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Tae-Ho Jang,
Sung-Jun Lee,
Chang-Hoon Woo,
Kyung Jin Lee,
Ju-Hong Jeon,
Dong-Sup Lee,
Kihang Choi,
In-Gyu Kim, Young Whan Kim,
Tae-Jin Lee,
Hyun Ho Park
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ABSTRACT: Genotoxic stress induced apoptosis is mediated by the formation of PIDDosome, which is a caspase-2 activating complex composed of three protein components, PIDD, RAIDD, and caspase-2. Here, synthetic TAT-fused peptides designed by the structure of PIDD and RAIDD, TAT-Y814A and TAT-R147E, respectively, were produced and tested for their ability to inhibit PIDDosome formation in vitro as well as to attenuate genotoxic stress-induced apoptosis in human renal cancer cells. The results show that TAT-Y814A and TAT-R147E have the potential to inhibit formation of the PIDDosome in a dose-dependent manner. Furthermore, both peptides partially inhibit genotoxic stress mediated apoptosis and activation of caspase2 and caspase3 in Caki cells. These results suggest that TAT-Y814A (also TAT-R147E) is a novel inhibitor of genotoxic stress-induced apoptosis that may serve as a prototype for anti-apoptotic drug development.
Biochemical pharmacology 10/2011; 83(2):218-27. · 4.25 Impact Factor
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ABSTRACT: Pulmonary fibrosis is a potentially life-threatening disease that may be caused by overt or asymptomatic inflammatory responses. However, the precise mechanisms by which tissue injury is translated into inflammation and consequent fibrosis remain to be established. Here, we show that in a lung injury model, bleomycin induced the secretion of IL-6 by epithelial cells in a transglutaminase 2 (TG2)-dependent manner. This response represents a key step in the differentiation of IL-17-producing T cells and subsequent inflammatory amplification in the lung. The essential role of epithelial cells, but not inflammatory cells, TG2 was confirmed in bone marrow chimeras; chimeras made in TG2-deficient recipients showed reduced inflammation and fibrosis, compared with those in wild-type mice, regardless of the bone marrow cell phenotype. Epithelial TG2 thus appears to be a critical inducer of inflammation after noninfectious pulmonary injury. We further demonstrated that fibroblast-derived TG2, acting downstream of transforming growth factor-β, is also important in the effector phase of fibrogenesis. Therefore, TG2 represents an interesting potential target for therapeutic intervention.
Journal of Experimental Medicine 08/2011; 208(8):1707-19. · 13.85 Impact Factor
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ABSTRACT: Ribosomal proteins are a major component of ribosomes, which catalyze protein synthesis. One ribosomal protein, L7a (RPL7a), which is a component of the 60S large ribosomal subunit, has additional functions involved in cell growth and differentiation that occur via interaction with human thyroid hormone receptor (THR) and retinoic acid receptor (RAR) and in turn inhibit the activities of the two nuclear hormone receptors. In this study, the N-terminal domain of human RPL7a was overexpressed in Escherichia coli using an engineered C-terminal His tag. The N-terminal domain of human RPL7a was then purified to homogeneity and crystallized at 293 K. X-ray diffraction data were collected to a resolution of 3.5 Å from a crystal belonging to the tetragonal space group P4(1)22 or P4(3)22 with unit-cell parameters a = 92.28, b = 92.28, c = 236.59 Å.
Acta Crystallographica Section F Structural Biology and Crystallization Communications 04/2011; 67(Pt 4):510-2. · 0.51 Impact Factor
