Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.148 (Thy1)
 1,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mice generated by homologous recombination which carry a large deletion of the p53 tumour suppressor gene have a high incidence of spontaneous Thy1-positive thymic lymphoma. Extra-thymic lymphomas are rare. Apoptosis following gamma-irradiation in thymocytes from these animals in vitro is p53-dependent and there is a marked gene dose effect: heterozygotes show partial resistance to irradiation-induced cell death. Apoptosis in the T-cell zones of lymph nodes following in vivo gamma-irradiation was p53-dependent, but the gene dosage effect was less marked than that noted for thymocytes. Apoptosis was induced in vivo by ligation of CD4 on the cell surface following intravenous injection of anti-CD4 monoclonal antibody. Apoptosis was counted in lymph node sections using a semi-automated morphometric system. This showed no evidence of p53 dependency. In contrast to a previous report, which used a different line of p53-deficient mice, splenocytes from p53-null mice did not differ significantly from wild-type cells with respect to in vitro proliferative activity and response to mitogenic stimulation by concanavalin A. This may be due to strain differences. Therefore, whilst p53 has a role in the deletion of lymphocytes which have acquired pathological DNA strand breaks which may lead to mutations, the results of this study imply that p53 is not involved in the control of apoptosis following engagement of surface receptors, nor in response to physiological DNA breaks and normal recombination events during T-cell ontogeny.
 ...
PMID:Apoptosis induced by gamma-irradiation, but not CD4 ligation, of peripheral T lymphocytes in vivo is p53-dependent. 912 Jul 20

Inflammation is characterized by an excess of cell proliferation often leading to fibrosis and sclerosis with subsequent loss of organ function. We hypothesized that these features may be ameliorated by induction of cell cycle arrest and apoptosis as result of therapy with matrix metalloproteinase (MMP) inhibitors. In our study, mesangial cells and experimental mesangial proliferative glomerulonephritis provided the model of inflammation. First, we investigated the effect of the MMP inhibitor BB-1101 in anti-Thy1.1 nephritis. The numbers of apoptotic glomerular cells in nephritic rats increased about 4 and 6 times as a result of BB-1101 therapy, observed 11 and 14 days after induction of disease, respectively. Subsequently, rat mesangial cells were exposed to an MMP inhibitor in vitro. Fluorescence-activated cell sorter analyses of cells exposed to RO111-3456 demonstrated a dose-dependent cell cycle arrest in the G(0)/G(1) phase associated with increased expression of statin. The cell cycle arrest was followed by apoptosis as investigated by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) biotin nick-end labeling (TUNEL) and acridine orange/ethidium bromide stainings, as well as by annexin V binding. The induction of p53, p21, and bax, but not the Fas/FasL pathway appeared to play an important pathogenetic role. In summary, MMP inhibitors induce cell cycle arrest followed by apoptosis in mesangial cells. These features help to explain the anti-inflammatory effects of these compounds, such as reduction of mesangial cell proliferation and attenuation of extracellular matrix accumulation. In conclusion, induction of cell cycle arrest with subsequent apoptosis may offer new perspectives in the therapy of inflammation even beyond kidney diseases.
 ...
PMID:Matrix metalloproteinase inhibitors cause cell cycle arrest and apoptosis in glomerular mesangial cells. 1125 28

Internalization and subcellular fate of free doxorubicin or its polymeric conjugates based on poly N-(2-hydroxypropyl)methacrylamide (pHPMA), either non-targeted or targeted with anti-Thy1.2 or anti-CD71 monoclonal antibody was tested on EL-4 mouse T-cell lymphoma, SW620 human colorectal carcinoma and OVCAR-3 human ovarian adenocarcinoma. Doxorubicin fluorescence allowed us to follow the internalization and intracellular distribution of tested conjugates by laser scanning confocal microscopy and/or by fluorescent microscopy. Whereas free doxorubicin was always detectable only in the nuclei of treated cells, detectable fluorescence of doxorubicin bound to a polymeric carrier, targeted or non-targeted, was detectable up to 3 days of incubation only in the cytoplasmatic structures. While free doxorubicin causes apoptosis in the populations of tested cancer cell lines, significant number of apoptotic cells was never found in cell cultures exposed to targeted or non-targeted polymeric conjugates. In contrast to free doxorubicin, which is a strong inducer of p53 expression, increased p53 expression was never observed after the treatment with the polymeric drug. High-performance liquid chromatographic analysis shows that the percentage of cleaved doxorubicin is very low even after 48 h of incubation of tested cells with the polymeric conjugate, and cannot be the only reason for the toxicity of the conjugate. We suggest that: (a) after the treatment with pHPMA-bound drug, the cells die by necrosis and (b) the toxicity of pHPMA-based conjugates is a combination of the toxic effect of released doxorubicin and the toxic effect of doxorubicin in polymer-bound form directed against cell membranes.
 ...
PMID:Differences in the intracellular fate of free and polymer-bound doxorubicin. 1194 91

