The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform
Michael J Tisdale - One of the best experts on this subject based on the ideXlab platform.
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induction of Protein Catabolism in myotubes by 15 s hydroxyeicosatetraenoic acid through increased expression of the ubiquitin proteasome pathway
British Journal of Cancer, 2003Co-Authors: Alison S Whitehouse, Jwan Khal, Michael J TisdaleAbstract:Proteolysis through the ubiquitin–proteasome pathway has an important role in the regulation of the cell cycle and division, differentiation and development, as well as a variety of other basic cellular processes (Ciechanover et al, 2000). In addition, this pathway plays an important role in the wasting of skeletal muscle seen in a range of catabolic processes, including starvation, sepsis, metabolic acidosis, weightlessness, severe trauma, denervation atrophy and cancer cachexia (Lecker et al, 1999). In this process, Proteins are degraded into peptides within the 20S proteasome, a cylindrical structure of four stacked rings, each composed of seven subunits surrounding a central cavity. The inner β rings contain proteolytic enzymes, while the two outer α rings surround a small cavity through which Protein substrates must enter. Cellular Proteins are marked for degradation by attachment of a polyubiquitin chain. While the ubiquitin-conjugating enzyme (E214k) was suggested to be the rate-limiting step in the pathway in starvation (Wing and Banville, 1994), it has recently been shown that E214k knockout is not associated with decreased Protein Catabolism (Adegoke et al, 2002). Instead, ubiquitin-Protein ligases (E3) may play a more important role in muscle atrophy and E3 knockout is clearly associated with increased Protein Catabolism (Bodine et al, 2001; Gomes et al, 2001).
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Induction of Protein Catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin–proteasome pathway
British Journal of Cancer, 2003Co-Authors: Alison S Whitehouse, Jwan Khal, Michael J TisdaleAbstract:Proteolysis through the ubiquitin–proteasome pathway has an important role in the regulation of the cell cycle and division, differentiation and development, as well as a variety of other basic cellular processes (Ciechanover et al, 2000). In addition, this pathway plays an important role in the wasting of skeletal muscle seen in a range of catabolic processes, including starvation, sepsis, metabolic acidosis, weightlessness, severe trauma, denervation atrophy and cancer cachexia (Lecker et al, 1999). In this process, Proteins are degraded into peptides within the 20S proteasome, a cylindrical structure of four stacked rings, each composed of seven subunits surrounding a central cavity. The inner β rings contain proteolytic enzymes, while the two outer α rings surround a small cavity through which Protein substrates must enter. Cellular Proteins are marked for degradation by attachment of a polyubiquitin chain. While the ubiquitin-conjugating enzyme (E214k) was suggested to be the rate-limiting step in the pathway in starvation (Wing and Banville, 1994), it has recently been shown that E214k knockout is not associated with decreased Protein Catabolism (Adegoke et al, 2002). Instead, ubiquitin-Protein ligases (E3) may play a more important role in muscle atrophy and E3 knockout is clearly associated with increased Protein Catabolism (Bodine et al, 2001; Gomes et al, 2001).
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induction of Protein Catabolism and the ubiquitin proteasome pathway by mild oxidative stress
Cancer Letters, 2002Co-Authors: Maria Cristina Cintra Gomesmarcondes, Michael J TisdaleAbstract:Muscle wasting in cancer cachexia is associated with increased levels of malondialdehyde (MDA) in gastrocnemius muscles, suggesting an increased oxidative stress. To determine whether oxidative stress contributes to muscle Protein Catabolism, an in vitro model system, consisting of C2C12 myotubes, was treated with either 0.2 mM FeSO4, 0.1 mM H2O2, or both, to replicate the rise in MDA content in cachexia. All treatments caused an increased Protein Catabolism and a decreased myosin expression. There was an increase in the proteasome chymotrypsin-like enzyme activity, while immunoblotting showed an increased expression of the 20S proteasome α-subunits, p42, and the ubiquitin-conjugating enzyme, E214k. These results show that mild oxidative stress increases Protein degradation in skeletal muscle by causing an increased expression of the major components of the ubiquitin-proteasome pathway. © 2002 Elsevier Science Ireland Ltd. All rights reserved.
