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MicroRNAs targeting pyruvate dehydrogenase kinase 1

Frankel, Rebecca LU (2015) KEMK03 20151
Department of Chemistry
Abstract
Cancer, a group of diseases with abnormal cell growth, is today very common in our society. There are different forms of cancer, which all display different symptoms, but still have mutual characteristics. One such is the way cancer cells create energy which, like healthy cells, starts with glycolysis of glucose to pyruvate. In healthy cells, with sufficient oxygen supply, the enzyme pyruvate dehydrogenase will then help transform the pyruvate to acetyl CoA, which is transported into the mitochondria where it further reacts to create a supply of energy. There is, however, an enzyme that lowers the efficiency of the pyruvate dehydrogenase, with the similar name pyruvate dehydrogenase kinase. It can hinder the creation of acetyl CoA, thus... (More)
Cancer, a group of diseases with abnormal cell growth, is today very common in our society. There are different forms of cancer, which all display different symptoms, but still have mutual characteristics. One such is the way cancer cells create energy which, like healthy cells, starts with glycolysis of glucose to pyruvate. In healthy cells, with sufficient oxygen supply, the enzyme pyruvate dehydrogenase will then help transform the pyruvate to acetyl CoA, which is transported into the mitochondria where it further reacts to create a supply of energy. There is, however, an enzyme that lowers the efficiency of the pyruvate dehydrogenase, with the similar name pyruvate dehydrogenase kinase. It can hinder the creation of acetyl CoA, thus blocks it from entering the mitochondria. Cancer cells has a higher concentration of this inhibitor enzyme, and instead get their energy by reacting pyruvate into lactate, which create less energy forcing cancer cells to consume more glucose. The reason for this still being favourable for the cancer cells is due to the fact that the programmed cell death - apoptosis - is regulated in the mitochondria, inter alia, through the flow of acetyl CoA. By decreasing this influx, cancer cells may therefore hinder apoptosis, thus explaining their uncontrolled cellular proliferation.
To reduce this inhibitor enzyme's activity, a regulation method called RNA interference can be exploited. It uses small, double stranded RNA molecules (microRNA, also shortened miRNA) to bind to the enzyme’s messenger RNA - the template for the protein. By this interference, less enzyme that may inhibit pyruvate dehydrogenase, is created, leading to an augmentation of acetyl CoA's creation and inflow into the mitochondria, letting the apoptosis being regulated as usual. However, not all miRNA target this enzyme, so research to find the ones that do is required. This can be done via different databases, such as TargetScan, which has been taken advantage of in this study. (Less)
Popular Abstract (Swedish)
Cancer, samlingsnamnet på ett antal sjukdomar med okontrollerad cellväxt, är idag väldigt vanligt förekommande i vårt samhälle. Det finns olika typer av cancer, som alla uppvisar olika symptom, men som ändå har gemensamma kännetecken. En av dessa är hur cancercellerna skapar sin energi vilket, precis som i friska celler, börjar med att sockermolekylen glukos genomgår ett antal reaktioner för att slutligen bilda pyruvat. I friska celler, med tillräckligt med syre, hjälper sedan enzymet pyruvatdehydrogenas till att transformera pyruvatet till acetyl-CoA som därefter transporteras in i cellens kraftstation – mitokondrien – där den reagerar vidare och skapar energi i stora mängder. Det finns dock ett annat enzym som minskar effektiviteten av... (More)
Cancer, samlingsnamnet på ett antal sjukdomar med okontrollerad cellväxt, är idag väldigt vanligt förekommande i vårt samhälle. Det finns olika typer av cancer, som alla uppvisar olika symptom, men som ändå har gemensamma kännetecken. En av dessa är hur cancercellerna skapar sin energi vilket, precis som i friska celler, börjar med att sockermolekylen glukos genomgår ett antal reaktioner för att slutligen bilda pyruvat. I friska celler, med tillräckligt med syre, hjälper sedan enzymet pyruvatdehydrogenas till att transformera pyruvatet till acetyl-CoA som därefter transporteras in i cellens kraftstation – mitokondrien – där den reagerar vidare och skapar energi i stora mängder. Det finns dock ett annat enzym som minskar effektiviteten av pyruvatdehydrogenas, med det snarlika namnet pyruvatdehydrogenaskinas. Denna kan hindra bildandet av acetyl-CoA, som därmed inte går in i mitokondrien. Detta inhibitorenzym har en förhöjd halt i cancerceller, som istället får sin energi genom att pyruvat reageras till laktat, vilket ger mindre energi än i mitokondrien som således leder till att cancerceller behöver använda mer glukos. Anledningen till att detta ändå är gynnsamt för cancercellerna är för att den programmerade celldöden – apoptos – regleras i mitokondrien bland annat genom inflödet av acetyl-CoA. Genom att minska inströmmandet av detta kan cancercellerna därmed förhindra apoptosen, vilket sålunda förklarar deras okontrollerande cellväxt.
