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)

Many if not most tissues need a controlled number of stem cells to maintain normal function. Cancer can be seen as a process of disturbed tissue homeostasis, in which too many cells have or acquire too primitive identity. Here we measured how oncogenes and tumour suppressors affect the differentiation capacity, proportion and characteristics of progenitor cells in a model tissue. Neural progenitor cells (NPCs) were exposed to human papilloma virus E6, E7 or E6/E7 oncogenes, which degrade tumour suppressors p53 and pRb family members, respectively. E6/E7-expressing or p53-/- NPCs were able to differentiate, but simultaneously retained high capacity for self-renewal, proliferation, ability to remain multipotent in conditions promoting differentiation and showed delayed cell cycle exit. These functions were mediated through p53 and pRb family, and involved MEK-ERK signalling. Decreased amount of p53 increased self-renewal and proliferation, whereas pRb affected only proliferation. Our results suggest that the oncogenes increase whereas p53 and pRb family tumour suppressors decrease the number and proportion of progenitor cells. These findings provide one explanation how oncogenes and tumour suppressors control tissue homeostasis and highlight their importance in stem cell self- renewal, linked both to cancer and life-long tissue turnover.
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PMID:E6/E7 oncogenes increase and tumor suppressors decrease the proportion of self-renewing neural progenitor cells. 1653 24

The MET oncogene was causally involved in the pathogenesis of a rare tumor, i.e., the papillary renal cell carcinoma, in which activating mutations, either germline or somatic, were identified. MET activating mutations are rarely found in other human tumors, whereas at higher frequencies, MET is amplified and/or overexpressed in sporadic tumors of specific histotypes, including osteosarcoma. In this work, we provide experimental evidence that overexpression of the MET oncogene causes and sustains the full-blown transformation of osteoblasts. Overexpression of MET, obtained by lentiviral vector-mediated gene transfer, resulted in the conversion of primary human osteoblasts into osteosarcoma cells, displaying the transformed phenotype in vitro and the distinguishing features of human osteosarcomas in vivo. These included atypical nuclei, aberrant mitoses, production of alkaline phosphatase, secretion of osteoid extracellular matrix, and striking neovascularization. Although with a lower tumorigenicity, this phenotype was superimposable to that observed after transfer of the MET gene activated by mutation. Both transformation and tumorigenesis were fully abrogated when MET expression was quenched by short-hairpin RNA or when signaling was impaired by a dominant-negative MET receptor. These data show that MET overexpression is oncogenic and that it is essential for the maintenance of the cancer phenotype.
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PMID:MET overexpression turns human primary osteoblasts into osteosarcomas. 1665 28

Pituitary tumor initiation and progression are associated with a plethora of genetic imbalances. Several genetic abnormalities have been described in pituitary tumors, from mutations in intracellular signaling (constitutive activation adenylyl cyclase) and growth factor pathways (epidermal growth factor receptor [EGFR]) to imbalance in cell cycle regulators (p16, p27, pRb). Unfortunately, most of these observations do not provide validated predictors of clinical behavior or of recurrence. The pituitary gland is notably plastic, and intrinsic and extrinsic stimuli result in profound growth changes ranging from hypoplasia to hyperplasia. The impact of pituitary tropic status on influencing neoplastic potential is difficult to test in human samples because the gland is not readily accessible for ongoing morphological observation. Animal models represent a functional approach to testing this hypothesis, and transgenic mouse models of pituitary tumor transforming gene (PTTG) inactivation or overexpression support the notion that pituitary tropic status directly correlates with likelihood for pituitary tumor formation. Understanding the mechanisms underlying changes in pituitary plasticity and their relationship to tumor development may contribute to the ability of regulating the development and progression of pituitary tumors.
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PMID:Implication of pituitary tropic status on tumor development. 1680 18

