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)

While investigating endonucleases potentially involved in apoptosis, an antisera was raised to bovine deoxyribonuclease II, but it recognized a smaller protein of 26 kDa protein in a variety of cell lines. The 26 kDa protein underwent proteolytic cleavage to 22 kDa concomitantly with DNA digestion in cells induced to undergo apoptosis. Sequencing of the 26 kDa protein identified it as the Rho GDP-dissociation inhibitor D4-GDI. Zinc, okadaic acid, calyculin A, cantharidin, and the caspase inhibitor z-VAD-fmk, all prevented the cleavage of D4-GDI, DNA digestion, and apoptosis. The 26 kDa protein resided in the cytoplasm of undamaged cells, whereas following cleavage, the 22 kDa form translocated to the nucleus. Human D4-GDI, and D4-GDI mutated at the caspase 1 or caspase 3 sites, were expressed in Chinese hamster ovary cells which show no detectable endogenous D4-GDI. Mutation at the caspase 3 site prevented D4-GDI cleavage but did not inhibit apoptosis induced by staurosporine. The cleavage of D4-GDI could lead to activation of Jun N-terminal kinase which has been implicated as an upstream regulator of apoptosis in some systems. However, the results show that the cleavage of D4-GDI and translocation to the nucleus do not impact on the demise of the cell.
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PMID:Cleavage and nuclear translocation of the caspase 3 substrate Rho GDP-dissociation inhibitor, D4-GDI, during apoptosis. 1038 42

Our earlier study demonstrated that in vivo acute treatment with trimethyltin chloride (TMT) produces severe neuronal damage in the dentate gyrus and cognition impairment in mice. In the present study, we assessed whether TMT was capable of causing neuronal degeneration in the olfactory bulb (OB) and anterior olfactory nucleus (AON) of the mouse brain. An intraperitoneal injection of TMT at the dose of 2.8 mg/kg led to a dramatic increase in the number of degenerating cells, which were reactive with antibody against single-stranded DNA, in the granule cell layer (GCL) of the OB and AON 1 day and 2 days later, respectively. TMT treatment produced a marked translocation of phospho-c-Jun-N-terminal kinase from the cytoplasm to the nucleus in the AON. Expectedly, a marked increase in phospho-c-Jun-positive cells was seen in the AON after the treatment. In addition to the AON, the mitral cell layer of the olfactory bulb showed the presence of phospho-c-Jun-positive cells after the treatment. However, the GCL had no cells positive for either phospho-c-Jun-N-terminal kinase or phospho-c-Jun at any time after the treatment with TMT. Similarly, TMT-induced nuclear translocation of the lysosomal enzyme deoxyribonuclease II was seen in the AON, but not in the GCL. On the other hand, TMT elicited the expression of activated caspase 3 in the GCL but not in the AON. Taken together, our results suggest that TMT is capable of causing neuronal degeneration in the murine OB and AON through different cascades in the two structures.
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PMID:In vivo acute treatment with trimethyltin chloride causes neuronal degeneration in the murine olfactory bulb and anterior olfactory nucleus by different cascades in each region. 1818 23

Neural progenitor cells play an essential role in both the developing embryonic nervous system and in the adult brain, where the capacity for self-renewal would be important for normal brain functions. In the present study, we used embryonic cortical neural progenitor cells to investigate the effects of trimethyltin chloride (TMT) on the survival of neural progenitor cells. In cultures of cortical neural progenitor cells, the formation of round neurospheres was observed in the presence of epidermal growth factor and basic fibroblast growth factor within 9 days in vitro. The neurospheres were then harvested for subsequent replating and culturing for assessment of cell viability in either the presence or absence of TMT at the concentration of 5microM. Lasting exposure to TMT produced not only nuclear condensation in the cells in a time-dependent manner over a period of 6-24h, but also the release of lactate dehydrogenase into the culture medium. Immunoblot and immunocytochemical analyses revealed that TMT had the ability to activate both caspase-3 and calpain, as well as to cause nuclear translocation of deoxyribonuclease II, which is located within cytoplasm in intact cells. Additionally, treatment with a calpain inhibitor [trans-epoxysuccinyl-l-leucylamido-(4-guanidino) butane] and a caspase inhibitor [Z-Val-Ala-Asp(OMe)-CH2F] produced a significant reduction in damaged cells induced by TMT. Taken together, our data indicate that neural progenitor cells are highly susceptible to TMT in undergoing cell death via the activation of 2 parallel pathways, ones involving calpain and the other, caspase-3.
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PMID:High susceptibility of cortical neural progenitor cells to trimethyltin toxicity: involvement of both caspases and calpain in cell death. 1952 17