Mesangial cells play a prominent role in renal inflammatory disorders, especially in IgA nephropathy. This disease represents the most common form of glomerulonephritis that eventually leads to progressive kidney failure requiring renal replacement therapy. In kidney transplants, IgA nephropathy displays a high recurrence rate in the order of 50%. Increased cell proliferation rates and extracellular matrix (ECM) accumulation are crucial targets in the therapy of glomerulonephritis, including IgA nephropathy. The active role of matrix metalloproteinases (MMP) in the regulation of these two features is rapidly emerging. We studied a model of a specific type of mesangial cell-mediated glomerular inflammation, such as experimental mesangial proliferative glomerulonephritis and cultured proliferating mesangial cells. In addition, these tools allowed us to evaluate a new therapeutic strategy based on MMP inhibition. Inhibition of MMP activity and synthesis by antisense technology and by a synthetic inhibitor in vitro, successfully reverted the inflammatory mesangial cell phenotype to the physiologically existing resting state. In vivo, a hydramate-based MMP inhibitor attenuated excess mesangial cell proliferation and ECM accumulation in anti-Thy1.1 nephritis. The anti-proliferative effect was achieved by the induction of cell cycle arrest followed by apoptosis, mediated by the induction of p53, p21 and bax, but not by the Fas/FasL pathway. In conclusion, MMP inhibitors provide a new approach to the therapy of inflammation probably even beyond the field of renal disorders.
 ...
PMID:The role of matrix metalloproteinases in the activation of mesangial cells. 1218 Aug 53

C3H/He mice produce myeloid leukemias after whole body irradiation of 1-3Gy as compared with non-irradiated controls that produce fewer than 1% of leukemia [Radiatiton Research 127 (1991) 146]. Thus, p53-deficient C57BL/6 strain, a malignant lymphoma prone, was crossed back into C3H/He strain. Lethally irradiated wild-type mice to which p53-deficient bone marrow cells were transplanted (transplantation assay) showed dramatic change in the propensity of leukemia of myeloid lineages, the cells lacking CD3, Thy1.2, sIgM, B220, Mac-1, Gr-1, but being positive for c-Kit and CD44. Furthermore, transplanted mice subjected to 3Gy irradiation gave rise to a faster development of leukemia and a higher frequency of double-lineage leukemias than the non-irradiated control.
 ...
PMID:Stem-cell leukemia: p53 deficiency mediated suppression of leukemic differentiation in C3H/He myeloid leukemia. 1244 80

We investigated the effects of focused ultrasound (FUS) on specific molecular signaling and cellular response in three closely related human Tk6 lymphoblast cell lines that differed only in their p53 status. The applied ultrasound parameters fell between the physical dose range, which is safely used in medical diagnostics (peak pressure<0.1 MPa) and that used for high-energy FUS thermal ablation therapy (peak pressure>10 MPa). Based on cDNA microarrays and protein analysis, we found that FUS at the intermediate peak pressure of 1.5 MPa induced a complex signaling cascade with upregulation of proapoptotic genes [e.g., p53, p21, Thy1 (CD 90)]. Simultaneously, FUS downregulated cellular survival components (e.g., bcl-2, SOD). The p53 status was important for the reaction of the cells to ultrasound. Apoptosis and G1 arrest were induced primarily in p53+ cells, while p53- cells showed less apoptosis but exhibited G2 arrest. Likewise, the proliferation of lymphoblasts was much more strongly inhibited in p53+ than in p53- cells. Microarray analysis further demonstrated an upregulation of genes involved in oxidative stress (e.g., ferritin), suggesting that indirect sonochemical effects via reactive oxygen species play a causative role in the interaction of ultrasound with lymphoblasts. An important characteristic of FUS in therapeutic ultrasound applications is its ability to be administered to the human body in a targeted manner while sparing intermediate tissues. Therefore, our data indicate that this noninvasive, mechanical wave transmission, which is free of ionizing radiation, has the potential to specifically induce localized cell signals and apoptosis.
 ...
PMID:Apoptosis signals in lymphoblasts induced by focused ultrasound. 1523 31

Apoptosis and incomplete DNA methylation reprogramming in cloned embryos reduce cloning efficiency. 5-aza-2'-deoxycytidine (5-aza-dC) is proven to regulate apoptosis and DNA methylation reprogramming, however, the treatment method and potential role of 5-aza-dC during cloned embryo development are still not well studied. This study displayed that treating donor cells with 5-aza-dC (AN group) significantly reduced the blastocyst rate, while treating cloned embryos (NA group) or both donor cells and cloned embryos (ANA group) significantly promoted the blastocyst formation, and the ANA group was the best treatment of 5-aza-dC to enhance the development of cloned embryos. Then, compared with the NT group, the ANA group showed the significantly enhanced nuclear remodeling. The apoptotic cell numbers and rates of blastocysts were significantly reduced, and the expression levels of significantly upregulated anti-apoptosis gene Bcl2l1 and downregulated pro-apoptosis genes Bax, P53 and Caspase3 were observed in the ANA group. Further study demonstrated that the transcription levels of DNA methylation reprogramming genes Dnmt1, Dnmt3a, Tet1 and Tet3 were significantly upregulated, and, significant genomic DNA remethylation, DNA demethylation of pluripotency gene Oct4, and DNA remethylation of tissue specific gene Thy1 were observed at the blastocyst stage in the ANA group. Embryo development related genes including Igf2, H19, Oct4, Nanog, Sox2, Eif1a, Cdx2 and ATP1b1 were significantly upregulated, and Thy1 and Col5a2 were remarkably silenced at the 4-cell and blastocyst stages in the ANA group. In conclusion, the best 5-aza-dC treatment enhanced the development of cloned embryos by inhibiting apoptosis and improving DNA methylation reprogramming.
 ...
PMID:Optimizing 5-aza-2'-deoxycytidine treatment to enhance the development of porcine cloned embryos by inhibiting apoptosis and improving DNA methylation reprogramming. 3261 1