Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that combretastatin-A4 prodrug (CA4P), anantitubulin/antiangiogenic agent isolated from the South African willow tree Combretum caffrum, induced cell death primarily through mitotic catastrophe in a panel of human B-lymphoid tumors. In this study, we investigated the molecular aspects of the mitotic catastrophe and whether or not it shares the same pathways of apoptosis. For this we studied the effect of CA4P on selected markers of apoptosis [caspases 9 and 3, poly(ADP-ribose) polymerase (PARP), bcl-2, and bax] and G2-M protein regulators (p53, MDM2, 14-3-3sigma, GADD45, cdc2, cdc25, chk1, wee1, p21, and cyclin B1). The chronic lymphocytic leukemia cell line WSU-CLL was used for this purpose. Western blot analysis showed that 24 h of CA4P (5 nM) exposure induces caspase 9 activation and PARP cleavage. However, the addition of Z-Val-Ala-Asp-fluoromethylketone (a general caspase inhibitor) or Z-Leu-Glu(OMe)-His-Asp(OMe)-CH2F (a caspase 9 inhibitor) before CA4P treatment did not block cell death. No change in bcl-2 or bax protein expression was observed. Exposure of WSU-CLL cells to 4 and 5 nM CA4P was associated with overproduction of total p53 and no dramatic change in MDM2, 14-3-3sigma, GADD45, the cyclin-dependent kinase cdc2, its inhibitory phosphorylation, the cdc2-inhibitory kinase (wee1), chk1, or cdc25 hyperphosphorylation. The overaccumulation of p21 and cyclin B1 protein was obvious at 24 h. Furthermore, CA4P treatment showed an increase in the expression of a marker of mitosis (mitotic protein monoclonal-2 antibody) and an overaccumulation of the cyclin B in the nucleus. Our findings suggest that CA4P induces mitotic catastrophe and arrest of WSU-CLL cells mostly in the M phase independent of p53 and independent of chk1 and cdc2 phosphorylation pathways. Apoptosis is a secondary mechanism of death in a small proportion of cells through activation of caspase 9 and PARP cleavage. The two mechanisms of cell death, i.e., mitotic catastrophe and apoptosis, are independent of each other in our model.
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PMID:Combretastatin-A4 prodrug induces mitotic catastrophe in chronic lymphocytic leukemia cell line independent of caspase activation and poly(ADP-ribose) polymerase cleavage. 1217 7

The mouse endostatin cDNA was cloned by the total RNA of Chinese Kunming mouse liver as template with RT-PCR. The results of sequencing showed one base pair difference. The ctg was replaced by gtg(L22545 in GenBank) at position 278 base pair, causing the encoded amino acid from reported Val to Leu in this experiment. This new endostatin cDNA was registered in GenBank with an accession number of AF257775. The recombinant eukaryotic expression plasmid pSecTag2-ES was then constructed and transfected into COS-7 cells for transient expression. The results of testing by Western blotting showed an expression fragment in supernatants of pSecTag2-ES transfected COS-7 cells at 48 and 72 hours of transfection. Cultured HUVECs were used to detect the biological effect of supernatants in pSecTag2-ES transfected COS-7 after 48 hours of transfection. 3H incorporation assay showed an obvious inhibition of endothelial cell prolifetation. The results demonstrated primary that the cloned endostatin cDNA had biological activity.
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PMID:[Cloning of mouse endostatin and primary analysis on its biological activity]. 1252 Sep 59

