Restoration of p53 Functions Protects Cells from Concanavalin A-Induced Apoptosis
Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA.Molecular Cancer Therapeutics (Impact Factor: 5.68). 02/2010; 9(2):471-9. DOI: 10.1158/1535-7163.MCT-09-0732
A great majority of human cancers encounter disruption of the p53 network. Identification and characterization of molecular components important in both p53-dependent and p53-independent apoptosis might be useful in developing novel therapies. Previously, we reported that concanavalin A (Con A) induced p73-dependent apoptosis of cells lacking functional p53. In the present study, we investigated the mechanism and role of p53 in protection from apoptosis induced by Con A. Treatment with Con A resulted in apoptosis of p53-null ovarian cancer, SKOV3, or Li-Fraumeni syndrome, MDAH041 (041), cells. However, their isogenic pairs, SKP53 and TR9-7, expressing wild-type p53 were much less sensitive and were protected by G(1) arrest. Inhibition of p53 function rendered these cells sensitive to Con A. Con A-induced apoptosis was accompanied by upregulation of forkhead box O1a (FOXO1a) and Bcl-2-interacting mediator (Bim), which were strongly inhibited after p53 expression and rescued after p53 ablation. Moreover, ablation of Bim by short hairpin RNA protected cells from apoptosis. Taken together, our study suggests that Con A induces apoptosis of cells lacking p53 by activating FOXO1a-Bim signaling and that expression of p53 protects these cells by inducing G(1) arrest and by downregulating the expression of both FOXO1a and Bim, identifying a novel cross-talk between FOXO1a and p53 transcription factors.
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ABSTRACT: As digital-to-analog converters get ever faster and more accurate, it becomes ever more feasible to replace analog waveform generation for a transmit exciter with digital circuitry. Simple equations have been obtained which relate clutter cancellation achievable with an LFM pulse compressor to clock timing jitter variance, LFM waveform bandwidth, digital IF frequency, and the sampling frequency. Equations derived in this paper show that the clutter cancellation ratio consists only of terms which contain the standard deviation of the jitter squared, σ<sub>τ</sub><sup>2</sup> and terms with jitter raised to the 4th power, σ<sub>τ</sub><sup>4</sup>. All σ<sub>τ </sub><sup>2</sup> terms are inversely proportional to the number of samples in the LFM waveform. The σ<sub>τ</sub><sup>2</sup> terms dominate when the combination of jitter, digital IF, and waveform bandwidths are low enough. All jitter σ<sub>τ</sub><sup>4</sup> terms are not reduced by the number of samples and do not benefit by an increase in sampling frequency. The σ<sub>τ</sub><sup>4</sup> terms dominate when the combination of jitter, digital IF,and waveform bandwidths are too large. Clutter cancellation performance as it depends upon timing jitter is evaluated numerically for a variety of parameter values and checked by simulation. The results show that good clutter cancellation performance can be achieved with a digital waveform generator provided that the timing jitter is low enough for the digital IF and waveform bandwidth usedRadar Conference, 2000. The Record of the IEEE 2000 International; 02/2000
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ABSTRACT: Plant lectins, carbohydrate-binding proteins distributed widely in a variety of plant species, have been well-known to possess a broad range of significant biological functions such as anti-tumor, anti-fungal and anti-viral activities. Amongst the seven major lectin families, legume lectins have been drawing a rising attention for cancer biologists due to their remarkable anti-tumor properties compared to other lectin families. In this review, we mainly focus on analyzing the anti-tumor activities of Concanavalin A (ConA), the first and most typical representative of legume lectin family, and its related mechanisms of cell death implicated in apoptosis and autophagy. We present the up-to-date experimental advancements that ConA is able to induce cancer cell apoptosis through mitochondria-dependent and p73-mediated pathways, as well as ConA can induce cancer cell autophagy through a mitochondria-dependent signaling pathway. In addition, we further discuss the pre-clinical studies of ConA for its potential cancer therapeutic applications. In conclusion, these findings may shed light on the complicated molecular mechanisms of ConA-induced cancer cell death, thereby opening a new perspective for plant lectins as potential anti-neoplastic drugs in future cancer therapeutics.Current Molecular Pharmacology 11/2010; 3(3):123-8. DOI:10.2174/1874467211003030123
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ABSTRACT: Porphyrins are used as photosensitizer (PS) in photodynamic therapy in cancer treatment. Nevertheless, the development of photochemotherapy in oncology remains limited, because of the low selectivity of PSs. In order to allow PS targeting toward tumor-associated antigens, for the first time a white-light activatable porphyrin, [5-(4-(5-carboxy-1-butoxy)-phenyl)-10,15,20-tris(4-N-methyl)-pyridiniumyl)-porphyrin] (TrMPyP) was covalently linked to Morniga G (MorG), a galactose-specific binding plant lectin, known to recognize with high-affinity tumor-associated T/Tn antigen in cell-free systems. Firstly, using fluorescein-labeled MorG, the sugar-dependent binding and uptake of lectin by Tn-positive (Jurkat lymphoid leukemia) cells was demonstrated. Secondly, the TrMPyP-MorG conjugate was molecularly characterized. Cytometric and confocal microscopic analysis demonstrated that PS covalent linking to MorG preserved sugar-dependent specific binding and uptake of lectin by Jurkat leukemia lymphocytes. Thirdly, the conjugate (with a 1:1 PS:lectin ratio) that was bound and quickly (5 min) taken-up, induced greater than 90% cytotoxicity upon irradiation at 10 nm concentration, whereas the free PS was absolutely nontoxic. On the contrary, normal lymphocytes strongly resisted to the conjugate-mediated phototoxicity. Thus, owing to their binding and endocytosis capacities, plant lectins represent promising molecules for targeting of tumor glycan alteration and to enhance the efficiency of specific delivery of PSs to tumor cells.Photochemistry and Photobiology 11/2010; 87(2):370-7. DOI:10.1111/j.1751-1097.2010.00858.x · 2.27 Impact Factor
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