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Oncogenic K-RAS subverts the antiapoptotic role of N-RAS and alters modulation of the N-RAS:gelsolin complex.
Keller JW, Haigis KM, Franklin JL, Whitehead RH, Jacks T, Coffey RJ
(2007) Oncogene 26: 3051-9
MeSH Terms: Animals, Apoptosis, Apoptosis Regulatory Proteins, Caco-2 Cells, Cell Line, Cell Survival, Colorectal Neoplasms, Gelsolin, Genes, ras, HCT116 Cells, Humans, Mice, Proto-Oncogene Proteins p21(ras), ras Proteins
Show Abstract · Added August 12, 2010
Activating mutations in members of the RAS family of genes are among the most common genetic events in human tumorigenesis. Once thought to be functionally interchangeable, it is increasingly recognized that the classical members of this protein family (H-RAS, N-RAS and K-RAS4B) exhibit unique and shared functions that are highly context-dependent. Herein, we demonstrate that the presence of an oncogenic KRAS allele results in elevated levels of GTP-bound N-RAS (N-RAS.GTP) in two human colorectal cancer cell lines, HCT 116 and DLD-1, compared to their isogenic counterparts in which the mutant KRAS allele has been disrupted by homologous recombination. N-RAS subserves an antiapoptotic role in cells expressing wild-type K-RAS; this function is compromised, however, by the presence of mutant K-RAS, and these cells display increased sensitivity to apoptotic stimuli. We additionally identify a physical interaction between N-RAS and gelsolin, a factor that has been shown to promote survival and show that the N-RAS:gelsolin complex is modulated differently in wild-type and mutant K-RAS environments following apoptotic challenge. These findings represent the first biochemical evidence of a functional relationship between endogenous RAS proteins and identify a dynamic physical interaction between endogenous N-RAS and gelsolin that correlates with survival.
1 Communities
2 Members
0 Resources
14 MeSH Terms
Transforming growth factor beta mimetics: discovery of 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid, a biaryl hydroxamate inhibitor of histone deacetylase.
Glaser KB, Li J, Aakre ME, Morgan DW, Sheppard G, Stewart KD, Pollock J, Lee P, O'Connor CZ, Anderson SN, Mussatto DJ, Wegner CW, Moses HL
(2002) Mol Cancer Ther 1: 759-68
MeSH Terms: Acetylation, Animals, Biphenyl Compounds, Blotting, Western, Cell Cycle, Cell Division, Cell Line, Collagenases, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, Dose-Response Relationship, Drug, Enzyme Inhibitors, Epithelial Cells, Fibroblasts, Fibronectins, G1 Phase, Gelsolin, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Inhibitory Concentration 50, Keratinocytes, Luciferases, Lung, Mice, Mink, Models, Chemical, Phenotype, Plasminogen Activator Inhibitor 1, Promoter Regions, Genetic, S Phase, Time Factors, Transfection, Transforming Growth Factor beta
Show Abstract · Added May 27, 2014
Transforming growth factor beta (TGF-beta) is a multifunctional protein that has been shown to possess potent growth-inhibitory activity. To identify small molecular weight compounds with TGF-beta-like activities, high throughput screening was performed using mink lung epithelial cells stably transfected with a TGF-beta-responsive plasminogen activator inhibitor 1 promoter/luciferase construct. Biaryl hydroxamate compounds were identified that demonstrated TGF-beta-like activities. 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid (A-161906) demonstrated complete TGF-beta-like agonist activity in the plasminogen activator inhibitor 1/luciferase construct. A-161906 inhibited the proliferation of multiple cell lines in a concentration-dependent manner. Cells were growth arrested at the G1-S checkpoint similar to TGF-beta. Consistent with the G1-S arrest, A-161906 induced the expression of the cyclin-dependent kinase inhibitor p21waf1/cip1. A-161906 produced many cellular effects similar to that of TGF-beta but did not displace labeled TGF-beta from its receptors. Cells with mutations in either of the TGF-beta receptors I or II were growth-arrested by A-161906. Therefore, the site of action of A-161906 appears to be distal to the receptors and possibly involved with the signaling events controlled by TGF-beta. The TGF-beta mimetic effect of A-161906 can be partially, if not entirely, explained by its activity as a histone deacetylase (HDAC) inhibitor. A-161906 demonstrated potent HDAC-inhibitory activity (IC50 = 9 nM). A-161906 is a novel small molecular weight compound (< 400 MW) having TGF-beta mimetic activity as a result of its potent HDAC-inhibitory activity. These results and those of others demonstrate the importance of HDACs in regulation of the TGF-beta signaling pathway(s).