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mechanism of attenuation of skeletal muscle Protein Catabolism in cancer cachexia by eicosapentaenoic acid
Cancer Research, 2001Co-Authors: Alison S Whitehouse, Helen J Smith, Joanne L Drake, Michael J TisdaleAbstract:Cancer cachexia is characterized by selective depletion of skeletal muscle Protein reserves. Soleus muscles from mice bearing a cachexia-inducing tumor (MAC16) showed an increased Protein degradation in vitro, as measured by tyrosine release, when compared with muscles from nontumor-bearing animals. After incubation under conditions that modify different proteolytic systems, lysosomal, calcium-dependent, and ATP-dependent proteolysis were found to contribute to the elevated Protein Catabolism. Treatment of mice bearing the MAC16 tumor with the polyunsaturated fatty acid, eicosapentaenoic acid (EPA), attenuated loss of body weight and significantly suppressed Protein Catabolism in soleus muscles through an inhibition of an ATP-dependent proteolytic pathway. The ATP-ubiquitin-dependent proteolytic pathway is considered to play a major role in muscle Catabolism in cachexia, and functional proteasome activity, as determined by “chymotrypsin-like” enzyme activity, was significantly elevated in gastrocnemius muscle of mice bearing the MAC16 tumor as weight loss progressed. When animals bearing the MAC16 tumor were treated with EPA, functional proteasome activity was completely suppressed, together with attenuation of the expression of 20S proteasome a-subunits and the p42 regulator, whereas there was no effect on the expression of the ubiquitin-conjugating enzyme (E214k). These results suggest that EPA induces an attenuation of the up-regulation of proteasome expression in cachectic mice, and this was correlated with an increase in myosin expression, confirming retention of contractile Proteins. EPA also inhibited growth of the MAC16 tumor in a dose-dependent manner, and this correlated with suppression of the expression of the 20S proteasome a-subunits in tumor cells, suggesting that this may be the mechanism of tumor growth inhibition. Thus EPA antagonizes loss of skeletal muscle Proteins in cancer cachexia by down-regulation of proteasome expression, and this may also be the mechanism for inhibition of tumor growth.
Jeffrey A Haspel - One of the best experts on this subject based on the ideXlab platform.
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adventures in spacetime circadian rhythms and the dynamics of Protein Catabolism
Autophagy, 2019Co-Authors: Mikhail Ryzhikov, Anna Ehlers, Jeffrey A HaspelAbstract:ABSTRACTCircadian rhythms help cells to organize complex processes, but how they shape the kinetics of Protein Catabolism is unclear. In a recent paper, we employed proteomics to map daily biologic...
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Adventures in spacetime: circadian rhythms and the dynamics of Protein Catabolism.
Autophagy, 2019Co-Authors: Mikhail Ryzhikov, Anna Ehlers, Jeffrey A HaspelAbstract:ABSTRACTCircadian rhythms help cells to organize complex processes, but how they shape the kinetics of Protein Catabolism is unclear. In a recent paper, we employed proteomics to map daily biological rhythms in autophagic flux in mouse liver, and correlated these rhythms with proteasome activity. We also explored the effect of inflammation caused by endotoxin on autophagy dynamics. Our data provide insight into how circadian rhythms serve as a framework for connecting the spatial, temporal, and metabolic aspects of autophagy at a system-wide level. Our observations also have implications for how to optimize autophagy-directed therapies in patients.
Dana S. Hardin - One of the best experts on this subject based on the ideXlab platform.
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Protease inhibitor therapy improves Protein Catabolism in prepubertal children with HIV infection.
Journal of Pediatric Endocrinology and Metabolism, 2020Co-Authors: Dana S. Hardin, Kenneth J. Ellis, Julie Rice, Marilyn DoyleAbstract:UNLABELLED: Past studies in adults have reported that loss of lean tissue mass (LTM) is associated with accelerated rates of Protein Catabolism. To date, studies of Protein kinetics from pediatric patients infected by HIV have not been published; however, poor linear growth and weight loss are well-documented. The first aim of this study was to test the hypothesis that Protein Catabolism is high in pediatric patients with HIV. Protease inhibitors (PI) have proven to be effective therapy for pediatric HIV patients. One action of these drugs is that of lowering the viral burden, and several studies suggest that these drugs result in increased growth and weight velocity. Our second aim was to determine whether PI therapy improves Protein Catabolism. METHODS: We studied eight children infected with HIV (ages 2.9-6.2 years, Tanner stage I, CD4 counts 100,000-300,000, 5 F/3 M) and eight healthy age- and gender-matched controls. Measures of Protein turnover were conducted using the stable isotope [1-(13C)]leucine. Body composition was measured by dual X-ray absorptiometry (DXA) scan for determination of LTM, and indirect calorimetry for measurement of resting energy expenditure. Children with HIV infection were studied at baseline and after 6 weeks of PI therapy; control children were studied only once. RESULTS: Protein Catabolism, represented as leucine rate of appearance (Ra) in the fasted state, was higher in the HIV-infected children at baseline compared to control children. After 6 weeks of PI therapy, leucine Ra decreased, but not to the range found in control children. Leucine Ra correlated with viral burden. LTM significantly improved in all patients. CONCLUSION: These results suggest that similar to HIV-infected adults, HIV-infected children have higher than normal Protein Catabolism. Furthermore, our measures suggest that short-term PI therapy results in improved Protein Catabolism and LTM.
