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951.
A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2 总被引:24,自引:0,他引:24
Qi JH Ebrahem Q Moore N Murphy G Claesson-Welsh L Bond M Baker A Anand-Apte B 《Nature medicine》2003,9(4):407-415
Tissue inhibitor of metalloproteinases-3 (TIMP3) is one of four members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases (MMP). TIMP3, which encodes a potent angiogenesis inhibitor, is mutated in Sorsby fundus dystrophy, a macular degenerative disease with submacular choroidal neovascularization. In this study we demonstrate the ability of TIMP3 to inhibit vascular endothelial factor (VEGF)-mediated angiogenesis and identify the potential mechanism by which this occurs: TIMP3 blocks the binding of VEGF to VEGF receptor-2 and inhibits downstream signaling and angiogenesis. This property seems to be independent of its MMP-inhibitory activity, indicating a new function for this molecule. 相似文献
952.
953.
We have developed a genetic system, called degrakine, that specifically and stably inactivates chemokine receptors (CKR) by redirecting the ability of the HIV-1 protein, Vpu, to degrade CD4 in the endoplasmic reticulum (ER) via the host proteasome machinery. To harness Vpu's proteolytic targeting capability to degrade new receptors, we fused a chemokine with the C terminal region of Vpu. The fusion protein, or degrakine, accumulates in the ER, trapping and functionally inactivating its target CKR. We have demonstrated that degrakines based on SDF-1 (CXCL12), MDC (CCL22) and RANTES (CCL5) specifically inactivate their respective receptor functions. Using a retroviral vector expressing the SDF-1 degrakine, we have established that CXCR4 is required for the homing of hematopoietic stem/progenitor cells (HSPC) to the bone marrow immediately after transplantation. Thus the degrakine provides an effective genetic tool to dissect receptor functions in a number of biological systems in vitro and in vivo. 相似文献
954.
Xuemei?Li Ziyi?Li Alice?Jouneau Qi?ZhouEmail author Jean-Paul?Renard 《Reproductive biology and endocrinology : RB&E》2003,1(1):84
Cloning mammals by nuclear transfer is a powerful technique that is quickly advancing the development of genetically defined
animal models. However, the overall efficiency of nuclear transfer is still very low and several hurdles remain before the
power of this technique will be fully harnessed. Among these hurdles include an incomplete understanding of biologic processes
that control epigenetic reprogramming of the donor genome following nuclear transfer. Incomplete epigenetic reprogramming
is considered the major cause of the developmental failure of cloned embryos and is frequently associated with the disregulation
of specific genes. At present, little is known about the developmental mechanism of reconstructed embryos. Therefore, screening
strategies to design nuclear transfer protocols that will mimic the epigenetic remodeling occurring in normal embryos and
identifying molecular parameters that can assess the developmental potential of pre-implantation embryos are becoming increasingly
important. A crucial need at present is to understand the molecular events required for efficient reprogramming of donor genomes
after nuclear transfer. This knowledge will help to identify the molecular basis of developmental defects seen in cloned embryos
and provide methods for circumventing such problems associated with cloning the future application of this technology. 相似文献
955.
Adrenomedullin is a potent vasodilator peptide originally isolated from a pheochromocytoma. Recently, a novel adrenomedullin receptor has been identified as a complex of calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 2 (RAMP2). To explore the pathophysiological roles of adrenomedullin and its receptor component RAMP2 in ischemic cardiovascular diseases, we studied the changes of adrenomedullin and RAMP2 mRNA in myocardium and aorta in rats with isoproterenol (ISO)-induced myocardial impairment. In ISO-treated rats, heart became enlarged markedly, the ratio of heart to body weight was increased by 54% (P<0.01), and myocardial malondialdehyde content and plasma lactate dehydrogenase activity was elevated by 43% (P<0.01) and 138% (P<0.01), respectively. Immunoreactive adrenomedullin (ADM) in plasma, myocardium and aorta was augmented by 116.7% (P<0.01), 50.8% (P<0.01) and 12.5% (P>0.05), respectively. ADM mRNA in myocardium and aorta was increased by 96.8% (P<0.01) and 38.5% (P<0.01), respectively. RAMP2 mRNA in myocardium and aorta was increased by 19.6% (P<0.05) and 15.8% (P<0.01), respectively. These results suggest that the increase of ADM level and the up-regulation of ADM and RAMP2 gene in myocardium and aorta may be significant in the pathogenesis of ischemic myocardiopathy. 相似文献
956.
Zheng Q Yang WM Yu WH Cai B Teng XC Xie Y Sun HZ Zhang MJ Huang ZX 《Protein engineering》2003,16(12):865-870
MT3 shows apparently different properties and function from MT1 even though they have 70% sequence homology. Possibly the two inserts, Thr5 and a negatively charged hexapeptide at position-55 in MT3, play important roles. A series of MT3 variants around the EAAEAE hexapeptide have been prepared by site-directed mutagenesis and their properties and reactivity towards pH, EDTA and DTNB have been studied. Our detailed studies revealed that the EAAEAE insert is essential to the property of MT3. It is the hexapeptide insert, to some extent, making the MT3 alpha-domain looser and lower stability of the metal-thiolate cluster, which could be accessed more easily. 相似文献
957.
