Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?

DeBerardinis, Ralph J.; Thompson, Craig B.

doi:10.1016/j.cell.2012.02.032

“…KEGG pathway analysis also revealed that BTZ treatment enriched pathways including SNARE interactions in vesicular transport and biosynthesis of unsaturated fatty acids ( Table 1). Upregulation of these pathways might contribute to altered cell polarity, cellular metabolism and cell signaling through clustering receptors in lipid rafts, which are known causes and hallmarks of human cancers [44,45]. Altogether, application of ProTA has provided the first systematic view of the pathways enriched during BTZ action.…”

Section: Gene Ontology and Pathway Analysesmentioning

confidence: 99%

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

Tao

¹

,

Tao

²

,

Yang

³

et al. 2014

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Global change in protein turnover (protein degradome) constitutes a central part of cellular responses to intrinsic or extrinsic stimuli. However, profiling protein degradome remains technically challenging. Recently, inhibition of the proteasome, e.g., by using bortezomib (BTZ), has emerged as a major chemotherapeutic strategy for treating multiple myeloma and other human malignancies, but systematic understanding of the mechanisms for BTZ drug action and tumor drug resistance is yet to be achieved. Here we developed and applied a dual-fluorescence-based Protein Turnover Assay (ProTA) to quantitatively profile global changes in human protein degradome upon BTZ-induced proteasomal inhibition. ProTA and subsequent network analyses delineate potential molecular basis for BTZ action and tumor drug resistance in BTZ chemotherapy. Finally, combined use of BTZ with drugs targeting the ProTA-identified key genes or pathways in BTZ action reduced BTZ resistance in multiple myeloma cells. Remarkably, BTZ stabilizes proteasome subunit PSMC1 and proteasome assembly factor PSMD10, suggesting a previously under-appreciated mechanism for regulating proteasome homeostasis. Therefore, ProTA is a novel tool for profiling human protein degradome to elucidate potential mechanisms of drug action and resistance, which might facilitate therapeutic development targeting proteostasis to treat human disorders.

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“…Further, this research builds on the work of Paxton et al (2012)-which showed the highest attrition of women in philosophy occurs at the undergraduate level-by qualitatively assessing the experiences of female undergraduate philosophy majors in order to gain a better understanding of what factors may be responsible for the retention 8 and attrition of women in the discipline. The goal of this project is to enhance understanding of this phenomenon from the perspective of the actual experiences of women in philosophy by exploring how they reflect on their careers as undergraduate students.…”

Section: Methodsologymentioning

confidence: 99%

“…Hydroxyurea is a therapeutic agent extensively used in the clinical treatment of hematological malignancies (7,8), chronic myelogenous leukemia (9), sickle-cell disease (10), carcinomas, and other diseases (7). Hydroxyurea is thought to specifically inhibit ribonucleotide reductase, depleting the pools of deoxyribonucleoside triphosphates, thereby leading to stalled replication forks that prevent cells from progressing through S phase (1).…”

Section: Introductionsmentioning

confidence: 99%

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2015

McNair

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About the ProgramThe Portland State University (PSU) Ronald E. McNair Scholars Program at Portland State University works with motivated and talented undergraduates who want to pursue PhDs. It introduces juniors and seniors who are first-generation and lowincome, and/or members of under-represented groups to academic research and to effective strategies for getting into and graduating from PhD programs.The McNair Scholars Program has academic-year activities and a full-time summer research internship. Scholars take academic and skills-building seminars and workshops during the year, and each scholar works closely with a faculty mentor on original research in the summer. Scholars present their research findings at the McNair Summer Symposium and at other conferences, and are encouraged to publish their papers in the McNair Journal and other scholarly publications.The Ronald E. McNair Post-baccalaureate Achievement Program was established in 1986 by the U.S. Department of Education and named in honor of Challenger Space Shuttle astronaut Dr. Ronald E. McNair. The program, whichhas been on campus since 2003, is funded by a $1,155,000 grant from the U.S. Department of Education and institutional cost-share funds.The McNair Scholars Program's student-centered approach relies heavily on faculty and university commitment. Activities and opportunities provided by the program focus on building a positive academic community for the scholars while they are undergraduates at PSU. About Ronald E. McNairRonald Erwin McNair was born October 21, 1950 in Lake City, South Carolina. While in junior high school, Dr. McNair was inspired to work hard and persevere in his studies by his family and by a teacher who recognized his scientific potential and believed in him. Dr While working as a staff physicist with Hughes Research Laboratory, Dr. McNair soon became a recognized expert in laser physics. His many distinctions include being a Presidential Scholar (1971-74), a Ford Foundation Fellow (1971-74), a National Fellowship Fund Fellow (1974, and a NATO Fellow (1975). He was also a sixth degree black belt in karate and an accomplished saxophonist. Because of his many accomplishments, he was selected by NASA for the space shuttle program in 1978.His first space shuttle mission launched successfully from Kennedy Space Center on February 3, 1984. Dr. Ronald E. McNair was the second African American to fly in space. Two years later he was selected to serve as mission specialist aboard the illfated U.S. Challenger space shuttle. He was killed instantly when the Challenger exploded one minute, thirteen seconds after it was launched. Dr. McNair was posthumously awarded the Congressional Space Medal of Honor. After his death in the Challenger Space Shuttle accident on January 28, 1986, members of Congress provided funding for the Ronald E. McNair Post-Baccalaureate Achievement Program. Their goal was to encourage low-income and first-generation college students, and students from historically underrepresented ethnic groups to expand their e...