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insulin like growth factor i levels predict weight height and Protein Catabolism in children and adolescents with cystic fibrosis
Journal of Pediatric Endocrinology and Metabolism, 2009Co-Authors: Michael Switzer, Julie Rice, Mark Rice, Dana S. HardinAbstract:: Multiple reports have demonstrated the benefit of growth hormone (GH) treatment in children with cystic fibrosis (CF) and previous studies have demonstrated low to normal insulin-like growth factor-I (IGF-I) levels in these patients. Most biological effects of GH are mediated by IGF-I; however, the relationship between height, weight and rate of growth has not been systematically studied in CF. We conducted a retrospective analysis of 52 patients (including control volunteers with CF) who had participated in previous studies of GH treatment to determine the relationship between levels of IGF-I and growth in children with CF. In a subset of these patients, we also evaluated the relationship between Protein Catabolism and IGF-I. Baseline IGF-I levels and IGF-I z-scores were correlated with same day measures of height, weight, height and weight z-scores. In a subset of patients, IGF-I levels were also correlated with leucine rate of appearance (a measure of Protein Catabolism). IGF-I levels were obtained every six months during our studies and were correlated with same day height, weight and Protein turnover. Height and weight velocity were calculated every six months from study baseline and were correlated with IGF-I levels. In all patients, whether treated with GH or controls, we found a positive linear correlation between IGF-I levels and height (r = 0.66, p < 0.0001) and weight (r = 0.61, p < 0.0001), as well as height and weight velocity. There was also a strong relationship between leucine rate of appearance and IGF-I. These results suggest a strong correlation between IGF-I and height, weight and Protein Catabolism and emphasize the need to normalize IGF-I levels in children with cystic fibrosis.
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Growth hormone improves Protein Catabolism and growth in prepubertal children with HIV infection
Clinical Endocrinology, 2005Co-Authors: Dana S. Hardin, Julie Rice, Marilyn Doyle, Andrew T. PaviaAbstract:Summary Introduction Poor linear growth and weight loss are well documented in children with human immunodeficiency virus (HIV) infection and past studies in adults and children have reported that loss of lean tissue mass (LTM) associated with accelerated rates of Protein Catabolism. We undertook this study to test the hypothesis that human recombinant GH would improve linear height in HIV-infected children. Our second goal was to determine if GH could reverse Protein Catabolism in HIV-infected children. Methods We studied six HIV-infected children (mean age 9·2 years, Tanner stage I, CD4 counts 110 000–292 000, two girls, four boys). Measures of Protein turnover were conducted using the stable isotope 1-[13C] leucine. Body composition was measured by dual X-ray absorptiometry (DXA) scan for determination of LTM. Viral burden and IGF-1 levels were measured. Studies were conducted at baseline and 6 months. Results The baseline growth velocity of these children was only 3·9 cm/year. After 6 months of GH, growth velocity increased to 7·9 cm/year. Protein Catabolism, represented as leucine rate of appearance (Ra) in the fasted state, was high at baseline, but decreased significantly after 6 months of GH therapy. Lean tissue mass significantly improved in all subjects. Viral burden did not increase significantly in any subject during GH therapy. Conclusion These results suggest that GH improves height and weight and reduces Protein Catabolism in HIV-infected children without negative effect on viral burden.
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Growth hormone decreases Protein Catabolism in children with cystic fibrosis.
