Browsing by Author "Kim, Sung-Woo"

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    Cell Line Specific Modulation of Extracellular Aβ42 by Hsp40
    (Public Library of Science, 2012-05-29) Carnni, Anna; Scott, Lucas O. M.; Ahrendt, Eva; Proft, Juliane; Winkfein, Robert J.; Kim, Sung-Woo; Colicos, Michael A.; Braun, Janice E. A.
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    Insights into the Functional Link between MtHsp40:MtHsp70 Network and Mitochondrial Homeostasis
    (2013-05-14) Lee, Byoung Chun; Kim, Sung-Woo; Johnston, Randal
    Mitochondrial apoptosis, morphology and function can be modulated by the activity of mitochondrial chaperones including mtHsp40 and mtHsp70. We found that both overexpression and depletion of mtHsp40 reversibly changed mitochondrial morphology from tubular network to fragmented puncta, in a process known as mitochondrial fragmentation, which was not coupled with apoptosis. Using domain deletion mutant constructs, we determined that mitochondrial targeting sequence (MTS) and DnaJ domain of mtHsp40 were required for mitochondrial fragmentation. Both inhibition and loss of mtHsp70 also caused mitochondrial fragmentation. Ectopic expression of mtHsp70, with the exception of substrate binding domain-deletion mutant, did not affect mitochondrial morphology. These data suggest that the stoichiometric ratio between mtHsp40 and mtHsp70 determines mitochondrial morphology independently of apoptosis. Mitochondrial fragmentation resulting from the imbalance between mtHsp40 and mtHsp70 was dependent on DRP1 level, but mitochondrial translocation of DRP1 was not detected in fragmented mitochondria. In addition, OPA1 short-isoform highly accumulated in fragmented mitochondria, suggesting that ratio between mtHsp40 and mtHsp70 is a determinant of OPA1 cleavage, which in turn determines mitochondrial morphology. Imbalance between mtHsp40 and mtHsp70 led to dramatic crista remodeling which enhances cancer cell sensitivity to drug-induced apoptosis, and lowered both ATP production and oxygen consumption rate in fragmented mitochondria, which resulted in cell-growth retardation. Collectively, we propose that perturbations of mtHsp40:mtHsp70 network might reduce their own activity, which causes OPA1 cleavage and mitochondrial fragmentation depending on DRP1 located in mitochondria, leading to mitochondrial innermembrane remodeling, indicating the apoptosis-independent coupling between mitochondrial homeostasis and mtHsp40:mtHsp70 network.
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    Insights into the molecular link between td1 and p53 and its role in apoptosis
    (2010) Trinh, Diane Linh Ngoc; Kim, Sung-Woo
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    Tid1 modulation of p53 ubiquitination in breast cancer cells
    (2012) Kim, Shin Hwan; Kim, Sung-Woo
    In this study, we showed that Tumorous Imaginal Disc 1 (Tidl) has the ability to indirectly modulate p53 ubiquitination in breast cancer cells. The over-expression of Tidl expression in MCF-7 cells led to suppression of p53 ubiquitination whereas its suppression led to enhanced ubiquitination. Tid 1 mediated suppression of p53 ubiquitination can enhance p53 half-life but not endogenous p53 level or p53 downstream targets. Over-expression of Tidl alone was unable to decrease the cell viability of MCF-7 cells but its combination with the proteasome inhibitor ALLN, there was a decrease in cell viability. A reduction in ATP level by Tidl over-expression is suggested to be one of the possible mechanisms that may suppress p53 ubiqutination. In summary, we propose that Tid 1 depletes cellular ATP levels, which in tum, inhibits ubiquitination­proteasome machinery, resulting in enhanced stability of p53.