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“…These findings suggest that the stability of the mitochondrial genome is increased in cancer compared to healthy cells, as a result of a decrease in ROS related mtDNA damage. Inhibited or suppressed energy production has also been observed in a wide variety of other diseases, including diabetes and neurodegenerative disorders (DeBerardinis, 2012). However, whether and to what extent altered or depressed metabolism can protect organisms from heritable (germline) mutations has not been studied.…”

Section: Introductionmentioning

confidence: 99%

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About the ProgramThe Portland State University (PSU) Ronald E. McNair Scholars Program at Portland State University works with motivated and talented undergraduates who want to pursue PhDs. It introduces juniors and seniors who are first-generation and lowincome, and/or members of under-represented groups to academic research and to effective strategies for getting into and graduating from PhD programs.The McNair Scholars Program has academic-year activities and a full-time summer research internship. Scholars take academic and skills-building seminars and workshops during the year, and each scholar works closely with a faculty mentor on original research in the summer. Scholars present their research findings at the McNair Summer Symposium and at other conferences, and are encouraged to publish their papers in the McNair Journal and other scholarly publications.The Ronald E. McNair Post-baccalaureate Achievement Program was established in 1986 by the U.S. Department of Education and named in honor of Challenger Space Shuttle astronaut Dr. Ronald E. McNair. The program, whichhas been on campus since 2003, is funded by a $1,155,000 grant from the U.S. Department of Education and institutional cost-share funds.The McNair Scholars Program's student-centered approach relies heavily on faculty and university commitment. Activities and opportunities provided by the program focus on building a positive academic community for the scholars while they are undergraduates at PSU. About Ronald E. McNairRonald Erwin McNair was born October 21, 1950 in Lake City, South Carolina. While in junior high school, Dr. McNair was inspired to work hard and persevere in his studies by his family and by a teacher who recognized his scientific potential and believed in him. Dr While working as a staff physicist with Hughes Research Laboratory, Dr. McNair soon became a recognized expert in laser physics. His many distinctions include being a Presidential Scholar (1971-74), a Ford Foundation Fellow (1971-74), a National Fellowship Fund Fellow (1974, and a NATO Fellow (1975). He was also a sixth degree black belt in karate and an accomplished saxophonist. Because of his many accomplishments, he was selected by NASA for the space shuttle program in 1978.His first space shuttle mission launched successfully from Kennedy Space Center on February 3, 1984. Dr. Ronald E. McNair was the second African American to fly in space. Two years later he was selected to serve as mission specialist aboard the illfated U.S. Challenger space shuttle. He was killed instantly when the Challenger exploded one minute, thirteen seconds after it was launched. Dr. McNair was posthumously awarded the Congressional Space Medal of Honor. After his death in the Challenger Space Shuttle accident on January 28, 1986, members of Congress provided funding for the Ronald E. McNair Post-Baccalaureate Achievement Program. Their goal was to encourage low-income and first-generation college students, and students from historically underrepresented ethnic groups to expand their e...

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Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?

Cited by 719 publications

References 97 publications

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

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