Disease relevance of Down-Regulation

• CONCLUSIONS: In severe meningococcal sepsis, protein C activation is impaired, a finding consistent with down-regulation of the endothelial thrombomodulin-endothelial protein C receptor pathway [1].
• Here we show that infection of differentiated blood vascular endothelial cells with Kaposi sarcoma-associated herpesvirus leads to their lymphatic reprogramming; induction of approximately 70% of the main lymphatic lineage-specific genes, including PROX1, a master regulator of lymphatic development; and downregulation of blood vascular genes [2].
• Nuclear run-on experiments show that the down-regulation of B2 genes during F9 embryonal carcinoma cell differentiation into endoderm occurs at the transcriptional level and that other class III genes, including those encoding tRNA, show a similar response [3].
• FRAXA expansion results in fragile X syndrome due to down regulation of expression of the FMR1 gene, which carries the hypermutable CGG repeat in the 5' untranslated portion of its first exon [4].
• Since TGF-beta 1 appears to inhibit keratinocyte growth through down-regulation of c-myc, it was hypothesized that these DNA tumor viruses might be modulating the response to TGF-beta 1 via this pathway [5].

Psychiatry related information on Down-Regulation

• Alternatively, decreased somatostatin-like immunoreactivity in Alzheimer's disease might indicate increased release of somatostatin and down regulation of postsynaptic receptors [6].
• Synapse-specific downregulation of NMDA receptors by early experience: a critical period for plasticity of sensory input to olfactory cortex [7].
• The results suggest that up-regulation of adenylate cyclase and down-regulation of Gi alpha could represent part of the molecular mechanism by which lithium alters brain function and exerts its clinical actions in the treatment of affective disorders [8].
• Here, we tested the hypothesis that RhoA/Rho-kinase contributes to diabetes-related erectile dysfunction and down-regulation of eNOS in the streptozotocin (STZ)-diabetic rat penis [9].
• Previous analyses of gene expression in a mouse model of Huntington's disease (R6/2) indicated that an N-terminal fragment of mutant huntingtin causes downregulation of striatal signaling genes and particularly those normally induced by cAMP and retinoic acid [10].

High impact information on Down-Regulation

• Additions of inhibitors of oxidative phosphorylation (such as oligomycin or di-nitrophenol) arrested the allose-mediated down-regulation [11].
• We show that XLF directly interacts with the XRCC4-Ligase IV complex in vitro and in vivo and that siRNA-mediated downregulation of XLF in human cell lines leads to radiosensitivity and impaired NHEJ [12].
• Induction of p21 results in downregulation of cyclin A-Cdk activity and accordingly attenuation of S phase progression [13].
• This epigenetic defect is associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 and downregulation of IGF2 [14].
• Calmodulin can effectively compete with Par-4 binding in a Ca2+-dependent manner, providing a route for Ca2+-mediated downregulation of D2DR efficacy [15].

Chemical compound and disease context of Down-Regulation

• Up- and down-regulation of various glutamate receptor subunits occur throughout development, following ischemia, seizures, repetitive activation of afferents, or chronic administration of a variety of drugs [16].
• In summary,hypokalemia, like lithium treatment, results in a decrease in AQP2 expression in rat collecting ducts, in parallel with the development of polyuria, and the degree of downregulation is consistent with the level of polyuria induced, supporting the view that there is a causative link [17].
• Hyponatremia in rats induces downregulation of vasopressin synthesis [18].
• Regional myocardial downregulation of the inhibitory guanosine triphosphate-binding protein (Gi alpha 2) and beta-adrenergic receptors in a porcine model of chronic episodic myocardial ischemia [19].
• Thus, we have demonstrated a new role for ASMase in TNF-alpha-induced liver failure through downregulation of MAT1A, and maintenance of SAM may be useful in the treatment of acute and chronic liver diseases [20].

