Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the role of DNA-dependent protein kinase (DNA-PK) and related it to proliferation and maturation of different lymphoid malignancies. DNA-PK and Ki-67 protein content was investigated in tumour samples of lymphoid malignancies, obtained from patients with low- and high-grade lymphomas, acute lymphoblastic leukaemia and multiple myeloma. All patients were untreated before sampling. Normal bone marrow, reactive tonsillar tissue and ordinary lymph node tissue were used as controls. We show here that lymphoid malignancies display differences in DNA-PK protein expression. Low-grade lymphoma, appearing as chronic lymphocytic leukaemia (CLL) displayed a significantly lower frequency of cells staining positive for DNA-PKcs and Ku86, but surprisingly not for Ku70, compared with acute lymphoblastic leukaemia (ALL) cells. When material from individual CLL patients was investigated, cells from lymph nodes showed a higher frequency of positive cells with respect to all DNA-PK subunits, compared with CLL cells infiltrating the bone marrow. High-grade lymphoma lymph node samples showed an increased frequency of cells staining positive for DNA-PKcs, Ku86 and Ki-67 compared with lymph node samples from low-grade lymphoma patients. Again, no difference in the Ku70 levels between the two lymphoma entities was noted. In multiple myeloma, the frequency of cells with positive staining for DNA-PKcs was similar to that detected in ALL and high-grade lymphoma. We conclude that with the exception of multiple myeloma, expression of DNA-PK coincides with the degree of maturation of lymphoid malignancies. In low- and high-grade lymphoma, DNA-PK is associated with the proliferation rate.
Exp Mol Pathol 2004 Aug
PMID:Expression of DNA-PKcs and Ku86, but not Ku70, differs between lymphoid malignancies. 1521 44

Objective. - Arginase is a nitric oxide synthase-alternative pathway for l-arginine breakdown leading to biosynthesis of urea and l-ornithine. Arginase pathway is inducible by inflammatory molecules-such as cytokines and bacterial endotoxin-in macrophages and smooth muscle cells. The presence of an arginase pathway in human endothelial cells and its possible modulation by inflammation are unknown. Methods. - We have: (i) characterised arginase pathway in terms of activity, isoform type and gene expression in a primary human umbilical vein endothelial cells (HUVEC) line; (ii) evaluated arginase functional role in cell proliferation with the aid of l-norvaline, an arginase inhibitor and (iii) determined the effects of tumour necrosis factor-alpha and endotoxin on arginase pathway. Results. - HUVEC showed a baseline arginase activity and expression of both arginase isoforms (arginase I and II (A-I and A-II, respectively)) which resulted in l-norvaline-inhibitable cellular polyamine synthesis. The baseline arginase activity is important for HUVEC proliferation as cell cycle analysis and nuclear factor Ki-67 immunostaining revealed. Following incubation with inflammatory molecules, arginase activity increased but HUVEC cell cycling decreased. Conclusions. - A-I and A-II are constitutively expressed in HUVEC where they take part to the regulation of cell cycling. Although arginase activity is positively modulated by inflammatory molecules, it is insufficient to counteract the overall cell cycling inhibiting effects of inflammation.
J Mol Cell Cardiol 2004 Aug
PMID:Arginase pathway in human endothelial cells in pathophysiological conditions. 1527 21

C-type natriuretic peptide (CNP) has been shown to play an important role in the regulation of vascular tone and remodeling. However, the physiological role of CNP in the lung remains unknown. Accordingly, we investigated whether CNP infusion attenuates bleomycin (BLM)-induced pulmonary fibrosis in mice. After intratracheal injection of BLM or saline, mice were randomized to receive continuous infusion of CNP or vehicle for 14 days. CNP infusion significantly reduced the total number of cells and the numbers of macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid. Interestingly, CNP markedly reduced bronchoalveolar lavage fluid IL-1beta levels. Immunohistochemical analysis demonstrated that CNP significantly inhibited infiltration of macrophages into the alveolar and interstitial regions. CNP infusion significantly attenuated BLM-induced pulmonary fibrosis, as indicated by significant decreases in Ashcroft score and lung hydroxyproline content. CNP markedly decreased the number of Ki-67-positive cells in fibrotic lesions of the lung, suggesting antiproliferative effects of CNP on pulmonary fibrosis. Kaplan-Meier survival curves demonstrated that BLM mice treated with CNP had a significantly higher survival rate than those given vehicle. These results suggest that continuous infusion of CNP attenuates BLM-induced pulmonary fibrosis and improves survival in BLM mice, at least in part by inhibition of pulmonary inflammation and cell proliferation.
Am J Physiol Lung Cell Mol Physiol 2004 Dec
PMID:C-type natriuretic peptide attenuates bleomycin-induced pulmonary fibrosis in mice. 1528 99