Levinson, Hillel S. (U.S. Army Natick Laboratories, Natick, Mass.), and Mildred T. Hyatt. Effect of sporulation medium on heat resistance, chemical composition, and germination of Bacillus megaterium spores. J. Bacteriol. 87:876-886. 1964.-Bacillus megaterium spores, grown on variously supplemented media, had varying concentrations of P, Ca, Mn, or dipicolinic acid. Supplementation with CaCl(2) yielded spores with increased heat resistance; addition of l-glutamate, l-proline, or increase of the phosphate concentration yielded spores with reduced heat resistance. Germination characteristics depended on both the sporulation medium and the germinant (glucose, l-alanine, l-leucine, or KNO(3)); pronounced differences were demonstrable with glucose and l-alanine, which trigger germination via different metabolic pathways. An increase in CaCl(2) during sporulation yielded spores with increased germination in glucose but not in l-alanine. Germination in l-alanine was optimal with spores produced on media containing 0.1 mm MnCl(2), but germination of such spores was minimal in glucose. An increase in the sporulation medium phosphate decreased the initial germination rate in glucose, but not in l-alanine. Spores produced in CaCl(2)-supplemented media had increased heat-activation requirements (increased dormancy) for germination induced by l-alanine, and decreased heat-shock requirements for glucose-induced germination. An increase of sporulation phosphate yielded spores with reduced dormancy for germination induced by l-alanine, but with unchanged dormancy on the other germinants. Spores produced with added l-glutamate had reduced dormancy for glucose-induced germination, and increased dormancy for germination induced by l-alanine. Addition of CaCl(2) or l-glutamate to the sporulation medium yielded spores with increased sensitivity to "ionic germination" (with KI). Spores from synthetic medium were incapacitated for full postgerminative development, as shown by repression of the changes in oxygen-uptake rate which accompany normal cell division.
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PMID:EFFECT OF SPORULATION MEDIUM ON HEAT RESISTANCE, CHEMICAL COMPOSITION, AND GERMINATION OF BACILLUS MEGATERIUM SPORES. 1413 27

Hyatt, Mildred T. (Quartermaster Research and Engineering Center, Natick, Mass.) and Hillel S. Levinson. Conditions affecting Bacillus megaterium spore germination in glucose or various nitrogenous compounds. J. Bacteriol. 83:1231-1237. 1962.-The possibility that there is more than one metabolic pathway for triggering germination of Bacillus megaterium spores was investigated. Spores were germinated in seven different "physiological germinants" under varying conditions of concentration, pH, combinations of germinants, temperature before and during germination, and chemical inhibition. l-Alanine and l-valine appear to induce germination via the same metabolic pathway (same inhibitors are effective, similar germination rate and temperature requirements); and glucose and glucosamine also appear to act similarly, but by a different pathway than l-alanine and l-valine. The other germinants, l-leucine, l-proline, and KNO(3), do not correspond in all respects either to the glucose-glucosamine or to the alanine-valine pair in response to the different germination conditions. It is concluded that B. megaterium spore germination occurs via more than one pathway.
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PMID:Conditions affecting Bacillus megaterium spore germination in glucose or various nitrogenous compounds. 1445 Mar 8

Alfalfa was grown hydroponically in 0, 0.6, and 4.8 millimolar K in order to determine the influence of tissue level of K on photosynthesis, dark respiration, photorespiration, stomatal and mesophyll resistance to CO(2), photosystem I and II activity, and synthesis and activity of ribulose 1,5-bisphosphate carboxylase (RuBPc).A severe (0.0 millimolar) and mild (0.6 millimolar) K deficiency, compared to plants grown at 4.8 millimolar K, produced a significant decrease in photosynthesis and photorespiration, but an increase in dark respiration. Both deficient K levels increased hydrophyllic resistance to CO(2), but only the severe deficiency increased stomatal resistance.Photosystem I and II activity of isolated chloroplasts was not affected by K deficiency. The apparent activity of a crude RuBPc preparation was significantly reduced in severely deficient plants. Activity of the enzyme could not be restored to normal rates by the addition of K to the reaction medium.The specific activity of RuBPc isolated from severely K-deficient and K-sufficient leaflets was not significantly different, suggesting that K does not function in RuBPc activity. Incorporation of [(14)C]leucine into RuBPc, as a measure of synthesis, by K-deficient leaflets was reduced to 15% of K-sufficient leaflets. The addition of K to the reaction medium stimulated [(14)C]leucine incorporation into RuBPc and 10 millimolar KNO(3) increased incorporation to 80% of K-sufficient leaflets. Actinomycin D and cycloheximide suppressed the K-stimulated incorporation of [(14)C]leucine into RuBPc, suggesting that the K-stimulated synthesis of RuBPc most likely represents de novo synthesis.
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PMID:Role of Potassium in Carbon Dioxide Assimilation in Medicago sativa L. 1666 Aug 30