Biological context of Down-Regulation

• Phosphorylation and downregulation of Yan is facilitated by a protein called Mae [21].
• Therefore, Drosophila cyclin E, which forms a complex with the Dmcdc2c kinase, controls progression through S phase and its down-regulation limits embryonic proliferation [22].
• We propose that ESCRT-I represents a conserved component of the endosomal sorting machinery that functions in both yeast and mammalian cells to couple ubiquitin modification to protein sorting and receptor downregulation in the MVB pathway [23].
• The downregulation of PS1 in these U937 transfectants results in reduced growth with an increased fraction of the cells in apoptosis [24].
• Whereas the down-regulation of myc seems to be an early event of F9 differentiation occurring within the first 24 h, the post-transcriptional regulation of p53 occurs at a later stage (two to three days), possibly as a consequence of cell cycle changes [25].

Anatomical context of Down-Regulation

• CD4 down-regulation is strongly enhanced by the association of Nef with cell membranes through myristoylation [26].
• Thus a critical amount of Oct-3/4 is required to sustain stem-cell self-renewal, and up- or downregulation induce divergent developmental programmes [27].
• This distinct lineage restriction site is accompanied by downregulation of genes for regulators of erythroid and megakaryocyte development [28].
• This systemic deficiency is associated with circulating tumour-derived soluble MICA, causing the downregulation of NKG2D and in turn severe impairment of the responsiveness of tumour-antigen-specific effector T cells [29].
• Our data suggest that tumor cells can evade immune attack by down-regulation of the CD95 receptor and killing of lymphocytes through expression of CD95L [30].

Associations of Down-Regulation with chemical compounds

• We have located the distal boundary of the tyrosine kinase domain of the EGF receptor and have identified a distinct sequence in the C' terminus required for EGF-dependent receptor internalization, leading to receptor down-regulation and degradation [31].
• Conversely, down-regulation of NCX by siRNA compromised neuronal Ca2+ handling, transforming the Ca2+ transient elicited by non-excitotoxic glutamate concentrations into a lethal Ca2+overload [32].
• Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells [33].
• Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage [34].
• A mutant form of the SIVmac239 Nef, which contains changes in a putative SH3-binding domain (amino acids 104 and 107 have been changed from PxxP to AxxA), does not associate with cellular serine/threonine kinases, but is fully active in CD4 downregulation and associates with the cellular tyrosine kinase Src [35].

Gene context of Down-Regulation

• Mutations that prevent the normal developmental down-regulation of lin-14, activity delay or block VPC division and prevent vulval differentiation [36].
• These results support a role for RECK in the regulation of MMP-2 in vivo and implicate RECK downregulation in tumor angiogenesis [37].
• The two processes can be uncoupled, since, in PU.1-deficient pre-B cells, C/EBPs induce CD19 downregulation but not Mac-1 activation [38].
• Throughout development, Dpp transduction causes the graded transcriptional downregulation of the brinker (brk) gene [39].
• To explore whether downregulation of Chfr contributes directly to tumorigenesis, we generated Chfr knockout mice [40].

Analytical, diagnostic and therapeutic context of Down-Regulation

• In situ hybridizations demonstrate that antibody injection causes downregulation of pax[b] transcripts in the posterior midbrain and alteration of wnt-1 and eng-2 expression in this area [41].
• Ligation of this receptor leads to prominent downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production [42].
• The mechanism that results in the reduction of IL-4 synthesis in treated individuals is unknown, but because clinical improvement during immunotherapy is associated with the administration of the highest doses of allergen, we hypothesized that high concentration of allergen results in the downregulation of IL-4 synthesis in CD4+ T cells [43].
• Hypomagnesemia developed during chronic HCTZ administration and in NCC-knockout mice, an animal model of Gitelman syndrome, accompanied by downregulation of the epithelial Mg2+ channel transient receptor potential channel subfamily M, member 6 (Trpm6) [44].
• In site-directed mutagenesis/recombinant expression studies we have found that glycine at position 16 (Gly16) imparts an accelerated agonist-promoted downregulation of beta 2AR as compared to arginine at this position (Arg16) [45].

References