Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several forms of human dwarfism are due to activating mutations in FGFR3 highlighting the role of FGF signaling in the growth attenuation of cartilage. Here, we studied the effects of FGF2 on RCS chondrocytes. Treatment with FGF2 induced growth arrest in the G1 phase of the cell cycle and partial de-differentiation of cells manifested by changes in cell morphology, loss of the cartilage-like extracellular matrix, and down-regulation of aggrecan expression. FGF2 activated phospholipase Cgamma, protein kinase B, and Erk and p38 MAP kinases. Chemical inhibition of FGFR3 and MEK1/2 antagonized FGF2-mediated growth arrest. Expression of a dominant-negative Ras mutant resulted in a partial reversal of growth inhibition while expression of constitutively activated Ras led to Erk-dependent growth arrest, further demonstrating the role of the Ras/Erk pathway in this phenotype. At the molecular level, FGF2-induced growth arrest was initiated by disintegration of cyclin D3-cdk6 complex followed by increased association of p21(WAF1) and p27(Kip1) with the cyclin-cdk2 and cyclin-cdk4 complexes leading to inhibition of their kinase activities and ultimately to underphosphorylation of the p107 and p130 pocket proteins. Both p21(WAF1) and p27(Kip1) accumulated upon FGF2 treatment, but this accumulation occurred at the protein level at least partially due to interaction with transcriptionally induced cyclin D1.
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PMID:FGF2 inhibits proliferation and alters the cartilage-like phenotype of RCS cells. 1519 33

Activated Ras signaling can induce a permanent growth arrest in osteosarcoma cells. Here, we report that a senescence-like growth inhibition is also achieved in human carcinoma cells upon the transduction of H-Ras(V12). Ras-induced tumor senescence can be recapitulated by the transduction of activated, but not wild-type, MEK. The ability for H-Ras(V12) to suppress tumor cell growth is drastically compromised in cells that harbor endogenous activating ras mutations. Notably, growth inhibition of tumor cells containing ras mutations can be achieved through the introduction of activated MEK. Tumor senescence induced by Ras signaling can occur in the absence of p16 or Rb and is not interrupted by the inactivation of Rb, p107, or p130 via short hairpin RNA or the transduction with HPV16 E7. In contrast, inactivation of p21 via short hairpin RNA disrupts Ras-induced tumor senescence. In summary, this study uncovers a senescence-like program activated by Ras signaling to inhibit cancer cell growth. This program appears to be intact in cancer cells that do not harbor ras mutations. Moreover, cancer cells that carry ras mutations remain susceptible to tumor senescence induced by activated MEK. These novel findings can potentially lead to the development of innovative cancer intervention.
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PMID:Dissecting the senescence-like program in tumor cells activated by Ras signaling. 1713 42

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

The Mirk/dyrk1B gene is commonly amplified or upregulated in ovarian cancers, and Mirk is an active kinase in these cancers. Mirk mediates cancer cell survival by decreasing toxic ROS levels through maintaining expression of a series of antioxidant genes, possibly through its transcriptional activator functions. Mirk has the unusual property of being most active in quiescent cancer cells because of marked transcriptional downregulation by Akt/mTOR signaling and by MEK/erk signaling in cycling cells. Metastatic ovarian cancer cells form ascites, non-adherent multicellular aggregates floating within the peritoneal fluid. Most ascites cancer cells are in a reversible quiescent, dormant state, suggesting that Mirk might be expressed in these quiescent cells and thus a therapeutic target. The current studies show that ovarian cancer cell line spheroids that mimic ascites cancer spheroids were largely quiescent in G0/G1, and enriched in Mirk and the quiescence proteins, p130/Rb2 and the CDKI p27. Mirk kinase inhibition in spheroids made from established cell lines and in patient-derived ascites cancer cell spheroids reduced spheroid volume, disrupted spheroid structure to single cells, increased apoptosis, and decreased cell numbers. Earlier studies had shown that the mTOR inhibitor RAD001 increased transcription of the Mirk/dyrk1B gene, so treatments combined RAD001 with the most active Mirk kinase inhibitor. The number of ascites cells from 9 patients was reduced a similar amount by cisplatin, Mirk kinase inhibition or RAD001, but reduced substantially more, about 90%, by concurrent treatment with both the Mirk kinase inhibitor EHT5372 and RAD001. Addition of RAD001 increased the amount of toxic ROS induced by Mirk kinase inhibition. Two ascites samples taken one month apart gave similar drug responses, showing reproducibility of the techniques. Thus Mirk/dyrk1B kinase may be a therapeutic target in ovarian cancer ascites.
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PMID:Mirk kinase inhibition targets ovarian cancer ascites. 2506 3


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