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RISS 인기검색어
- 검색키워드
- 저자 : T. Scheffler (검색결과 4 건)
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Scheffler, T. L.,Scheffler, J. M.,Park, S.,Kasten, S. C.,Wu, Y.,McMillan, R. P.,Hulver, M. W.,Frisard, M. I.,Gerrard, D. E. American Physiological Society 2014 American journal of physiology. Cell physiology Vol.306 No.4
<P>An inverse relationship between skeletal muscle fiber cross-sectional area (CSA) and oxidative capacity suggests that muscle fibers hypertrophy at the expense of oxidative capacity. Therefore, our objective was to utilize pigs possessing mutations associated with increased oxidative capacity [AMP-activated protein kinase (AMPKγ<SUB>3</SUB><SUP>R200Q</SUP>)] or fiber hypertrophy [ryanodine receptor 1 (RyR1<SUP>R615C</SUP>)] to determine if these events occur in parallel. Longissimus muscle was collected from wild-type (control), AMPKγ<SUB>3</SUB><SUP>R200Q</SUP>, RyR1<SUP>R615C</SUP>, and AMPKγ<SUB>3</SUB><SUP>R200Q</SUP>-RyR1<SUP>R615C</SUP> pigs. Regardless of AMPK genotype, RyR<SUP>R615C</SUP> increased fiber CSA by 35%. In contrast, AMPKγ<SUB>3</SUB><SUP>R200Q</SUP> pig muscle exhibited greater citrate synthase and β-hydroxyacyl CoA dehydrogenase activity. Isolated mitochondria from AMPKγ<SUB>3</SUB><SUP>R200Q</SUP> muscle had greater maximal, ADP-stimulated oxygen consumption rate. Additionally, AMPKγ<SUB>3</SUB><SUP>R200Q</SUP> muscle contained more (∼50%) of the mitochondrial proteins succinate dehydrogenase and cytochrome <I>c</I> oxidase and more mitochondrial DNA. Surprisingly, RyR1<SUP>R615C</SUP> increased mitochondrial proteins and DNA, but this was not associated with improved oxidative capacity, suggesting that altered energy metabolism in RyR1<SUP>R615C</SUP> muscle influences mitochondrial proliferation and protein turnover. Thus pigs that possess both AMPKγ3<SUP>R200Q</SUP> and RyR<SUP>R615C</SUP> exhibit increased muscle fiber CSA as well as greater oxidative capacity. Together, our findings support the notion that hypertrophy and enhanced oxidative capacity can occur simultaneously in skeletal muscle and suggest that the signaling mechanisms controlling these events are independently regulated.</P>
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Lau, E.,Kluger, H.,Varsano, T.,Lee, K.,Scheffler, I.,Rimm, David L.,Ideker, T.,Ronai, Ze'ev A. Cell Press ; MIT Press 2012 Cell Vol.148 No.3
The transcription factor ATF2 elicits oncogenic activities in melanoma and tumor suppressor activities in nonmalignant skin cancer. Here, we identify that ATF2 tumor suppressor function is determined by its ability to localize at the mitochondria, where it alters membrane permeability following genotoxic stress. The ability of ATF2 to reach the mitochondria is determined by PKCε, which directs ATF2 nuclear localization. Genotoxic stress attenuates PKCε effect on ATF2; enables ATF2 nuclear export and localization at the mitochondria, where it perturbs the HK1-VDAC1 complex; increases mitochondrial permeability; and promotes apoptosis. Significantly, high levels of PKCε, as seen in melanoma cells, block ATF2 nuclear export and function at the mitochondria, thereby attenuating apoptosis following exposure to genotoxic stress. In melanoma tumor samples, high PKCε levels associate with poor prognosis. Overall, our findings provide the framework for understanding how subcellular localization enables ATF2 oncogenic or tumor suppressor functions.
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Wilkinson, J. R.,Yu, J.,Abbas, H. K.,Scheffler, B. E.,Kim, H. S.,Nierman, W. C.,Bhatnagar, D.,Cleveland, T. E. Taylor Francis 2007 Food additives and contaminants Vol.24 No.10
<P> Aflatoxins are toxic and carcinogenic polyketide metabolites produced by fungal species, including Aspergillus flavus and A. parasiticus. The biosynthesis of aflatoxins is modulated by many environmental factors, including the availability of a carbon source. The gene expression profile of A. parasiticus was evaluated during a shift from a medium with low concentration of simple sugars, yeast extract (YE), to a similar medium with sucrose, yeast extract sucrose (YES). Gene expression and aflatoxins (B1, B2, G1, and G2) were quantified from fungal mycelia harvested pre- and post-shifting. When compared with YE media, YES caused temporary reduction of the aflatoxin levels detected at 3-h post-shifting and they remained low well past 12 h post-shift. Aflatoxin levels did not exceed the levels in YE until 24 h post-shift, at which time point a tenfold increase was observed over YE. Microarray analysis comparing the RNA samples from the 48-h YE culture to the YES samples identified a total of 2120 genes that were expressed across all experiments, including most of the aflatoxin biosynthesis genes. One-way analysis of variance (ANOVA) identified 56 genes that were expressed with significant variation across all time points. Three genes responsible for converting norsolorinic acid to averantin were identified among these significantly expressed genes. The potential involvement of these genes in the regulation of aflatoxin biosynthesis is discussed.</P>
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