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Dana S. Hardin, Kenneth J. Ellis, Julie Rice, Maynard Dyson, Ruth Mcconnell, Dan K. SeilheimerAbstract:Despite aggressive nutritional therapy, low body weight and Protein Catabolism are common problems in children with cystic fibrosis. Previous studies by our group and others have demonstrated improvement in both height and weight in children with cystic fibrosis who were treated with human recombinant GH, and our group has recently documented improved clinical status and lean tissue mass as well. The purpose of this report is to summarize our findings of the effect of GH on whole body Protein kinetics in cystic fibrosis and to relate these findings to changes in TNF-α levels. We conducted a 1-yr study of 19 prepubertal children with cystic fibrosis (age 7–12 yr, all
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growth hormone decreases Protein Catabolism in children with cystic fibrosis
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Dana S. Hardin, Kenneth J. Ellis, Julie Rice, Maynard Dyson, Ruth Mcconnell, Dan K. SeilheimerAbstract:Despite aggressive nutritional therapy, low body weight and Protein Catabolism are common problems in children with cystic fibrosis. Previous studies by our group and others have demonstrated improvement in both height and weight in children with cystic fibrosis who were treated with human recombinant GH, and our group has recently documented improved clinical status and lean tissue mass as well. The purpose of this report is to summarize our findings of the effect of GH on whole body Protein kinetics in cystic fibrosis and to relate these findings to changes in TNF-α levels. We conducted a 1-yr study of 19 prepubertal children with cystic fibrosis (age 7–12 yr, all <94% of ideal body weight). Ten children were randomly assigned to take daily injections of GH (0.3 mg/kg·wk), and nine were randomly assigned to be controls. Baseline results from the subjects with cystic fibrosis were compared with results obtained from nine age- and gender-matched healthy children. Whole body Protein turnover was measured a...
Alison S Whitehouse - One of the best experts on this subject based on the ideXlab platform.
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induction of Protein Catabolism in myotubes by 15 s hydroxyeicosatetraenoic acid through increased expression of the ubiquitin proteasome pathway
British Journal of Cancer, 2003Co-Authors: Alison S Whitehouse, Jwan Khal, Michael J TisdaleAbstract:Proteolysis through the ubiquitin–proteasome pathway has an important role in the regulation of the cell cycle and division, differentiation and development, as well as a variety of other basic cellular processes (Ciechanover et al, 2000). In addition, this pathway plays an important role in the wasting of skeletal muscle seen in a range of catabolic processes, including starvation, sepsis, metabolic acidosis, weightlessness, severe trauma, denervation atrophy and cancer cachexia (Lecker et al, 1999). In this process, Proteins are degraded into peptides within the 20S proteasome, a cylindrical structure of four stacked rings, each composed of seven subunits surrounding a central cavity. The inner β rings contain proteolytic enzymes, while the two outer α rings surround a small cavity through which Protein substrates must enter. Cellular Proteins are marked for degradation by attachment of a polyubiquitin chain. While the ubiquitin-conjugating enzyme (E214k) was suggested to be the rate-limiting step in the pathway in starvation (Wing and Banville, 1994), it has recently been shown that E214k knockout is not associated with decreased Protein Catabolism (Adegoke et al, 2002). Instead, ubiquitin-Protein ligases (E3) may play a more important role in muscle atrophy and E3 knockout is clearly associated with increased Protein Catabolism (Bodine et al, 2001; Gomes et al, 2001).
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Induction of Protein Catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin–proteasome pathway
British Journal of Cancer, 2003Co-Authors: Alison S Whitehouse, Jwan Khal, Michael J TisdaleAbstract:Proteolysis through the ubiquitin–proteasome pathway has an important role in the regulation of the cell cycle and division, differentiation and development, as well as a variety of other basic cellular processes (Ciechanover et al, 2000). In addition, this pathway plays an important role in the wasting of skeletal muscle seen in a range of catabolic processes, including starvation, sepsis, metabolic acidosis, weightlessness, severe trauma, denervation atrophy and cancer cachexia (Lecker et al, 1999). In this process, Proteins are degraded into peptides within the 20S proteasome, a cylindrical structure of four stacked rings, each composed of seven subunits surrounding a central cavity. The inner β rings contain proteolytic enzymes, while the two outer α rings surround a small cavity through which Protein substrates must enter. Cellular Proteins are marked for degradation by attachment of a polyubiquitin chain. While the ubiquitin-conjugating enzyme (E214k) was suggested to be the rate-limiting step in the pathway in starvation (Wing and Banville, 1994), it has recently been shown that E214k knockout is not associated with decreased Protein Catabolism (Adegoke et al, 2002). Instead, ubiquitin-Protein ligases (E3) may play a more important role in muscle atrophy and E3 knockout is clearly associated with increased Protein Catabolism (Bodine et al, 2001; Gomes et al, 2001).