Progression of follicular lymphomas (FLs) is often accompanied by a spectrum of histologic changes and an aggressive clinical course. Although molecular alterations have been implicated in this event, the underlying factors are largely unknown. We studied the expression of selected tumor suppressor genes (P53 and retinoblastoma [RB]), oncogenes (MYC and BCL2), and a transferrin-receptor related protein (Trump) in sequential biopsies in 16 patients. Eleven patients progressed from grade I or II FL to aggressive B-cell lymphomas with diffuse morphology, whereas 5 patients presented with diffuse aggressive lymphomas and recurred with indolent lymphomas. Immunoreactivity for P53 correlated with higher histologic grade in lymphomas progressing from indolent to aggressive; however, only 1 patient who presented with aggressive lymphoma demonstrated a P53 gene mutation. Neither P53 immunoreactivity nor genotypic alterations correlated with presentation with an aggressive histology and relapse with FL. Growth fraction, as assessed by Ki-67 staining, and Trump expression correlated with histologic grade. Immunoreactivity for RB, BCL2, and MYC was seldom associated with progression. Eight of 9 cases tested exhibited identical immunoglobulin heavy and light chain rearrangements or identical BCL2 gene rearrangements in the sequential lymphomas. We conclude that P53 and Trump protein expression and proliferation activity correlate with histologic grade, but not with recurrence or progression of FL. Our results further indicate that progression of FL to diffuse aggressive lymphomas and presentation of an aggressive B-cell lymphoma followed by FL are clonally related.
Appl Immunohistochem Mol Morphol 2004 Jun
PMID:Immunophenotypic and genotypic characterization of progression in follicular lymphomas. 1535 33

With the rapidly growing understanding of tumor biology, molecular staging of cancer is expected to improve prognostication. This would be particularly important for cancers amenable to adjuvant treatment, such as colorectal carcinomas. To generate data for this, the tissue microarray technique may prove useful. Tissue microarrays were constructed with triplicate cores (0.6 mm diameter) from the invasive margins of a consecutive single-institution series of 184 colorectal carcinomas. Immunostaining for p53, p21, p27, Ecadherin, and beta-catenin was scored. Tumor cell proliferation was assessed by mitotic indices and Ki-67 labeling, apoptosis by quantification of apoptotic bodies. Reduced nuclear immunostaining for p21 (<10%) and p27 (< or =50%) and reduced membranous expression of Ecadherin were significantly associated with a poorer clinical course by univariate analysis. beta-catenin immunostaining had no prognostic impact. Mitotic and apoptotic indices as well as Ki-67 labeling below the median were indicators of poor prognosis. Complete absence of p53 nuclear staining was a significant adverse prognostic factor. By Cox regression, p53 = 0%, p53 = 0%, in combination with p27 < or = 50%, the mitotic index and the combined mitotic and apoptotic index added prognostic information to UICC stage. The authors found that growth pattern, lymphohistiocytic response, lymphatic permeation, and venous spread, too, each was a strong prognosticator in addition to UICC stage. The results support that tissue microarrays are a useful tool for screening immunohistochemical markers for prognostic use. An immunopanel of p21, p27, and p53 could be useful for prognostication in colorectal carcinoma in addition to UICC stage.
Appl Immunohistochem Mol Morphol 2004 Jun
PMID:Expression profiling of colorectal carcinomas using tissue microarrays: cell cycle regulatory proteins p21, p27, and p53 as immunohistochemical prognostic markers in univariate and multivariate analysis. 1535 35

The aim of this study was to investigate the consequences of insulin-like growth factors (IGF) and IGF receptor dysfunction in lung carcinomas. A correlation between increased expression (at mRNA and protein levels) for IGF-1 and IGF-1R and decreased apoptosis were found in large-cell carcinomas and adenocarcinomas. In 40% of informative adenocarcinomas expressing the highest values of IGF-2 and Ki-67 proteins, M6P/IGF-2R gene had LOH at one allele and a mutation in another allele. All four squamous cell carcinoma samples expressed LOH/mutation in the M6P/IGF-2R gene. The alphaIR3 strongly diminished proliferation and increased apoptosis in cultures established from squamous cell carcinomas overexpressing IGF-2 and IGF-1R. Telomerase activity was assessed in four squamous cell carcinomas. Cell treatment with IGF-1 increased telomerase activity. The opposite was observed when the cells were treated with alphaIR3, which inhibits the activity of IGF-1 receptors. Our findings suggest that disruption of the IGF/IGF receptors axis is involved in lung cancer formation.
Am J Respir Cell Mol Biol 2005 Jan
PMID:The consequences of insulin-like growth factors/receptors dysfunction in lung cancer. 1551 14