Angiogenesis is regulated by stimulators and inhibitors and involve multiple biological processes including endothelial cell proliferation, migration, cell-cell and cell-matrix adhesion, assembly into tube structures as well as apoptosis. Designing and developing peptides for therapeutic application to inhibit angiogenesis is an important area in antiangiogenic drug development. Small peptides have advantages over proteins for therapeutic application, due to their stability, solubility, increased bio-availability and lack of immune response in the host cell. Endogenous protein angiogenesis stimulators and inhibitors hold vital information for designing antiangiogenic peptides for drug development. These proteins function through their interaction with extracellular matrix molecules, cell surface receptors, proteases, as well as growth factors and cytokines. Conserved domains such as thrombospondin type 1 repeats (TSRs), kringle domains as well as critical amino acid residues present in these domains are involved in their functions. By exploiting these properties, several small peptides have been designed, synthetically made and being tested for therapeutic efficacy. Peptides derived from type 1 repeat of thrombospondin, alpha 4 and beta 1 chains of laminin, arginine rich N terminus of endostatin, leucine rich repeat 5 of decorin, pigment epithelium derived factor and N terminal of parathyroid hormone are examples of small antiangiogenic peptides derived from endogenous proteins. Such bioactive peptides are further modified physico-chemically to increase their potency and stability. In addition, phage-display library screening and combinatorial approach are also in use to identify novel antiangiogenic peptides targeting tumour and various proteins. This review will provide a comprehensive summary of the current status of the antiangiogenic peptides and their relevance for drug designing and development. Several critical issues that need to be resolved in translating this concept into clinical practice are also discussed.
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PMID:Developing antiangiogenic peptide drugs for angiogenesis-related diseases. 1762 40

The extracellular matrix is a dynamic repository harboring instructive cues that embody substantial regulatory dominance over many evolutionarily conserved intracellular activities, including proliferation, apoptosis, migration, motility, and autophagy. The matrix also coordinates and parses hierarchical information, such as angiogenesis, tumorigenesis, and immunological responses, typically providing the critical determinants driving each outcome. We provide the first comprehensive review focused on proteoglycan receptors, that is, signaling transmembrane proteins that use secreted proteoglycans as ligands, in addition to their natural ligands. The majority of these receptors belong to an exclusive subset of receptor tyrosine kinases and assorted cell surface receptors that specifically bind, transduce, and modulate fundamental cellular processes following interactions with proteoglycans. The class of small leucine-rich proteoglycans is the most studied so far and constitutes the best understood example of proteoglycan-receptor interactions. Decorin and biglycan evoke autophagy and immunological responses that deter, suppress, or exacerbate pathological conditions such as tumorigenesis, angiogenesis, and chronic inflammatory disease. Basement membrane-associated heparan sulfate proteoglycans (perlecan, agrin, and collagen XVIII) represent a unique cohort and provide proteolytically cleaved bioactive fragments for modulating cellular behavior. The receptors that bind the genuinely multifactorial and multivalent proteoglycans represent a nexus in understanding basic biological pathways and open new avenues for therapeutic and pharmacological intervention.
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PMID:Decoding the Matrix: Instructive Roles of Proteoglycan Receptors. 2617 9

Nucleus accumbens-associated protein-1 (NAC1) is a transcriptional repressor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and plays critical roles in tumor development, progression, and drug resistance. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. However, effective approaches for effective targeting of this nuclear protein remain elusive. In this study, we identified a core unit consisting of Met7 and Leu90 in NAC1's N-terminal domain (amino acids 1-130), which is critical for its homodimerization and stability. Furthermore, using a combination of computational analysis of the NAC1 dimerization interface and high-throughput screening (HTS) for small molecules that inhibit NAC1 homodimerization, we identified a compound (NIC3) that selectively binds to the conserved Leu-90 of NAC1 and prevents its homodimerization, leading to proteasomal NAC1 degradation. Moreover, we demonstrate that NIC3-mediated down-regulation of NAC1 protein sensitizes drug-resistant tumor cells to conventional chemotherapy and enhances the antimetastatic effect of the antiangiogenic agent bevacizumab both in vitro and in vivo These results suggest that small-molecule inhibitors of NAC1 homodimerization may effectively sensitize cancer cells to some anticancer agents and that NAC1 homodimerization could be further explored as a potential therapeutic target in the development of antineoplastic agents.
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PMID:Identification of a small-molecule compound that inhibits homodimerization of oncogenic NAC1 protein and sensitizes cancer cells to anticancer agents. 3110 55