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New Pathway on Cholesterol Regulation has been found. The breakthrough has come from our research work using proteomic and protein-protein interaction experiments. An E3 ligase, c-IAP1 has been found to process and ubiquitinate PCSK9 with K27 polyubiquitination, which target the PCSK9/LDLR to lysosome. The novel pathway descibed in the paper will open new avenues for cardivascular disease as PCSK9 now being considered as the hottest genetic validated target after statin.
Xu, W.; Liu, L.; Hornby, D. c-IAP1 Binds and Processes PCSK9 Protein: Linking the c-IAP1 in a TNF-α Pathway to PCSK9-Mediated LDLR Degradation Pathway. Molecules 2012, 17, 12086-12101.
Abstract: Recent genetic studies have shown that PCSK9, one of the key genes in cholesterol metabolism, plays a critical role by controlling the level of low-density lipoprotein receptor. However, how PCSK9 mediates LDLR degradation is still unknown. By combining a shotgun proteomic method and differential analysis of natural occurring mutations of the PCSK9 gene, we found that an E3 ubiquitin ligase c-IAP1 binds and processes PCSK9 protein. One of the ‘gain-of-function’ mutations, S127R, is defective with respect to binding to c-IAP1, and thus has defective autocatalytic activity. Knockdown of c-IAP1 impairs PCSK9 processing and autocatalytic cleavage. In c-IAP1 null mouse embryonic fibroblasts (MEFs), there is a dramatic decrease in secreted mature PCSK9 protein accompanied by a significant increase in LDLR protein levels compared with matched wild-type MEF cells. c-IAP1 also acts as an E3 ligase for ubiquitination of PCSK9. Ubiquitin containing only lysine-27 mediated PCSK9 ubiquitination by c-IAP1. Given K27-linked polyubiquitination promotes lysosomal localization, the finding indicates the c-IAP1 acts on both secretion of PCSK9 and its lysosomal localization. The novel pathway described here will open new avenues for exploring novel disease treatments.
We have used Quantum dot as bomb and antibody as targetting homing missile to kill the cancer cell. Just published in
Recent Research Breakthrough in NO
Linking mitochondrial signalling to ER-stress by nitric oxide
Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response.
Xu W, Liu L, Charles IG, Moncada S.
Nitric oxide (NO) is a pleiotropic signalling molecule that binds to cytochrome c oxidase (complex IV) reversibly and in competition with oxygen. This action of NO has both physiological and pathophysiological consequences. Here we report that endogenously generated NO, which disrupts the respiratory chain, may cause changes in mitochondrial calcium flux. This induces cleavage of the endoplasmic reticulum (ER) stress-regulated transcription factor p90 ATF6 into an active p50 form. Cleavage depends on a calcium-dependent serine protease through a regulated intramembrane proteolysis (RIP) process. p50 ATF6 then translocates to the nucleus to upregulate expression of the ER-resident molecular chaperone, glucose-regulated protein 78 (Grp78). The increase in Grp78 provides significant cytoprotection against toxic agents, including thapsigargin, a selective ER calcium-ATPase inhibitor. Cytoprotection is abolished after treatment with cyclosporin A (CsA), which disrupts mitochondrial calcium signalling, or with the calcium chelator BAPTA-AM. The NO-mediated ER stress response is diminished in rho(0) cells devoid of mitochondrial DNA, consistent with our evidence that NO-dependent mitochondrial disruption is coupled to the ER stress response.
Nat Cell Biol. 2004 Nov;6(11):1129-34. Epub 2004 Oct 24.
<(PDF) cited in mitochondria and NO.html
Recent Research Review NO & Cancer
Nitric oxide and COX-2 pathway;2009 Targeting Cyclooxygenase and Nitric Oxide Pathway Cross-Talk: A New Signal Transduction Pathway for Developing More Effective Anti- Inflammatory Drugs
Targeting Cyclooxygenase and Nitric Oxide Pathway Cross-Talk: A New Signal Transduction Pathway for Developing More Effective Anti- Inflammatory Drugs
Current Signal Transduction Therapy Volume 4. The Journal Site
iNOS , pam NOS antibodies and other NO prodcuts for sale from London Biotech Ltd
This page is devoted to the nitric oxide user and researcher . There are three different type of nitric oxide synthases: neuronal nitric oxide synthase(NOS1), inducible nitric oxide synthase(NOS2) and endothelium nitric oxide synthase(NOS3). Each of them have different tissue distributions and located on different human chromosomes. They may related to many human diseases, such as Alzheimer 's dieseases, Parkinson's. diabetes, asthma, heart disease, infection diseases.Some nitric oxide reagents, such as nitric oxide cDNAs, genomic DNAs, nitric oxide polymorphic markers, nitric oxide antibodies, Nitric oxide synthase proteins and other information will be helpful for these researchers. In my favorite site , you can find them all. This page also contain some information about human genetics, human identity, microsatellite information .
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The FASEB Journal Express Article 10.1096/fj.01-0590fje Published online December 28, 2001
Microencapsulated iNOS-expressing cells cause tumor suppression in mice
Weiming Xu, Lizhi Liu, and Ian G. Charles E-mail contact: rmgzigc@ucl.ac.uk
Macrophages can kill tumor cells by releasing high levels of nitric oxide (NO) and related reactive nitrogen species such as nitroxyl and peroxynitrite, after up-regulation of expression of the inducible nitric oxide synthase gene (iNOS). In this paper we describe two novel human cell lines that are capable of expressing high levels of iNOS under the control of analogues of either the insect hormone ecdysone or tetracycline. We have entrapped these iNOS-expressing cells within a semipermeable alginate-poly-L-lysine membrane as a means of delivery to tumor sites in a nude mouse model. These encapsulated cells can be induced to generate sustainable high concentrations NO and reactive nitrogen species at tumor sites after treatment either with ponasterone A or muristerone A or with doxycycline. Delivery of these iNOS-expressing cells to tumors formed from human ovarian cancer SKOV-3 cells results in 100% killing, whereas treatment of tumors formed from human colon cancer DLD-1 cells results in 54% killing. We show that in these iNOS-expressing cells, tumor killing is associated with concomitant up-regulation of the Fas/FasL proteins. FASEB J, 16, 213-215(2002).[Abstract] [PDF]
News on Nitric Oxide nature cell biology june 2000 volume 2 issue 6 pp 339 - 345 Nitric oxide upregulates expression of DNA-PKcs to protect cells from DNA-damaging anti-tumour agents Weiming Xu, Lizhi Liu, Graeme C. M. Smith and lan G. Charles Nitric Oxide and tumor.html,
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London Biotech LIMITED NEW biotech company to provide antibody, cDNA, expression plasmids and cell lines for nitric oxide, PCSK9 and GRP78 research London Biotech Ltd for advice in information or productsclick here to send
NEW biotech company to provide antibody, cDNA, expression plasmids and cell lines for nitric oxide, PCSK9 and GRP78 research
anti-breast cancer and prostate cancer potential
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