothelial cells possessing a high regenerative potential rather than a stem cell population.
...
PMID:Understanding urothelial carcinoma through cancer pathways. 1655 69

Sonic Hedgehog (Shh), a member of hedgehog peptides family, is expressed in gastric gland epithelium. To elucidate Shh function to gastric mucosal cells, we examined the effect of Shh on the proliferation of a rat normal gastric mucosal cell line, RGM-1. RGM-1 cells express essential components of Shh receptor system, patched-1, and smoothened. Shh enhanced DNA synthesis in RGM-1 cells and elevated intracellular calcium concentration ([Ca2+]i). In addition, Shh as well as calcium ionophore A32187 rapidly activated ERK. However, Shh failed to activate ERK under calcium-free culture condition. Pretreatment of cells with PD98059 attenuated the DNA synthesis promoted by Shh. Moreover, when cells were pretreated with cyclopamine, Shh could not elevate [Ca2+]i, activate ERK or promote DNA synthesis. On the other hand, although Shh induced Gli-1 nuclear accumulation in RGM-1 cells, Shh activated ERK even in cells pretreated with actinomycin D. These results indicate that Shh promotes the proliferation of RGM-1 cells through an intracellular calcium- and ERK-dependent but transcription-independent pathway via Patched/Smoothened receptor system.
...
PMID:Sonic hedgehog stimulates the proliferation of rat gastric mucosal cells through ERK activation by elevating intracellular calcium concentration. 1663 May 42

Medulloblastoma (MB) is the most common malignant brain tumour in children. Its aetiology is unknown, although several signalling pathways controlling cell proliferation are thought to participate in the progress of the neoplasm. Mutations of the genes encoding proteins participating in the pathways triggered by embryonic growth factors like Sonic hedgehog (Shh) or WNT are often found in MB. Another model of MB development is overexpression or mutation of several types of growth factor receptors, including IGF-IR, EGF-R and PDGFR, that have the ability to activate cellular kinases responsible for promoting cell proliferation. In order to test this hypothesis, in the current paper we tested the activation of two kinases, Akt/PKB (protein kinase B) and Erk (extracellular signal-regulated kinase) and their substrates in 10 sporadic medulloblastoma cases. We show that MBs are a highly heterogeneous group of tumours that show upregulation of various signalling pathways. Nevertheless, both Akt and Erk may contribute to the progression of MB, triggering, at least in some cases, the mTOR (mammalian target of rapamycin) pathway, controlling translation of several cell cycle-related proteins. We hypothesize that Akt and Erk activation may also be associated with downregulation of protein phosphatase 2A (PP2A).
...
PMID:Activation of Akt and Erk pathways in medulloblastoma. 1703 17

Sonic Hedgehog (Shh)-deficient mice have a severe lung branching defect. Recent studies have shown that hedgehog signaling is involved in vascular development and it is possible that the diminished airway branching in Shh-deficient mice is due to abnormal pulmonary vasculature formation. Therefore, we investigated the role of Shh in pulmonary vascular development using Shh/Tie2lacZ compound mice, which exhibit endothelial cell-specific LacZ expression, and Pecam-1 immunohistochemistry. In E11.5-13.5 Shh-deficient mice, the pulmonary vascular bed is decreased, but appropriate to the decrease in airway branching. However, when E12.5 Shh-deficient lungs were cultured for 4-6 days, the vascular network deteriorated compared to wild-type lungs. The expression of vascular endothelial growth factor (Vegf) or its receptor Vegfr2 (KDR/Flk-1) was not different between E12.5-13.5 Shh-deficient and wild-type lungs. In contrast, angiopoietin-1 (Ang1), but not Ang2 or the angiopoietin receptor Tie2, mRNA expression was downregulated in E12.5-E13.5 lungs of Shh null mutants. Recombinant Ang1 alone was unable to restore in vitro branching morphogenesis in Shh-deficient lungs. Conversely, the angiogenic factor fibroblast growth factor (Fgf)-2 alone or in combination with Ang1, increased vascularization and tubular growth and branching of Shh-deficient lungs in vitro. The angiogenic factors did not overcome the reduced smooth muscle cell differentiation in the Shh null lungs. These data indicate that early vascular development, mediated by Vegf/Vegfr2 signaling proceeds normally in Shh-deficient mice, while later vascular development and stabilization of the primitive network mediated by the Ang/Tie2 signaling pathway are defective, resulting in an abnormal vascular network. Stimulation of vascularization with angiogenic factors such as Fgf2 and Ang1 partially restored tubular growth and branching in Shh-deficient lungs, suggesting that vascularization is required for branching morphogenesis.
...
PMID:Angiogenic factors stimulate tubular branching morphogenesis of sonic hedgehog-deficient lungs. 1718 75

