Search results for "MAPK"
showing 10 items of 238 documents
Emerging MEK inhibitors
2010
IMPORTANCE OF THE FIELD: The Ras/Raf/MEK/ERK pathway is often activated by genetic alterations in upstream signaling molecules. Integral components of this pathway such as Ras and B-Raf are also activated by mutation. The Ras/Raf/MEK/ERK pathway has profound effects on proliferative, apoptotic and differentiation pathways. This pathway can often be effectively silenced by MEK inhibitors. AREAS COVERED BY THIS REVIEW: This review will discuss targeting of MEK which could lead to novel methods to control abnormal proliferation which arises in cancer and other proliferative diseases. This review will cover the scientific literature from 1980 to present and is a follow on from a review which fo…
Regulation of ERK1/2 activity upon contact inhibition in fibroblasts.
2011
Contact inhibition is a crucial mechanism regulating proliferation in vitro and in vivo. Despite its generally accepted importance for maintaining tissue homeostasis knowledge about the underlying molecular mechanisms of contact inhibition is still scarce. Since the MAPK ERK1/2 plays a pivotal role in the control of proliferation, we investigated regulation of ERK1/2 phosphorylation which is downregulated in confluent NIH3T3 cultures. We found a decrease in upstream signaling including phosphorylation of the growth factor receptor adaptor protein ShcA and the MAPK kinase MEK1/2 in confluent compared to exponentially growing cultures whereas involvement of ERK1/2 phosphatases in ERK1/2 inact…
Analysis of Differentially Activated Signaling Pathways in Myeloproliferative Disease Using Kinomics Chip Profiling
2008
Abstract In a multitude of cases, oncogenic mutations are gain of function mutations that confer a constitutively activated gene product. Currently, evidence from a large body of experimental studies suggests that oncogenic transformation induced by activating kinase mutations is not sufficiently explained by constitutive kinase activation alone but is a result of aberrantly activated signaling pathways in affected cells. The JAK2V617F-mutation is a highly prevalent molecular marker in Ph-negative myeloproliferative disease (MPD). In vitro, Ba/F3-cells expressing both erythropoietin receptor (EpoR) and the JAK2V617F-mutation show constitutive activation of the JAK-STAT pathway and cytokine …
IAPs and cell migration.
2015
Inhibitors of apoptosis (IAPs) constitute a family of cell signaling regulators controlling several fundamental biological processes such as innate immunity, inflammation, cell death, cell proliferation, and cell differentiation. Increasing evidence from in vivo and in vitro studies indicate a function for IAPs in the modulation of invasive and migratory properties of cells. Here, we present and discuss the mechanisms whereby IAPs can control cell migration.
Activity-dependent survival of developing neocortical neurons depends on PI3K signalling
2011
J. Neurochem. (2012) 120, 495–501. Abstract Spontaneous electrical network activity plays a major role in the control of cell survival in the developing brain. Several intracellular pathways are implicated in transducing electrical activity into gene expression dependent and independent survival signals. These include activation of phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt, activation of Ras and subsequently MAPK/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase and signalling via calcium/calmodulin-dependent protein kinase (CaMK). In the present study, we analyzed the role of these pathways for the control of neuronal survival …
Signal transduction pathways of the epidermal growth factor receptor in colorectal cancer and their inhibition by small molecules.
2012
While prognostic factors can help to classify the standard risk of subpopulations of patients with the same tumor entity, it is still not possible to predict the response of individual patients to specific therapies. The reason for such wide variation in cancer therapy responses remains largely unknown. The field of chemotherapy is currently undergoing a paradigm shift from classical cytotoxic chemotherapy to targeted therapy in order to kill tumor cells more efficiently with fewer side effects on normal tissue. In the present review, we focus on colorectal carcinoma, which is one of the most frequent tumor types worldwide and represents a leading cause of cancer-related deaths. The signali…
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…
Cilomilast counteracts the effects of cigarette smoke in airway epithelial cells.
2010
Abstract Cigarette smoke extracts (CSE) alter TLR4 expression and activation in bronchial epithelial cells. Cilomilast, a phosphodiesterase-4 inhibitor, inhibits cigarette smoke-induced neutrophilia. This study was aimed to explore whether cilomilast, in a human bronchial epithelial cell line (16-HBE), counteracted CSE effects. In particular, TLR4 expression, IP-10 and IL-8 release, lymphocyte and neutrophil chemotactic activity and ERK and IkBa phosphorylation in CSE and LPS-stimulated 16-HBE were assessed. CSE increased TLR4 expression, reduced IP-10 release and lymphocyte chemotactic activity and increased IL-8 release and neutrophil chemotactic activity. Cilomilast reduced TLR4 expressi…
An immune escape screen reveals Cdc42 as regulator of cancer susceptibility to lymphocyte-mediated tumor suppression.
2007
Abstract Adoptive cellular immunotherapy inducing a graft-versus-tumor (GVT) effect is the therapeutic mainstay of allogeneic hematopoietic stem cell transplantation (ASCT) for high-risk leukemias. Autologous immunotherapies using vaccines or adoptive transfer of ex vivo–manipulated lymphocytes are clinically explored in patients with various cancer entities. Main reason for failure of ASCT and cancer immunotherapy is progression of the underlying malignancy, which is more prevalent in patients with advanced disease. Elucidating the molecular mechanisms contributing to immune escape will help to develop strategies for the improvement of immunologic cancer treatment. To this end, we have und…
Docosahexaenoic acid inhibits cancer cell growth via p27Kip1, CDK2, ERK1/ERK2, and retinoblastoma phosphorylation
2006
Docosahexaenoic acid (DHA), a PUFA of the n-3 family, inhibited the growth of FM3A mouse mammary cancer cells by arresting their progression from the late-G(1) to the S phase of the cell cycle. DHA upregulated p27(Kip1) levels by inhibiting phosphorylation of mitogen-activated protein (MAP) kinases, i.e., ERK1/ERK2. Indeed, inhibition of ERK1/ERK2 phosphorylation by DHA, U0126 [chemical MAPK extracellularly signal-regulated kinase kinase (MEK) inhibitor], and MEK(SA) (cells expressing dominant negative constructs of MEK) resulted in the accumulation of p27(Kip1). MAP kinase (MAPK) inhibition by DHA did not increase p27(Kip1) mRNA levels. Rather, this fatty acid stabilized p27(Kip1) contents…