841 research outputs found
Transformation by Rho exchange factor oncogenes is mediated by activation of an integrin-dependent pathway.
Constitutive activation of growth factor receptor signaling pathways leads to uncontrolled growth, but why tumor cells become anchorage independent is less clear. The fact that integrins transmit signals required for cell growth suggests that constitutive activation of steps downstream from integrins mediates anchorage independence. Since the small GTPase Rho may mediate integrin signal transduction, the effects of serum and the Rho nucleotide exchange factor oncogenes dbl and lbc on cell growth and signaling pathways were examined. Our data show that these oncogenes induce anchorage-independent but serum-dependent growth and stimulation of signaling pathways. These results show, therefore, that anchorage-independent growth results from constitutive activation of integrin-dependent signaling events. They also support the view that Rho is a functionally important mediator of integrin signaling
Probabilities in the inflationary multiverse
Inflationary cosmology leads to the picture of a "multiverse," involving an
infinite number of (spatially infinite) post-inflationary thermalized regions,
called pocket universes. In the context of theories with many vacua, such as
the landscape of string theory, the effective constants of Nature are
randomized by quantum processes during inflation. We discuss an analytic
estimate for the volume distribution of the constants within each pocket
universe. This is based on the conjecture that the field distribution is
approximately ergodic in the diffusion regime, when the dynamics of the fields
is dominated by quantum fluctuations (rather than by the classical drift). We
then propose a method for determining the relative abundances of different
types of pocket universes. Both ingredients are combined into an expression for
the distribution of the constants in pocket universes of all types.Comment: 18 pages, RevTeX 4, 2 figures. Discussion of the full probability in
Sec.VI is sharpened; the conclusions are strengthened. Note added explaining
the relation to recent work by Easther, Lim and Martin. Some references adde
The subendothelial extracellular matrix modulates NF-κB activation by flow: a potential role in atherosclerosis
Atherosclerotic plaque forms in regions of the vasculature exposed to disturbed flow. NF-κB activation by fluid flow, leading to expression of target genes such as E-selectin, ICAM-1, and VCAM-1, may regulate early monocyte recruitment and fatty streak formation. Flow-induced NF-κB activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling. Therefore, we examined the involvement of the extracellular matrix in this process. Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-κB in response to flow, cells on collagen or laminin do not. In vivo, fibronectin and fibrinogen are deposited at atherosclerosis-prone sites before other signs of atherosclerosis. Ligation of integrin α2β1 on collagen prevents flow-induced NF-κB activation through a p38-dependent pathway that is activated locally at adhesion sites. Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-κB activation, suggesting a novel therapeutic strategy for treating atherosclerosis
Effects of cell tension on the small GTPase Rac
Cells in the body are subjected to mechanical stresses such as tension, compression, and shear stress. These mechanical stresses play important roles in both physiological and pathological processes; however, mechanisms transducing mechanical stresses into biochemical signals remain elusive. Here, we demonstrated that equibiaxial stretch inhibited lamellipodia formation through deactivation of Rac. Nearly maximal effects on Rac activity were obtained with 10% strain. GAP-resistant, constitutively active V12Rac reversed this inhibition, supporting a critical role for Rac inhibition in the response to stretch. In contrast, activation of endogenous Rac with a constitutively active nucleotide exchange factor did not, suggesting that regulation of GAP activity most likely mediates the inhibition. Uniaxial stretch suppressed lamellipodia along the sides lengthened by stretch and increased it at the adjacent ends. A fluorescence assay for localized Rac showed comparable changes in activity along the sides versus the ends after uniaxial stretch. Blocking polarization of Rac activity by expressing V12Rac prevented subsequent alignment of actin stress fibers. Treatment with Y-27632 or ML-7 that inhibits myosin phosphorylation and contractility increased lamellipodia through Rac activation and decreased cell polarization. We hypothesize that regulation of Rac activity by tension may be important for motility, polarization, and directionality of cell movement
A Role for P21-Activated Kinase in Endothelial Cell Migration
The serine/threonine p21-activated kinase (PAK) is an effector for Rac and Cdc42, but its role in regulating cytoskeletal organization has been controversial. To address this issue, we investigated the role of PAK in migration of microvascular endothelial cells. We found that a dominant negative (DN) mutant of PAK significantly inhibited cell migration and in-creased stress fibers and focal adhesions. The DN effect mapped to the most NH2-terminal proline-rich SH3-binding sequence. Observation of a green fluorescent protein-tagged α-actinin construct in living cells revealed that the DN construct had no effect on membrane ruffling, but dramatically inhibited stress fiber and focal contact motility and turnover. Constitutively active PAK inhibited migration equally well and also increased stress fibers and focal adhesions, but had a somewhat weaker effect on their dynamics. In contrast to their similar effects on motility, DN PAK decreased cell contractility, whereas active PAK increased contractility. Active PAK also increased myosin light chain (MLC) phosphorylation, as indicated by staining with an antibody to phosphorylated MLC, whereas DN PAK had little effect, despite the increase in actin stress fibers. These results demonstrate that although PAK is not required for extension of lamellipodia, it has substantial effects on cell adhesion and contraction. These data suggest a model in which PAK plays a role coordinating the formation of new adhesions at the leading edge with contraction and detachment at the trailing edge
Optically induced dynamic nuclear spin polarisation in diamond
The sensitivity of Magnetic Resonance Imaging (MRI) depends strongly on
nuclear spin polarisation and, motivated by this observation, dynamical nuclear
spin polarisation has recently been applied to enhance MRI protocols
(Kurhanewicz, J., et al., Neoplasia 13, 81 (2011)). Nuclear spins associated
with the 13 C carbon isotope (nuclear spin I = 1/2) in diamond possess uniquely
long spin lattice relaxation times (Reynhardt, E.C. and G.L. High, Prog. in
Nuc. Mag. Res. Sp. 38, 37 (2011)) If they are present in diamond nanocrystals,
especially when strongly polarised, they form a promising contrast agent for
MRI. Current schemes for achieving nuclear polarisation, however, require
cryogenic temperatures. Here we demonstrate an efficient scheme that realises
optically induced 13 C nuclear spin hyperpolarisation in diamond at room
temperature and low ambient magnetic field. Optical pumping of a
Nitrogen-Vacancy (NV) centre creates a continuously renewable electron spin
polarisation which can be transferred to surrounding 13 C nuclear spins.
Importantly for future applications we also realise polarisation protocols that
are robust against an unknown misalignment between magnetic field and crystal
axis.Comment: This is the revision submitted to NJ
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