Search results for "serine"
showing 10 items of 590 documents
Evaluation and clinical analyses of downstream targets of the Akt inhibitor GDC-0068.
2013
Abstract Purpose: The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound. Experimental Design: We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker se…
The novel dual PI3K/mTOR inhibitor GDC-0941 synergizes with the MEK inhibitor U0126 in non-small cell lung cancer cells.
2011
Lung cancer is a malignant disease with poor outcome, which has led to a search for new therapeutics. The PI3K/Akt/mTOR and Ras/raf/Erk pathways are key regulators of tumor growth and survival. In the present study, their roles were evaluated by MTT assay, flow cytometry and Western blotting in lung cancer cells. We found that a high efficacy of antitumor activity was shown with GDC-0941 treatment in two gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460. In addition, H460 cells with activating mutations of PIK3CA were relatively more sensitive to GDC-0941 than A549 cells with wild-type PIK3CA. Furthermore, GDC-0941 was highly efficacious in combination with U0…
Involvement of the transcription factor FoxM1 in contact inhibition
2012
Contact inhibition is a crucial mechanism regulating proliferation in vitro and in vivo. Although it is generally accepted that contact inhibition plays a pivotal role in maintaining tissue homeostasis, the molecular mechanisms of contact inhibition are still not fully understood. FoxM1 is known as a proliferation-associated transcription factor and is upregulated in many cancer types. Vice versa, anti-proliferative signals, such as TGF-β and differentiation signals decrease FoxM1 expression. Here we investigated the role of FoxM1 in contact inhibition in fibroblasts. We show that protein expression of FoxM1 is severely and rapidly downregulated upon contact inhibition, probably by inhibiti…
p42 MAPK phosphorylates 80 kDa MARCKS at Ser-113.
1996
Abstract It is demonstrated here that p42 MAPKinase (p42 MAPK) phosphorylates the M yristoylated A lanine- R ich C - K inase S ubstrate (MARCKS) at Ser-113. In permeabilised Swiss 3T3 cells activation of protein kinase C (PKC) leads to p42 MAPK activation, but only the protein kinase C sites in MARCKS become phosphorylated and not Ser-113. The mitogen platelet-derived growth factor (PDGF) elicits the same response. These results demonstrate that while Ser-113 is a substrate for p42 MAPK in vitro and can be phosphorylated in vivo as shown by Taniguchi et al. [(1994) J. Biol. Chem. 269, 18299–18302], its phosphorylation is not subject to acute regulation by p42 MAPK in Swiss 3T3 cells.
The Late Endosomal Adaptor Molecule p14 (LAMTOR2) Regulates TGFβ1-Mediated Homeostasis of Langerhans Cells
2014
Langerhans cells (LCs), a sub-population of dendritic cells (DCs) in the skin, participate in the regulation of immunity and peripheral tolerance. The adaptor molecule p14 is part of the late endosomal/lysosomal adaptor and mitogen-activated protein kinase and mammalian target of rapamycin (mTOR) activator/regulator (LAMTOR) complex, which mediates the activation of lysosome-associated extracellular signaling regulated kinase (ERK) and the mTOR cascade. In previous work, we demonstrated that CD11c-specific deficiency of p14 disrupts LC homeostasis by affecting the LAMTOR-mediated ERK and mTOR signaling. In this study, we extended our analysis on p14 deficiency specifically in LCs. Langerin-…
Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways.
2011
Chemotherapy remains a commonly used therapeutic approach for many cancers. Indeed chemotherapy is relatively effective for treatment of certain cancers and it may be the only therapy (besides radiotherapy) that is appropriate for certain cancers. However, a common problem with chemotherapy is the development of drug resistance. Many studies on the mechanisms of drug resistance concentrated on the expression of membrane transporters and how they could be aberrantly regulated in drug resistant cells. Attempts were made to isolate specific inhibitors which could be used to treat drug resistant patients. Unfortunately most of these drug transporter inhibitors have not proven effective for ther…
Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response.
2012
The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cas…
Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: How mutations can result in therapy resistance and how to overcome resistance
2012
// James A. McCubrey 1 , Linda S. Steelman 1 , William H. Chappell 1 , Stephen L. Abrams 1 , Richard A. Franklin 1 , Giuseppe Montalto 2 , Melchiorre Cervello 3 , Massimo Libra 4 , Saverio Candido 4 , Grazia Malaponte 4 , Maria C. Mazzarino 4 , Paolo Fagone 4 , Ferdinando Nicoletti 4 , Jorg Basecke 5 , Sanja Mijatovic 6 , Danijela Maksimovic-Ivanic 6 , Michele Milella 7 , Agostino Tafuri 8 , Francesca Chiarini 9 , Camilla Evangelisti 9 , Lucio Cocco 10 , Alberto M. Martelli 9,10 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA 2 Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy 3 Consi…
Activation of MAP kinase p38 is critical for the cell-cycle–controlled suppressor function of regulatory T cells
2007
AbstractRegulatory T cells play an essential role in the control of self-tolerance and processes of adaptive immunity. Tolerogenic IL-10–modulated human dendritic cells (IL-10DCs) induce anergic T cells with strong suppressive properties (iTregs) that inhibit the activation of effector T cells. In this study, we evaluated the interaction between cell-cycle regulation and intracellular signaling in these iTregs. Analysis of signal transduction events revealed a down-regulation of the mitogen-activated protein kinases (MAPKs) Jun N-terminal kinase (JNK) and a nonactivation of extracellular-signal–regulated kinase (ERK) in contrast to a marked activation of p38 MAPK and the p38 effector MAPK-a…
Identification of the phosphoglycerate dehydrogenase isoform EDA9 as the essential gene for embryo and male gametophyte development in Arabidopsis
2013
[EN] Three different pathways of serine (Ser) biosynthesis have been described in plants: the Glycolate pathway, which is part of the Photorespiratory pathway, and 2 non-Photorespiratory pathways, the Glycerate and the Phosphorylated pathways. The Phosphorylated Pathway of Ser Biosynthesis (PPSB) has been known to exist since the 1950s, but its biological relevance was not revealed until quite recently when the last enzyme of the pathway, the Phosphoserine Phosphatase, was functionally characterized. In the associated study1, we characterized a family of genes coding for putatite phosphoglycerate dehydrogenases (PGDH, 3-PGDH, and EDA9), the first enzyme of the PPSB. A metabolomics study usi…