The Sonic hedgehog (Shh) and FGF signaling pathways regulate growth and differentiation in many regions of the nervous system, but interactions between these pathways have not been studied extensively. Here, we examine the relationship between Shh and FGF signaling in granule cell precursors (GCPs), which are the most abundant neural progenitors in the cerebellum and the putative cell of origin for the childhood brain tumor medulloblastoma. In these cells, Shh induces a potent proliferative response that is abolished by coincubation with basic FGF. FGF also inhibits transcription of Shh target genes and prevents activation of a Gli-responsive promoter in fibroblasts, which suggests that it blocks Shh signaling upstream of Gli-mediated transcription. FGF-mediated inhibition of Shh responses requires activation of FGF receptors and of ERK and JNK kinases, because it can be blocked by inhibitors of these enzymes. Finally, FGF promotes differentiation of GCPs in vitro and in vivo and halts proliferation of tumor cells from patched (ptc) mutant mice, a model for medulloblastoma. These findings suggest that FGF is a potent inhibitor of Shh signaling and may be a useful therapy for tumors involving activation of the hedgehog pathway.
...
PMID:Fibroblast growth factor blocks Sonic hedgehog signaling in neuronal precursors and tumor cells. 1729 56

Since IGF-I is an important chondrocyte growth factor, we sought to examine the intracellular mechanisms by which it exerts two of its pivotal effects, stimulation of proliferation and differentiation. We used the mesenchymal chondrogenic cell line RCJ3.1C5.18, which progresses spontaneously to differentiated growth plate chondrocytes. This differentiation process could be enhanced by exogenous IGF-I. Pharmacological inhibition of the phosphatidylinositol-3 (PI-3) kinase by LY294002, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)1/2 by U0126, the protein kinase (PK) A pathway by H-89 or KT5720, and the PKC pathway by bisindolylmaleimide suppressed IGF-I-stimulated cell proliferation. In contrast, IGF-I-enhanced early cell differentiation, as assessed by collagen type II and aggrecan gene expression, was not affected by MAPK/ERK1/2 pathway inhibition, but significantly diminished by inhibition of the PI-3 kinase, the PKC and the PKA pathway. Moreover, terminal differentiation of chondrocytes in response to IGF-I, as assessed by gene expression of alkaline phosphatase, Indian hedgehog, and collagen type X, were only interrupted by PI-3 kinase pathway inhibition. In conclusion, IGF-I exerts its differential effect on chondrocyte proliferation vs differentiation through the use of at least four partially interacting intracellular signaling pathways, whose activity is temporarily regulated. When chondrocytes progress from proliferating cells to early and terminal differentiating cells, they progressively inactivate IGF-I-related intracellular signaling pathways. This mechanism might be essential for the complex and cell stage-specific anabolic action of IGF-I in the growth plate.
...
PMID:Signaling mechanisms leading to regulation of proliferation and differentiation of the mesenchymal chondrogenic cell line RCJ3.1C5.18 in response to IGF-I. 1744 38

