Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to investigate the mechanisms by which marine lipids rich in long chain omega-3 fatty acids inhibit autoimmune disease and prolong the survival rate in female (NZB/NZW) F1 (B/W) mice, an animal model for human SLE. Nutritionally adequate semipurified diets containing at 10% either corn oil (CO) or fish oil (FO) were fed from 1 mo of age and were monitored for proteinuria and survival. Proteinuria was detected earlier and became progressively severe in CO-fed mice. The average life span was significantly shortened by the CO diet (266.7 days +/- 12.5), whereas FO extended the survival significantly (402.1 days +/- 26.1; p < 0.001). A cross-sectional study at 6.5 mo of age revealed an increased proliferative response to T cell mitogens including bacterial superantigens and decreased serum anti-dsDNA Ab titers in the FO group compared with the CO group. Furthermore, splenocytes from the FO group when stimulated with Con A had higher IL-2 and lower IL-4 production similar to that of young (3.5 mo) mice. Flow cytometric analyses of splenocytes revealed lower Ig+, higher lymphocyte endothelial cell adhesion molecule-1, and lower Pgp-1+ cells within CD4+ and CD8+ subsets in FO-fed mice. Also, elevated IL-2 and IL-4 and significantly higher TGF-beta 1 and lower c-myc and c-ras mRNA expression and higher TGF-beta 1 and significantly lower c-Myc and c-Ha-Ras proteins were detected in spleens of FO-fed mice. Fatty acid analysis revealed significantly higher linoleic (18:2 omega-6) and arachidonic (20:4 omega-6) acid levels in splenocytes of the CO-fed group and higher eicosapentaenoic (20:5 omega-3) and docosahexanoic (22:6 omega-3) acid levels in the FO-fed group, indicating that changes in membrane fatty acid composition may contribute to the altered immune function and gene expression during the development of murine SLE.
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PMID:Increased TGF-beta and decreased oncogene expression by omega-3 fatty acids in the spleen delays onset of autoimmune disease in B/W mice. 820 22

In response to changes in the external environment cells must initiate a coordinated program of gene expression for them to adapt. IEX-1 (immediate early response gene X-1) is precisely regulated by multiple transcription factors among which p53, NF-kappaB/rel, Sp1 and c-Myc play central roles, to ensure rapid and transient expression of IEX-1 in cells under a variety of stress conditions. Overexpression of IEX-1 renders some cells sensitive to apoptosis and accelerates cell cycle progression, but reduces proliferation of other cells, whereas disruption of IEX-1 expression is associated with decreases in both apoptosis and cell cycle progression. In sharp contrast to in vitro studies, in vivo constitutive expression of IEX-1 prevents activated T cells but not B cells from apoptosis, as shown using IEX-1-transgenic mice that target IEX-1 expression specifically to lymphocytes driven by the Emu enhancer. The animals developed a lupus-like disease and subsequently a high incidence of T cell lymphomas when they aged, due to insufficient apoptosis of T cells. These varied effects of IEX-1 on cell death and cell cycle progression in a cell-context dependent fashion implicate that IEX-1 is involved in more than one signaling pathway, understanding of which will certainly improve our knowledge with respect to cancer biology, cell death and cell cycle regulation.
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PMID:Roles of the stress-induced gene IEX-1 in regulation of cell death and oncogenesis. 1251 Jan 47

Myc proteins regulate cell growth and are oncogenic in many cancers. Although these proteins are validated molecular anticancer targets, new therapies aimed at modulating myc have yet to emerge. A benzodiazepine (Bz-423) that was discovered in efforts to find new drugs for lupus was found recently to have antiproliferative effects on Burkitt's lymphoma cells. We now show that the basis for the antiproliferative effects of Bz-423 is the rapid and specific depletion of c-myc protein, which is coupled to growth-suppressing effects on key regulators of proliferation and cell cycle progression. c-Myc is depleted as a result of signals coupled to Bz-423 binding its molecular target, the oligomycin sensitivity-conferring protein subunit of the mitochondrial F(1)F(o)-ATPase. Bz-423 inhibits F(1)F(o)-ATPase activity, blocking respiratory chain function and generating superoxide, which at growth-inhibiting concentrations triggers proteasomal degradation of c-myc. Bz-423-induced c-myc degradation is independent of glycogen synthase kinase but is substantially blocked by mutation of the phosphosensitive residue threonine 58, which when phosphorylated targets c-myc for ubiquitination and subsequent proteasomal degradation. Collectively, this work describes a new lead compound, with drug-like properties, which regulates c-myc by a novel molecular mechanism that may be therapeutically useful.
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PMID:The immunomodulatory benzodiazepine Bz-423 inhibits B-cell proliferation by targeting c-myc protein for rapid and specific degradation. 1645 38