Autophosphorylation of the catalytic subunit of the DNA-dependent protein kinase is required for efficient end processing during DNA double-strand break repair
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Ding Q Reddy YV Wang W Woods T Douglas P Ramsden DA Lees-Miller SP Meek K 《Molecular and cellular biology》2003,23(16):5836-5848
The DNA-dependent protein kinase (DNA-PK) plays an essential role in nonhomologous DNA end joining (NHEJ) by initially recognizing and binding to DNA breaks. We have shown that in vitro, purified DNA-PK undergoes autophosphorylation, resulting in loss of activity and disassembly of the kinase complex. Thus, we have suggested that autophosphorylation of the DNA-PK catalytic subunit (DNA-PKcs) may be critical for subsequent steps in DNA repair. Recently, we defined seven autophosphorylation sites within DNA-PKcs. Six of these are tightly clustered within 38 residues of the 4,127-residue protein. Here, we show that while phosphorylation at any single site within the major cluster is not critical for DNA-PK's function in vivo, mutation of several sites abolishes the ability of DNA-PK to function in NHEJ. This is not due to general defects in DNA-PK activity, as studies of the mutant protein indicate that its kinase activity and ability to form a complex with DNA-bound Ku remain largely unchanged. However, analysis of rare coding joints and ends demonstrates that nucleolytic end processing is dramatically reduced in joints mediated by the mutant DNA-PKcs. We therefore suggest that autophosphorylation within the major cluster mediates a conformational change in the DNA-PK complex that is critical for DNA end processing. However, autophosphorylation at these sites may not be sufficient for kinase disassembly. 相似文献
958.
Wu SL Ma J Qi HL Zhang Y Zhang XY Chen HL 《Molecular and cellular biochemistry》2003,254(1-2):193-202
Forskolin (FSK) is known as an up-regulator of intracellular cAMP and inhibitor of cancer growth and metastasis. The effects of FSK on the metastasis potential and its mechanisms were studied using a human hepatocarcinoma cell line, H7721. It was found that FSK stimulated cell growth, increased cAMP in the cells, and enhanced the metastasis-related phenotypes, including adhesion to laminin (Ln) and human umbilical vein epithelial cells (HUVEC), chemotactic migration and invasion. These effects were supposed to result from the increase of the SLex expression induced by FSK, since only the monoclonal antibody of SLex showed a significant attenuation of the enhanced metastasis-associated phenotypes. Using H7721 cells transfected with the sense or antisense cDNA of protein kinase B (PKB) and some inhibitors of signal transduction, it was discovered that FSK up-regulated the expression of SLex via PKB, but it was independent of phosphotidylinositide-3-kinase (PI-3K). A subtype of atypical protein kinase C (-PKC) might also participate in the up-regulation of SLex expression by FSK, and cAMP/PKA pathway is a negative regulator of SLex expression on H7721 cells. It can be concluded that FSK shows a metastasis-promoting effect ex vivo. 相似文献
959.
Ran Q Van Remmen H Gu M Qi W Roberts LJ Prolla T Richardson A 《Free radical biology & medicine》2003,35(9):1101-1109
A previous study using mice null for Gpx4 indicates that PHGPx plays a critical role in antioxidant defense and is essential for the survival of the mouse. In the present study, we further analyzed the stress response of MEFs (murine embryonic fibroblasts) derived from mice heterozygous for the Gpx4 gene (Gpx4(+/-) mice). MEFs from Gpx4(+/-) mice have a 50% reduction in PHGPx expression without any changes in the activities of other major antioxidant defense enzymes. Compared to MEFs from Gpx4(+/+) mice, MEFs from Gpx4(+/-) mice were more sensitive to exposure to the oxidizing agent t-butyl hydroperoxide (t-BuOOH), and t-BuOOH exposure induced increased apoptosis in MEFs from Gpx4(+/-) mice. When cultured at low cell density, MEFs from Gpx4(+/-) mice also showed retarded growth under normal culture conditions (20% oxygen) that was reversed by culturing under low oxygen (2% oxygen). In addition, oxidative damage was increased in the MEFs from the Gpx4(+/-) mice, as indicated by increased levels of F(2)-isoprostanes and 8-oxo-2-deoxyguanosine in these cells. Our data demonstrate that MEFs from Gpx4(+/-) mice are more sensitive to oxidative stress because of reduced expression of PHGPx. 相似文献
960.
The human aristaless-related homeobox ( ARX) gene is mutated in several patients with X-linked mental retardation and/or other neurologic pathologies. We report the isolation and expression pattern of a Xenopus arx gene. Similar to other vertebrate arx genes, Xenopus arx is expressed in the developing telencephalon, diencephalon, and floor plate. 相似文献