För att minska inhibitorenzymets aktivitet kan en regleringsmetod som kallas RNA interferens utnyttjas. Denna använder små, dubbelsträngade RNA-molekyler (mikroRNA, även förkortat miRNA) till att binda till genen som kodar för enzymet, i processen precis innan proteinet bildas, då den fortfarande är ett ”messenger RNA” – templatet för proteinet. Genom att göra detta minskar följaktligen mängden enzym som kan inhibera pyruvatdehydrogenaset, vilket skulle kunna göra att mer acetyl-CoA kan bildas och transporteras in i mitokondrien, så att apoptosen kan ske som den ska. Det är dock inte alla miRNA som gör detta för just pyruvatdehydrogenaskinas, så efterforskning krävs för att hitta exakt vilka som gör det. Detta kan göras genom olika databaser, så som TargetScan, vilket även har gjorts i detta arbete. (Less)
Please use this url to cite or link to this publication:
author
Frankel, Rebecca LU
supervisor
organization
course
KEMK03 20151
year
type
M2 - Bachelor Degree
subject
keywords
Biochemistry, gene regulation, microRNA, cancer, biokemi
language
English
id
5473638
date added to LUP
2015-07-02 15:30:22
date last changed
2015-07-02 15:30:22
@misc{5473638,
  abstract     = {Cancer, a group of diseases with abnormal cell growth, is today very common in our society. There are different forms of cancer, which all display different symptoms, but still have mutual characteristics. One such is the way cancer cells create energy which, like healthy cells, starts with glycolysis of glucose to pyruvate. In healthy cells, with sufficient oxygen supply, the enzyme pyruvate dehydrogenase will then help transform the pyruvate to acetyl CoA, which is transported into the mitochondria where it further reacts to create a supply of energy. There is, however, an enzyme that lowers the efficiency of the pyruvate dehydrogenase, with the similar name pyruvate dehydrogenase kinase. It can hinder the creation of acetyl CoA, thus blocks it from entering the mitochondria. Cancer cells has a higher concentration of this inhibitor enzyme, and instead get their energy by reacting pyruvate into lactate, which create less energy forcing cancer cells to consume more glucose. The reason for this still being favourable for the cancer cells is due to the fact that the programmed cell death - apoptosis - is regulated in the mitochondria, inter alia, through the flow of acetyl CoA. By decreasing this influx, cancer cells may therefore hinder apoptosis, thus explaining their uncontrolled cellular proliferation.
To reduce this inhibitor enzyme's activity, a regulation method called RNA interference can be exploited. It uses small, double stranded RNA molecules (microRNA, also shortened miRNA) to bind to the enzyme’s messenger RNA - the template for the protein. By this interference, less enzyme that may inhibit pyruvate dehydrogenase, is created, leading to an augmentation of acetyl CoA's creation and inflow into the mitochondria, letting the apoptosis being regulated as usual. However, not all miRNA target this enzyme, so research to find the ones that do is required. This can be done via different databases, such as TargetScan, which has been taken advantage of in this study.},
  author       = {Frankel, Rebecca},
  keyword      = {Biochemistry,gene regulation,microRNA,cancer,biokemi},
  language     = {eng},
  note         = {Student Paper},
  title        = {MicroRNAs targeting pyruvate dehydrogenase kinase 1},
  year         = {2015},
}