Adrenocorticotropin is the major regulator of adrenocortical development and function. It acts mainly through the cAMP-dependent protein kinase A (PKA) pathway. Our aim was to study the interaction of tumor necrosis factor-alpha (TNFalpha) and the PKA pathway in adrenocortical cell proliferation and apoptosis. The PKA activator Dibutyryl cAMP ((Bu)2cAMP) strongly induced differentiation and inhibited proliferation in the human adrenocortical cell line NCI-H295R (H295R). TNFalpha induced apoptosis of H295R cells. Interestingly, (Bu)2cAMP treatment clearly enhanced TNFalpha-induced apoptosis in H295R cells, but not in another human adrenocortical cell line SW-13, the mouse adrenocortical Y-1 cell line or the human HeLa cell line. This synergistic effect was not due to the (Bu)2cAMP-induced glucocorticoid secretion since dexamethasone had no significant effect on the TNFalpha-induced apoptosis. (Bu)2cAMP treatment rapidly increased the expression of the proto-oncogene c-myc in H295R cells, but not in SW-13, Y-1 or HeLa cells. In transient c-myc transfection assay, c-myc expression associated with decreased expression of the proliferation marker Ki-67 in H295R cells. In conclusion, cAMP-dependent protein kinase activation reduced proliferation and augmented TNFalpha-induced apoptosis in adrenocortical H295R cells, and these effects were associated with increased c-myc expression.
J Mol Endocrinol 2004 Oct
PMID:cAMP-dependent protein kinase activation inhibits proliferation and enhances apoptotic effect of tumor necrosis factor-alpha in NCI-H295R adrenocortical cells. 1552 5

Laser-assisted microdissection (LAM) is now widely used to obtain specific cell populations from heterogeneous tissues. A major disadvantage of LAM is poor tissue morphology during microscopy, in part because coverslips are not used. Immunohistochemical labeling can improve identification of target cells but may affect the subsequent analysis of the microdissected tissue. We studied the effect of immunohistochemistry (IHC) on mRNA recovery from labeled cells after microdissection from both frozen and formalin-fixed, paraffin-embedded (FFPE) sections, using Melan-A and Ki-67 staining in lymph nodes with metastatic melanoma as a model. We developed rapid protocols for immunostaining in an attempt to limit loss of mRNA during procedures. A sensitive real-time quantitative reverse transcription-PCR was used to measure mRNA. We found a marked decrease in the mRNA yield from 500 microdissected cells from frozen and paraffin sections after immunostaining for both markers. Recovery of mRNA decreased by up to 89%, comparing the immunostained with the routinely stained sections. Interestingly, the ratio between mRNA for the two markers was similar in all stains, indicating that immunostained sections may be used for mRNA analysis. We also investigated the effect of storing membrane-mounted sections for microdissection under different conditions. Slides mounted with paraffin sections could be stored at room temperature for up to 90 days with no significant decrease in mRNA recovery.
Diagn Mol Pathol 2004 Dec
PMID:The influence of immunohistochemistry on mRNA recovery from microdissected frozen and formalin-fixed, paraffin-embedded sections. 1553 13

PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC50, 0.011 micromol/L) and Cdk6 (IC50, 0.016 micromol/L), having no activity against a panel of 36 additional protein kinases. It is a potent antiproliferative agent against retinoblastoma (Rb)-positive tumor cells in vitro, inducing an exclusive G1 arrest, with a concomitant reduction of phospho-Ser780/Ser795 on the Rb protein. Oral administration of PD 0332991 to mice bearing the Colo-205 human colon carcinoma produces marked tumor regression. Therapeutic doses of PD 0332991 cause elimination of phospho-Rb and the proliferative marker Ki-67 in tumor tissue and down-regulation of genes under the transcriptional control of E2F. The results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors.
Mol Cancer Ther 2004 Nov
PMID:Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. 1554 82

The distinction among inflammatory, benign, and malignant lesions of the biliary tract can at times be difficult. Several methods have been used, including immunohistochemistry (IHC), with variable success. We evaluated a panel of IHC stains to determine their utility in discriminating between bile duct lesions. Formalin-fixed, paraffin-embedded 4-microm sections from 12 inflammatory lesions, 10 bile duct adenomas, and 13 bile duct carcinomas were immunostained using a modified avidin-biotin-complex technique after epitope enhancement using antibodies for p53, Ki-67, and bcl-2. For p53 and bcl-2, greater than 1% of cells staining positive was interpreted as positive. The proliferation index was calculated by determining the number of Ki-67-positive cells in a 1000 cell count. In the inflammatory group, 0 of 12 reacted with anti-p53, 2 of 12 were positive with anti-bcl-2, and the proliferation index with was 22.9% +/- 3.9%. Two of 10 bile duct adenomas showed reactivity with anti-bcl-2, and none were decorated with anti-p53 or Ki-67. In the carcinoma group, 6 of 13 were positive with anti-p53, 9 of 12 were positive with anti-bcl-2, and the proliferation index was 35.3% +/- 5.5%. The proliferation rates differed significantly between groups (P < 0.05). The presence of bcl-2 and p53 immunoreactivity coupled with a high proliferative rate in a biliary tract lesion suggests a malignant process. A panel using these antibodies may be useful in difficult cases.
Appl Immunohistochem Mol Morphol 2004 Sep
PMID:Immunohistochemical analysis of biliary tract lesions. 1555 30


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