Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitro as well as new vessel growth ex vivo (p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction ( p ! 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis ( annexin V staining, p ! 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n=3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth. Copyright (C) 2007 S. Karger AG, Basel

W-Band GaAs HEMT MMIC Subharmonically Pumped Diode Mixers with 20 GHz IF Bandwidth

Two subharmonically pumped (SHP) diode mixers are designed for wideband W-band RF frequencies, fixed LO frequency operation. These mixers are fabricated on a 4-mil substrate using 0.1- µµµµm GaAs MMIC process. Both simulation and test results show that the mixers are with 12.25 and 11.75 dB average conversion losses, respectively. Both mixers have IF bandwidth wider than 20 GHz. The conversion loss flatness of the symmetric circuit is within ±1.25 dB. To our knowledge, these are the state-of-the-art result on low-conversion-loss wideband MMIC SHP diode mixers

Further inspection of the stochastic growth model by an analytical approach

It has been argued that a clear understanding of the stochastic growth model can best be achieved by working out an approximate analytical solution. This paper follows that idea but streamlines the presentation of the loglinear approximate solution for the neoclassical model of capital accumulation. By focusing on the partial elasticity of capital stock with respect to its lag term, this paper is able to confirm analytically some conclusions based on numerical calculations in previous papers, and to clarify why a simpler solution arises in several special cases.published_or_final_versio

On the validity and identification of long-run restrictions for a cointegrated system

The identification approach suggested in Blanchard and Quah [1989 The dynamic effects of aggregate supply and demand disturbances. Am. Econ. Rev. 79:655-673] and King et al. [1991 Stochastic trends and economic flucuations. Am. Econ. Rev. 81:819-840] makes use of the long-run properties of structural disturbances. This paper provides economic underpinning for the use of long-run identifying restrictions by showing formally its validity for the class of exogenous growth models under certain conditions. This paper also obtains the minimum number of restrictions, in addition to the long-run restrictions, required for the identification of structural disturbances in a co-integrated system. © 2000 Elsevier Science B.V. All rights reserved.postprin

Cross-Regulation of Protein Stability by p53 and Nuclear Receptor SHP

We report here a novel interplay between tumor suppressor p53 and nuclear receptor SHP that controls p53 and SHP stability. Overexpression of p53 causes rapid SHP protein degradation, which does not require the presence of Mdm2 and is mediated by the proteosome pathway. Overexpressing SHP alone does not affect p53 stability. However, SHP destabilizes p53 by augmentation of Mdm2 ubiquitin ligase activity toward p53. The single amino acid substitution in the SHP protein SHPK170R increases SHP binding to p53 relative to SHP wild-type, whereas SHPG171A variant shows a diminished p53 binding. As a result of the cross-regulation, the tumor suppressor function of p53 and SHP in inhibition of colon cancer growth is compromised. Our findings reveal a unique scenario for a cross-inhibition between two tumor suppressors to keep their expression and function in check