Sonic hedgehog (Shh) has been reported to act as a mitogen and survival factor for muscle satellite cells. However, its role in their differentiation remains ambiguous. Here, we provide evidence that Shh promotes the proliferation and differentiation of primary cultures of chicken adult myoblasts (also termed satellite cells) and mouse myogenic C2 cells. These effects are reversed by cyclopamine, a specific chemical inhibitor of the Shh pathway. In addition, we show that Shh and its downstream molecules are expressed in adult myoblast cultures and localize adjacent to Pax7 in muscle sections. These gene expressions are regulated during postnatal muscle growth in chicks. Most importantly, we report that Shh induces MAPK/ERK and phosphoinositide 3-kinase (PI3K)-dependent Akt phosphorylation and that activation of both signaling pathways is essential for Shh's signaling in muscle cells. However, the effect of Shh on Akt phosphorylation is more robust than that on MAPK/ERK, and data suggest that Shh influences these pathways in a manner similar to IGF-I. By exploiting specific chemical inhibitors of the MAPK/ERK and PI3K/Akt signaling pathways, UO126 and Ly294002, respectively, we demonstrate that Shh-induced Akt phosphorylation, but not that of MAPK/ERK, is required for its promotive effects on muscle cell proliferation and differentiation. Taken together, we suggest that Shh acts in an autocrinic manner in adult myoblasts, and provide first evidence of a role for PI3K/Akt in Shh signaling during myoblast differentiation.
...
PMID:Sonic hedgehog promotes proliferation and differentiation of adult muscle cells: Involvement of MAPK/ERK and PI3K/Akt pathways. 1768 59

Indian Hedgehog (Ihh)--Parathyroid related protein (PTHrP) and Fibroblast Growth Factor 3 (FGFR3) signaling pathways are important in regulating endochondral bone formation. In the growth plate, Ihh and PTHrP are involved in a feedback loop to increase proliferation and delay differentiation of chondrocytes. Fibroblast Growth Factor Receptor 3 (FGFR3) conversely decreases proliferation and hastens differentiation with an agonist. Since proliferation is the hallmark of chondrosarcoma cells, we hypothesized that Ihh/PTHrP and FGF3R pathways may be dysfunctional on these cells. Therefore, we sought to investigate the role of these signaling pathways in the Swarm rat chondrosarcoma cells utilizing expression and functional studies. Semiquantitative RT-PCR analysis demonstrated difference in expression between normal growth plate chondrocytes and chondrosarcoma cells (JWS). JWS had an increased mRNA expression of FGF2 and FGFR3 suggesting a mechanism to reverse the proliferative rate of the cells. Immunohistochemical analysis showed increased staining for FGFR3 and patched-1 (Ihh receptor) in JWS compared to the rat tibia growth plate (p = 0.O004 and 0.02 respectively). In vitro functional experiments demonstrated that the use of FGF2, a FGFR3 receptor agonist, dramatically decreased the proliferative rate of Swarm chondrosarcoma cells (LTC). Cyclopamine, a hedgehog inhibitor, did not have a significant effect on their proliferative rate. However, when cyclopamine was used on normal chondrocytes, it effectively decreased the proliferative rate of these cells, suggesting abnormalities in this pathway in the chondrosarcoma cells. In conclusion, our investigation describes dissimilarity in the Indian Hedgehog and FGFR3 signaling pathways between the rat chondrosarcoma cells and native rat chondrocytes. Understanding the underlying mechanisms may provide a target for future therapy for chondrosarcoma.
...
PMID:Indian hedgehog signaling pathway differences between swarm rat chondrosarcoma and native rat chondrocytes. 1790 24

Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to current clinical treatments represents a major challenge in treating and curing the most aggressive and metastatic cancers. This review summarizes recent advances in our understanding of the cellular origin and molecular mechanisms at the basis of cancer initiation and progression as well as the heterogeneity of cancers arising from the malignant transformation of adult stem/progenitor cells. We describe the critical functions provided by several growth factor cascades, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF) receptor (KIT), hedgehog and Wnt/beta-catenin signalling pathways that are frequently activated in cancer progenitor cells and are involved in their sustained growth, survival, invasion and drug resistance. Of therapeutic interest, we also discuss recent progress in the development of new drug combinations to treat the highly aggressive and metastatic cancers including refractory/relapsed leukaemias, melanoma and head and neck, brain, lung, breast, ovary, prostate, pancreas and gastrointestinal cancers which remain incurable in the clinics. The emphasis is on new therapeutic strategies consisting of molecular targeting of distinct oncogenic signalling elements activated in the cancer progenitor cells and their local microenvironment during cancer progression. These new targeted therapies should improve the efficacy of current therapeutic treatments against aggressive cancers, and thereby preventing disease relapse and enhancing patient survival.
...
PMID:Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers. 1797 79


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

---