0 Communities
1 Members
0 Resources
34 MeSH Terms
Motile areas of leech neurites are rich in microfilaments and two actin-binding proteins: gelsolin and profilin.
Neely MD, Macaluso E
(1997) Proc Biol Sci 264: 1701-6
MeSH Terms: Actin Cytoskeleton, Animals, Cell Movement, Cells, Cultured, Contractile Proteins, Gelsolin, Leeches, Microfilament Proteins, Neurites, Profilins
Show Abstract · Added September 13, 2014
Cell motility is produced by changes in the dynamics and organization of actin filaments. The aim of the experiments described here was to test whether growing neurites contain two actin-binding proteins, gelsolin and profilin, that regulate polymerization of actin and affect non-neuronal cell motility. The distribution of gelsolin, profilin and the microfilaments was compared by immunocytochemistry of leech neurons growing in culture. We observed that microfilaments are enriched in the peripheral motile areas of the neurites. Both gelsolin and profilin are also concentrated in these regions. Gelsolin is abundant in filopodia and is associated with single identifiable microfilament bundles in lamellipodia. Profilin is not prominent in filopodia and shows a diffuse staining pattern in lamellipodia. The colocalization of gelsolin and profilin in motile, microfilament-rich areas supports the hypothesis that they synergistically regulate the actin dynamics that underlie neurite growth.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Electrical activity, growth cone motility and the cytoskeleton.
Neely MD, Nicholls JG
(1995) J Exp Biol 198: 1433-46
MeSH Terms: Action Potentials, Animals, Axons, Calcium, Calcium Channels, Cell Movement, Cells, Cultured, Cytoskeleton, Drosophila melanogaster, Electric Stimulation, Gelsolin, Leeches, Neurons
Show Abstract · Added September 13, 2014
The development of the nervous system takes place in two main steps: first an extensive preliminary network is formed and then it is pruned and trimmed to establish the final form. This refinement is achieved by mechanisms that include cell death, selective growth and loss of neurites and the stabilization and elimination of synapses. The focus of this review is on selective neurite retraction during development, with particular emphasis on the role of electrical activity. In many developing vertebrate and invertebrate neurones, the frequency and duration of ongoing impulse activity determine the final arborizations and the pattern of connections. When impulse traffic is silenced, axons fail to retract branches that had grown to inappropriate destinations in the mammalian visual system, cerebellum and neuromuscular junctions. Similarly, in crustaceans, Drosophila melanogaster and leeches, refinements in axonal morphology during development are influenced by impulse activity. From experiments made in culture, it has been possible to mimic these events and to show a clear link between the density of voltage-activated calcium channels in a neurite and its retraction following stimulation. The distribution of these calcium channels in turn is determined by the substratum with which the neurites are in contact or by the formation of synapses. Several lines of evidence suggest that calcium entry into the growth cone leads to collapse by disruption of actin filaments. One candidate for coupling membrane events to neurite retraction is the microfilament-associated protein gelsolin which, in its calcium-activated state, severs actin filaments. Open questions that remain concern the differential effects of activity on dendrites and axons as well as the mechanisms by which the growth cone integrates information derived from stimuli in the cell and in the extracellular environment.
0 Communities
1 Members
0 Resources
13 MeSH Terms