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mechanism of attenuation of skeletal muscle Protein Catabolism in cancer cachexia by eicosapentaenoic acid
Cancer Research, 2001Co-Authors: Alison S Whitehouse, Helen J Smith, Joanne L Drake, Michael J TisdaleAbstract:Cancer cachexia is characterized by selective depletion of skeletal muscle Protein reserves. Soleus muscles from mice bearing a cachexia-inducing tumor (MAC16) showed an increased Protein degradation in vitro, as measured by tyrosine release, when compared with muscles from nontumor-bearing animals. After incubation under conditions that modify different proteolytic systems, lysosomal, calcium-dependent, and ATP-dependent proteolysis were found to contribute to the elevated Protein Catabolism. Treatment of mice bearing the MAC16 tumor with the polyunsaturated fatty acid, eicosapentaenoic acid (EPA), attenuated loss of body weight and significantly suppressed Protein Catabolism in soleus muscles through an inhibition of an ATP-dependent proteolytic pathway. The ATP-ubiquitin-dependent proteolytic pathway is considered to play a major role in muscle Catabolism in cachexia, and functional proteasome activity, as determined by “chymotrypsin-like” enzyme activity, was significantly elevated in gastrocnemius muscle of mice bearing the MAC16 tumor as weight loss progressed. When animals bearing the MAC16 tumor were treated with EPA, functional proteasome activity was completely suppressed, together with attenuation of the expression of 20S proteasome a-subunits and the p42 regulator, whereas there was no effect on the expression of the ubiquitin-conjugating enzyme (E214k). These results suggest that EPA induces an attenuation of the up-regulation of proteasome expression in cachectic mice, and this was correlated with an increase in myosin expression, confirming retention of contractile Proteins. EPA also inhibited growth of the MAC16 tumor in a dose-dependent manner, and this correlated with suppression of the expression of the 20S proteasome a-subunits in tumor cells, suggesting that this may be the mechanism of tumor growth inhibition. Thus EPA antagonizes loss of skeletal muscle Proteins in cancer cachexia by down-regulation of proteasome expression, and this may also be the mechanism for inhibition of tumor growth.
Josh Rabinowitz - One of the best experts on this subject based on the ideXlab platform.
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abstract lb 279 quantitative flux measurements of serum Protein Catabolism in pdac and other kras mutant cancers
Cancer Research, 2015Co-Authors: Michel Nofal, Kevin Zhang, Josh RabinowitzAbstract:Activating KRAS mutations are prevalent in human cancer and are associated with poor prognosis. Among these malignancies is pancreatic ductal adenocarcinoma (PDAC), which is universally KRAS-driven and almost universally lethal. PDAC tumors are extremely fibrotic and hypovascularized, limiting perfusion of nutrients into the tumor, and tumor cells exhibit an altered metabolic program to support survival and proliferation in this environment. One metabolic activity upregulated in these tumor cells is the uptake and Catabolism of serum Protein. This process yields a substantial alternative source of amino acids and can support the proliferation of cultured cells lacking free essential amino acids. However, existing methods for assaying the uptake and degradation of intact Protein provide qualitative outputs, and as such, do not yield accurate estimates of flux from serum Protein to amino acid monomers. Here, we present a method for quantitative measurement of the catabolic production of amino acids from serum Protein in cultured cells. By culturing cells in medium containing fully 13C-labeled glucose and amino acids supplemented with unlabeled albumin, we distinguish amino acids taken up as monomers from the medium from serum Protein-derived amino acids. Using a variant of classical metabolic flux analysis, we derive flux estimates for serum Protein Catabolism from measurements of amino acid abundance and isotopic labeling over time. Our method is highly sensitive (i.e. can estimate “baseline” serum Protein Catabolism in KRAS wild-type cell lines) and yields precise estimates of amino acid influx from serum Protein for all Proteinogenic amino acids. We have measured serum Protein Catabolism in a variety of cultured cell lines and find that Protein Catabolism yields amino acids in comparable amounts to conventional uptake in various pancreatic and non-pancreatic lines. This approach enables estimation of Protein catabolic flux in any cell line and can be used to assay the effects of various genetic and pharmacological perturbations on serum Protein Catabolism with high sensitivity and while accounting for growth rate differences. Citation Format: Michel Nofal, Kevin Zhang, Josh Rabinowitz. Quantitative flux measurements of serum Protein Catabolism in PDAC and other KRAS-mutant cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-279. doi:10.1158/1538-7445.AM2015-LB-279