Multiple endocrine neoplasia type 2A (MEN2A) is predisposed by mutations in the RET proto-oncogene. Low expression of the cyclin-dependent kinase inhibitor (CDKI) p27(Kip1) is present in thyroid tumors, and recent evidence demonstrates p27 downregulation by the active RET mutant, RET/PTC1, found in papillary thyroid carcinoma. This implicates decreased p27 activity as an important event during thyroid tumorigenesis. However, p27(-/-) mice develop MEN-like tumors only in combination with loss of another CDKI, p18(Ink4c). This suggests that p18 and p27 functionally collaborate in suppression of tumorigenesis, that loss of both is critical in the development of MEN tumors and that both p18 and p27 are regulated by RET. We report that induction of the constitutively active MEN2A-specific RET mutant, RET2A(C634R), correlates with reduced p18/p27, and elevated cyclin D protein levels, leading to increased CDK activity, increased pRb phosphorylation and proliferation under growth arrest conditions. Mechanistically, RET2A represses p18/p27 mRNA levels while elevating cyclin D1 mRNA levels. RET2A expression also correlates with decreased p27 protein stability. RET2A-mediated regulation of p18 and p27, but not of cyclins D1 and D2, requires functional mitogen-activated protein kinase signaling. Additionally, RET2A-dependent p18 repression is required and sufficient to increase cell proliferation. Perhaps most significantly, MEN2A adrenal tumors also display these changes in cell cycle expression profile, demonstrating the biological relevance of our cell culture studies. Our results demonstrate for the first time that RET2A regulates p18, and suggest that loss of not only p27 but also of p18 expression is a key step in MEN tumorigenesis.
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PMID:Simultaneous downregulation of CDK inhibitors p18(Ink4c) and p27(Kip1) is required for MEN2A-RET-mediated mitogenesis. 1695 32

Raf/MEK/ERK signaling in skeletal muscle cells affects several aspects of myogenesis that are correlated with the duration and intensity of the input signal. 23A2RafER(DD) myoblasts directing elevated levels of Raf kinase for 24 h are mitotically inactive. Removal of the stimulus results in cell cycle re-entry and proliferation. Using a proteomic approach, E2F5 and LEK1 were detected in the nuclei of Raf-arrested myoblasts. Disruption of MEK1 activity prevents phosphorylation of ERK1/2 and nuclear translocation of E2F5 and LEK1. The pocket proteins, p107 and p130, remain in the cytoplasm of growth arrested myoblasts irrespective of Raf/ERK activation while pRb translocates to the nucleus. Importantly, both E2F5 and LEK1 are found in the nuclei of non-dividing satellite cells and myonuclei in vivo and in vitro. Our results indicate that Raf-arrested myoblasts may serve as a model system for satellite cell cycle studies and that E2F5 and LEK1 translocation to the nucleus is an important first step during entry into quiescence.
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PMID:E2F5 and LEK1 translocation to the nucleus is an early event demarcating myoblast quiescence. 1729 7

Cervical cancer is a virus-induced disease that is caused by the integration of high-risk infecting human papillomaviruses (HPV) in the host genome. For this reason, the carcinogenesis process of cervical cancer is associated to the expression of the viral oncogenic proteins E6 and E7. These proteins are capable of inactivating p53 and pRb, which induces a continuous cell proliferation with the increasing risk of accumulation of DNA damage that eventually leads to cancer. Moreover, cervical cancer can be prevented by prophylactic HPV vaccines; their molecular characteristics and mechanism of action are reviewed. Ultimately, new molecular targets for cervical cancer like proteasome, the EGFR family and IGF family are exposed.
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PMID:Molecular biology of cervical cancer. 1759 48

A majority of breast cancers are hormone-responsive, and require estrogen for growth, and respond to hormonal therapy that blocks estrogen receptor action. Breast tumors with low levels of or completely lacking estrogen receptor fail to respond to antiestrogen therapy yet require estrogen for tumor initiation. To address the importance of local estrogen in oncogene-mediated breast tumorigenesis, we have crossed MMTV-aromatase with MMTV-HER2/neu and examined the incidence of breast cancer in double transgenic mice in comparison with parental strains. Double transgenic mice show normal mammary development and express both transgenes at similar levels to that of parental strains. Tumor incidence in double transgenic mice (<5%) decreased compared to HER2/neu mice (>65%). In addition to a significant decrease in tumorigenesis, these mice expressed ERalpha as well as high levels of ERbeta along with decreased levels of cyclin D1 and phosphorylated pRb among other changes. Furthermore, experiments using THC (ERalpha-agonist and ERbeta-antagonist) clearly demonstrate the critical role of ERbeta in HER2/neu-mediated tumorigenesis. These studies provide the first genetic evidence that estrogen receptor, mainly ERbeta than ERalpha and its dependent changes play an important role in regulating mammary tumorigenesis. These findings provide further evidence for development and testing of novel therapeutic approaches based on selective regulation of estrogen receptors (ERalpha and beta)-dependent actions for the treatment and prevention of breast cancers.
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PMID:HER-2/neu x aromatase double transgenic mice model: the effects of aromatase overexpression on mammary tumorigenesis. 1760 17

