Home About us Contact
|
Home About us Contact | ||
|
|
||
Potent Suppressor (potent + suppressor)
Selected AbstractsDifferential effects of Mxi1-SR, and Mxi1-SR, in Myc antagonismFEBS JOURNAL, Issue 17 2007Claire Dugast-Darzacq Mxi1 belongs to the Myc-Max-Mad transcription factor network. Two Mxi1 protein isoforms, Mxi1-SR, and Mxi1-SR,, have been described as sharing many biological properties. Here, we assign differential functions to these isoforms with respect to two distinct levels of Myc antagonism. Unlike Mxi1-SR,, Mxi1-SR, is not a potent suppressor of the cellular transformation activity of Myc. Furthermore, although Mxi1-SR, exhibits a repressive effect on the MYC promoter in transient expression assays, Mxi1-SR, activates this promoter. A specific domain of Mxi1-SR, contributes to these differences. Moreover, glyceraldehyde-3-phosphate dehydrogenase interacts with Mxi1-SR, and enhances its ability to activate the Myc promoter. Our findings suggest that Mxi1 gains functional complexity by encoding isoforms with shared and distinct activities. [source] Isolation and identification of 1,-hydroxy-3-epi-vitamin D3, a potent suppressor of parathyroid hormone secretionJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2005Alex J. Brown Abstract Since our original demonstration of the metabolism of 1,,25(OH)2D3 into 1,,25(OH)2 -3-epi-D3 in human keratinocytes, there have been several reports indicating that epimerization of the 3 hydroxyl group of vitamin D compounds is a common metabolic process. Recent studies reported the metabolism of 25OHD3 and 24(R),25(OH)2D3 into their respective C-3 epimers, indicating that the presence of 1, hydroxyl group is not necessary for the 3-epimerization of vitamin D compounds. To determine whether the presence of a 25 hydroxyl group is required for 3-epimerization of vitamin D compounds, we investigated the metabolism of 1,OHD3, a non-25 hydroxylated vitamin D compound, in rat osteosarcoma cells (ROS 17/2.8). We noted metabolism of 1,OHD3 into a less polar metabolite which was unequivocally identified as 1,OH-3-epi-D3 using the techniques of HPLC, GC/MS, and 1H-NMR analysis. We also identified 1,OH-3-epi-D3 as a circulating metabolite in rats treated with pharmacological concentrations of 1,OHD3. Thus, these results indicated that the presence of a 25 hydroxyl group is not required for 3-epimerization of vitamin D compounds. Furthermore, the results from the same studies also provided evidence to indicate that 1,OH-3-epi-D3, like 1,OHD3, is hydroxylated at C-25. We then evaluated the biological activities of 1,OH-3-epi-D3. Treatment of normal rats every other day for 7 days with 2.5 nmol/kg of 1,OH-3-epi-D3 did not raise serum calcium, while the same dose of 1,OHD3 increased serum calcium by 3.39,±,0.52 mg/dl. Interestingly, in the same rats which received 1,OH-3-epi-D3 we also noted a reduction in circulating PTH levels by 65,±,7%. This ability of 1,OH-3-epi-D3 to suppress PTH levels in normal rats without altering serum calcium was further tested in rats with reduced renal function. The results indicated that the ED50 of 1,OH-3-epi-D3 for suppression of PTH was only slightly higher than that of 1,,25(OH)2D3, but that the threshold dose of the development of hypercalcemia (total serum Ca >,10.5 mg/dl) was nearly 80 times higher. These findings indicate that 1,OH-3-epi-D3 is a highly selective vitamin D analog with tremendous potential for treatment of secondary hyperparathyroidism in chronic renal failure patients. © 2005 Wiley-Liss, Inc. [source] Peptide-induced suppression of collagen-induced arthritis in HLA,DR1 transgenic miceARTHRITIS & RHEUMATISM, Issue 12 2002Linda K. Myers Objective To identify peptides capable of altering the immune response to type II collagen (CII) in the context of HLA,DR. Methods Immunizing mice transgenic for the human HLA,DRB1*0101 immune response gene with CII elicits an arthritis (collagen-induced arthritis [CIA]) that resembles rheumatoid arthritis. We have previously identified an immunodominant determinant of CII, CII (263,270), recognized by T cells in the context of DR1. To produce synthetic peptides with the potential of disrupting the DR1-restricted immune response, synthetic analog peptides were developed that contain site-directed substitutions in critical positions. These peptides were used to treat CIA in DR1 transgenic mice. Results An analog peptide, CII (256,276, N263, D266), that inhibited T cell responses in vitro, was identified. When DR1 mice were coimmunized with CII and CII (256,276, N263, D266), the incidence and severity of arthritis were greatly reduced, as was the antibody response to CII. Moreover, CII (256,276, N263, D266) was effective in down-regulating the immune responses to CII and arthritis, even when administered 2 weeks following immunization with CII. Spleen and lymph node cells from CII-immunized mice cultured with CII (256,276, N263, D266) in vitro produced increased amounts of interleukin-4 (IL-4) compared with cells cultured with the wild-type peptide, CII (256,276). Furthermore, CII (256,276, N263, D266) was incapable of preventing arthritis in DR1 IL-4,/, mice (genetically deficient in IL-4). Conclusion These data establish that CII (256,276, N263, D266) is a potent suppressor of the DR-mediated immune response to CII. Its effect is mediated, at least in part, by IL-4. These experiments represent the first description of an analog peptide of CII recognized by T cells in the context of a human major histocompatibility complex molecule that can suppress autoimmune arthritis. [source] Emergence of protein kinase CK2 as a key target in cancer therapyBIOFACTORS, Issue 3 2010Janeen H. Trembley Abstract Protein kinase CK2, a protein serine/threonine kinase, plays a global role in activities related to cell growth, cell death, and cell survival. CK2 has a large number of potential substrates localized in diverse locations in the cell including, for example, NF-,B as an important downstream target of the kinase. In addition to its involvement in cell growth and proliferation it is also a potent suppressor of apoptosis, raising its key importance in cancer cell phenotype. CK2 interacts with diverse pathways which illustrates the breadth of its impact on the cellular machinery of both cell growth and cell death giving it the status of a "master regulator" in the cell. With respect to cancer, CK2 has been found to be dysregulated in all cancers examined demonstrating increased protein expression levels and nuclear localization in cancer cells compared with their normal counterparts. We originally proposed CK2 as a potentially important target for cancer therapy. Given the ubiquitous and essential for cell survival nature of the kinase, an important consideration would be to target it specifically in cancer cells while sparing normal cells. Towards that end, our design of a tenascin based sub-50 nm (i.e., less than 50 nm size) nanocapsule in which an anti-CK2 therapeutic agent can be packaged is highly promising because this formulation can specifically deliver the cargo intracellularly to the cancer cells in vivo. Thus, appropriate strategies to target CK2 especially by molecular approaches may lead to a highly feasible and effective approach to eradication of a given cancer. [source] Inhibition of LPS-induced chemokine production in human lung endothelial cells by lipid conjugates anchored to the membraneBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2002G Ch Beck In acute respiratory distress syndrome (ARDS) induced by endotoxins, a high production of inflammatory mediators by microvascular lung endothelial cells (LMVEC) can be observed. Activation of cells by endotoxins may result in elevated secretion of phospholipase A2 (sPLA2) which is thought to contribute to tissue damage. The present study was undertaken to investigate the role of sPLA2 in chemokine production in human lung microvascular endothelial cells (LMVEC) stimulated with the endotoxins lipopolysaccharide (LPS) and lipoteichoic acid (LTA). In particular, we investigated the effects of sPLA2 inhibitors, specifically, the extracellular PLA2 inhibitors (ExPLIs), composed of N-derivatized phosphatidyl-ethanolamine linked to polymeric carriers, and LY311727, a specific inhibitor of non-pancreatic sPLA2. ExPLIs markedly inhibited LPS and LTA induced production and mRNA expression of the neutrophile attracting chemokines IL-8, Gro-, and ENA-78, as well as of the adhesion molecules ICAM-1 and E-selectin. Concomitantly, ExPLIs inhibited the LPS-induced activation of NF-,B by LPS but not its activation by TNF-, or IL-1. Endotoxin mediated chemokine production in LMVEC seems not to involve PLA2 activity, since LPS stimulation was not associated with activation of intracellular or secreted PLA2. It therefore seems that the inhibitory effect of the ExPLIs was not due to their PLA2 inhibiting capacity. This was supported by the finding that the LPS-induced chemokine production was not affected by the selective sPLA2 inhibitor LY311727. It is proposed that the ExPLIs may be considered a prototype of potent suppressors of specific endotoxin-induced inflammatory responses, with potential implications for the therapy of subsequent severe inflammation. British Journal of Pharmacology (2002) 135, 1665,1674; doi:10.1038/sj.bjp.0704618 [source] | |||||||||||||