Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The diazo compound, 2,2'-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPC), is a water-soluble radical initiator that can be activated at mild temperatures (37 degrees -40 degrees C). Potential biomedical applications of this compound include the fabrication of hydrogels by radical polymerization (e.g., cell encapsulation or drug delivery) and the thermal sensitization of cancerous cells to induce localized cell death. In this study we evaluated whether this compound could induce cell death at 37 degrees C in vitro and in vivo using a tumor animal model. Cytotoxicity was quantitated with a sulfo-rhodamine B colorimetric assay by monitoring growth inhibition of human glioma cells in vitro. AIPC was entrapped in fibrin gel and exposed to cells in culture as a potential way to localize the compound in a controlled release environment. The mechanism of action for cell death was evaluated by quantitating caspase-3 activity in cells. In vivo studies included human glioma tumors that were grown subcutaneously in rats to study the effect of intra-tumor injections of AIPC. AIPC was also injected subcutaneously into normal tissue. Concentrations of 0.2% and 0.02% (w/v in RPMI medium) showed 93% and 84% inhibition of cell growth in vitro, respectively. Cell-growth inhibition using gel-entrapped AIPC was comparable to that obtained with AIPC in solution after 48 hr (86% inhibition at 0.2% w/v). Exposure to AIPC resulted in a significant increase of caspase activity (up to 163 units after 20 min), suggesting induced apoptosis as a possible mechanism of action of the AIPC. Histological pictures showed that, relative to normal tissue, cancerous tissue was more sensitive to the effects of AIPC.
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PMID:Cell-killing potential of a water-soluble radical initiator. 1151 51

PDZD2 (PDZ-domain-containing 2; also known as PAPIN, AIPC and PIN1) is a ubiquitously expressed multi-PDZ-domain protein. We have shown that PDZD2, which shows extensive homology to pro-interleukin-16 (pro-IL-16), is localized mainly to the endoplasmic reticulum (ER). Pro-IL-16 is cleaved in a caspase-3-dependent mechanism to generate the secreted cytokine IL-16. The abundant expression of PDZD2 in the ER, and its sequence similarity to pro-IL-16, suggests that similar post-translational processing of PDZD2 may occur. Indeed, western blotting and mass spectrometry analysis of conditioned medium from cells transfected with epitope-tagged PDZD2 show that there is secretion of a PDZD2 peptide of approximately 37 kDa (sPDZD2, for secreted PDZD2) that contains two PDZ domains. Expression of PDZD2 was detected in several tissues. Furthermore, sPDZD2 secretion is suppressed by the mutation of a sequence that shows similarity to caspase recognition motifs or by treatment with a caspase inhibitor. In summary, PDZD2 is the first reported multi-PDZ protein that is processed by proteolytic cleavage to generate a secreted peptide containing two PDZ domains.
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PMID:Proteolytic cleavage of PDZD2 generates a secreted peptide containing two PDZ domains. 1267 85

PDZ domains are versatile protein interaction modules with the ability to dimerize and to recognize internal and carboxy-terminal peptide motifs. Their function in mediating the formation of multi-molecular signaling complexes is best understood at neuronal and epithelial membranes. In a screen for interactors that regulate transcription factor function in pancreatic beta cells, we isolated two PDZ-containing proteins Bridge-1 (PSMD9) and PDZD2, which contain one and six PDZ domains, respectively. Here, we review their functions in the regulation of pancreatic beta cells as a nuclear coactivator or extracellular signaling molecule. Bridge-1 interacts with both E12 and PDX-1 to stimulate insulin promoter activity. Recent gain-of-function analysis in both cell and transgenic models has revealed its functions to regulate both insulin gene expression and pancreatic beta-cell survival. Little is known about the intracellular function of PDZD2 that is predominantly localized to the endoplasmic reticulum of INS-1E cells. Interestingly, PDZD2 is proteolytically processed by caspase-3 to generate a carboxy-terminal secreted protein (sPDZD2) containing two PDZ domains. Expressed in fetal pancreatic progenitor and INS-1E cells, sPDZD2 when added as recombinant protein exerts concentration-dependent mitogenic effects on beta-like cells. We propose that the PDZ domain proteins Bridge-1 and PDZD2 likely transduce signals that regulate insulin production, proliferation, and survival of pancreatic beta cells.
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PMID:The roles of the PDZ-containing proteins bridge-1 and PDZD2 in the regulation of insulin production and pancreatic beta-cell mass. 1927 70