Patients with chronic inflammatory bowel disease have a high risk of colon cancer. The molecules that initiate and promote colon cancer and the cancer pathways altered remain undefined. Here, using in vitro models and a mouse model of colitis, we show that nitric oxide (NO) species induce retinoblastoma protein (pRb) hyperphosphorylation and inactivation, resulting in increased proliferation through the pRb-E2F1 pathway. NO-driven pRb hyperphosphorylation occurs through soluble guanylyl cyclase/guanosine 3',5'-cyclic monophosphate signaling and is dependent on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase MEK/ERK and phosphatidylinositol 3-kinase/AKT pathways. Our results reveal a link between NO and pRb inactivation and provide insight into molecules that can be targeted in the prevention of the inflammation-to-cancer sequence.
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PMID:Nitric oxide inactivates the retinoblastoma pathway in chronic inflammation. 1790 36

Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue tumors with a very poor prognosis and largely resistant to chemotherapy. MPNSTs are characterized by activation of the Ras pathway by loss of tumor suppressor neurofibromatosis type 1. In view of this, MPNST may be susceptible to inhibition of the activated Ras/Raf/mitogen-activated protein kinase pathway by the B-Raf inhibitor sorafenib. MPNST (MPNST and ST8814) and dedifferentiated liposarcoma (LS141 and DDLS) human tumor cell lines were characterized for Ras activation and B-Raf expression. Tumor cells were treated with sorafenib and examined for growth inhibition, inhibition of phospho-MEK, phospho-ERK, cell cycle arrest, and changes in cyclin D1 and pRb expression. MPNSTs were sensitive to sorafenib at nanomolar concentrations. This appeared to be due to inhibition of phospho-MEK, phospho-ERK, suppression of cyclin D1, and hypophosphorylation of pRb at the CDK4-specific sites, resulting in a G(1) cell cycle arrest. These effects were not seen in the liposarcoma cells, which either did not express B-Raf or showed decreased Ras activation. Small interfering RNA-mediated depletion of B-Raf in MPNSTs also induced a G(1) cell cycle arrest in these cells, with a marked inhibition of cyclin D1 expression and Rb phosphorylation, whereas depletion of C-Raf did not affect either. With growth inhibition at the low nanomolar range, sorafenib, by inhibiting the mitogen-activated protein kinase pathway, may prove to be a novel therapy for patients with MPNST.
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PMID:Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells. 1841 2

Mesangioproliferative glomerulonephritis is associated with overactive PDGF receptor signal transduction. We show that the phytoalexin resveratrol dose dependently inhibits PDGF-induced DNA synthesis in mesangial cells with an IC(50) of 10 microM without inducing apoptosis. Remarkably, the increased SIRT1 deacetylase activity induced by resveratrol was not necessary for this inhibitory effect. Resveratrol significantly blocked PDGF-stimulated c-Src and Akt kinase activation, resulting in reduced cyclin D1 expression and attenuated pRb phosphorylation and cyclin-dependent kinase-2 (CDK2) activity. Furthermore, resveratrol inhibited PDGFR phosphorylation at the PI 3 kinase and Grb-2 binding sites tyrosine-751 and tyrosine-716, respectively. This deficiency in PDGFR phosphorylation resulted in significant inhibition of PI 3 kinase and Erk1/2 MAPK activity. Interestingly, resveratrol increased the activity of protein tyrosine phosphatase PTP1B, which dephosphorylates PDGF-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on PDGFR with concomitant reduction in Akt and Erk1/2 kinase activity. PTP1B significantly inhibited PDGF-induced DNA synthesis without inducing apoptosis. These results for the first time provide evidence that the stilbene resveratrol targets PTP1B to inhibit PDGFR mitogenic signaling.
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PMID:Resveratrol inhibits PDGF receptor mitogenic signaling in mesangial cells: role of PTP1B. 1856 37


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