Immunoglobulin gene somatic hypermutation (SHM) and class switch DNA recombination (CSR) play important roles in the generation of autoantibodies in systemic lupus erythematosus. Systemic lupus is characterized by the production of an array of pathogenic high-affinity mutated and class-switched, mainly IgG, antibodies to a variety of self-antigens, including nuclear components, such as dsDNA, histones, and chromatin. We previously found that MRL/Fas(lpr/lpr) mice, which develop a systemic autoimmune syndrome sharing many features with human lupus, display greatly upregulated CSR, particularly to IgG2a, in B cells of the spleen, lymph nodes, and Peyer's patches. In MRL/Fas(lpr/lpr) mice, the significant upregulation of CSR is associated with increased expression of activation-induced cytidine deaminase (AID), which is critical for CSR and SHM. We also found that HoxC4 directly activates the promoter of the AID gene to induce AID expression, CSR and SHM. Here, we show that in both lupus patients and lupus-prone MRL/Fas(lpr/lpr) mice, the expression of HoxC4 and AID is significantly upregulated. To further analyze the role of HoxC4 in lupus, we generated HoxC4(-/-) MRL/Fas(lpr/lpr) mice. In these mice, HoxC4-deficiency resulted in reduced AID expression, impaired CSR, and decreased serum anti-dsDNA IgG, particularly IgG2a, autoantibodies, which were associated with a reduction in IgG deposition in kidney glomeruli. In addition, consistent with our previous findings in MRL/Fas(lpr/lpr) mice that upregulated AID expression is associated with extensive DNA lesions, comprising deletions and insertions in the IgH locus, we found that c-Myc to IgH (c-Myc/IgH) translocations occur frequently in B cells of MRL/Fas(lpr/lpr) mice. The frequency of such translocations was significantly reduced in HoxC4(-/-) MRL/Fas(lpr/lpr) mice. These findings suggest that in lupus B cells, upregulation of HoxC4 plays a major role in dysregulation of AID expression, thereby increasing CSR and autoantibody production and promoting c-Myc/IgH translocations.
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PMID:AID dysregulation in lupus-prone MRL/Fas(lpr/lpr) mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations: modulation by HoxC4. 2158 11

The dog (canis lupus familiaris) is the only other species besides humans that develop spontaneous prostatic carcinomas (PCa) at a high frequency. The canine model is primarily utilized for the study of the PCa molecular mechanisms and provides a natural animal model for the study of potential therapies. In humans, the PCa frequently exhibits mutations in the C-MYC and a reduced expression of the E-cadherin and NKX3.1 proteins. This study's objective was to evaluate the NKX3.1, C-MYC, and E-cadherin expression in the canine normal prostate, benign prostatic hyperplasia (BPH), proliferative inflammatory atrophy (PIA) and PCa and to verify differences in expression and subcellular localization of these proteins in the prostatic carcinogenesis. A tissue microarray (TMA) slide was constructed, and immunohistochemistry with antibodies raised against C-MYC, NKX3.1, E-cadherin and p63 was performed using the peroxidase and DAB methods. The C-MYC protein expression was elevated in the cytoplasm and nuclei of the canine PCa and PIA compared with the normal prostate (P = 0.004. The NKX3.1 protein expression was reduced in 94.75% of the PCa and 100% of the PIA compared with the normal prostate (P = 0.0022). In fact, the expression of E-cadherin trended towards a decrease in carcinomas when compared to normal prostate and PIA. By immunohistochemistry, more p63-positive basal cells were observed in the PCa and PIA when compared with the normal prostate (P = 0.0002). This study has demonstrated that the carcinogenesis of canine prostatic tissue may be related to basal cell proliferation, the gain of C-MYC function and the loss of NKX3.1 protein expression.
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PMID:Alterations of C-MYC, NKX3.1, and E-cadherin expression in canine prostate carcinogenesis. 2403 Aug 51

The aberrant expansion of B1a cells has been observed in several murine autoimmune disease models; however, the mechanism of such proliferation of B1a cells is still limited. Here, we identify that Myb Like, SWIRM And MPN Domains 1 (MYSM1), a histone H2A deubiquitinase, plays an intrinsic role in the proliferation of B1a cells where MYSM1 deficiency results in the increased proliferation of B1a cells in mice. We demonstrate that MYSM1 recruits c-Myc to the promoter of miR-150 and stimulates the transcription of miR-150. Our further investigation shows that miR-150 decreases FMS-like tyrosine kinase 3 (FLT3) in B1a cells. In agreement with our animal studies, the percentage of FLT3+ B1 cells in Systemic Lupus Erythematosus (SLE) patients is significantly higher than healthy control. Thus, this study uncovers a novel pathway MYSM1/miR-150/FLT3 that inhibits proliferation of B1a, which may be involved in the pathogenesis of SLE.
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PMID:MYSM1/miR-150/FLT3 inhibits B1a cell proliferation. 2759 May 7