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The Role of ATF4 as a Mediator of the Hexosamine Biosynthesis Pathway in Intestinal Stem Cells

Show simple item record 2022-05-10T11:53:38Z 2022-05-10T11:53:38Z 2022-05-10
dc.title The Role of ATF4 as a Mediator of the Hexosamine Biosynthesis Pathway in Intestinal Stem Cells en
ethesis.faculty Maatalous-metsätieteellinen tiedekunta fi
ethesis.faculty Faculty of Agriculture and Forestry en
ethesis.faculty Agrikultur- och forstvetenskapliga fakulteten sv
ethesis.faculty.URI Helsingin yliopisto fi University of Helsinki en Helsingfors universitet sv
dct.creator Henriksson, Roselia
dct.issued 2022 xx
dct.abstract Tiivistelmä — Referat — Abstract Intestine renews itself from intestinal stem cells (ISCs) in response to cell damage and disease. Damaged and dead cells are replaced by ISCs through cell division followed by daughter cell differentiation. Disturbances in this process can lead to diseases such as cancer. Hexosamine biosynthetic pathway (HBP) is a mediator of systemic insulin signaling induced ISC proliferation. However, the full molecular mechanism of HBP mediated ISC proliferation is yet to be discovered. Deciphering the mechanisms of the regulation responsible for ISC renewal could pave way for disease etiology dependent on the rate of ISCs proliferation. In this project I use Drosophila genetic tools to elucidate transcriptional and translational level control of HBP regulated ISC proliferation. Glutamine Fructose-6-phosphate Amidotransferase (GFAT) activity limits the rate of N-Acetylglucosamine GlcNAc and consequently ISC proliferation. Thus, gfat2Δ1 mutant flies are used to study molecular regulation of HBP. Full midguts of Drosophila will be imaged using Aurox Clarity Spinning-disc Confocal system. Confocal 3D images will be analyzed using an image analysis software called linear analysis of midgut (LAM) to retain region specific data. Exploring ISC proliferation in relation to nutrient sensing pathways in the full midgut level is still novel and LAM provides region specific data in previously unprecedented detail. The end product of HBP pathway Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) was supplemented within the diet of the flies to observe its effect to the gfat2Δ1 ISC phenotype. UDP-GlcNac did not rescue the gfat2Δ1 ISCs. Usage of Drosophila genetic tools elucidated previously unknown transcriptional level regulation of HBP induced ISC proliferation: ATF4 knockdown in gfat2Δ1 mutant ISCs rescued gfat2Δ1 attenuated ISC division. In addition, ATF4 was indicated to possibly regulate the gfat2Δ1 phenotype via the regulation of growth through ribosome biogenesis and 4EBP translation inhibition. This study revealed the mediator of HBP, the transcription factor ATF4 to be the modulator of ISC proliferation. en
dct.subject ATF4
dct.subject Hexosamine biosynthesis pathway
dct.subject intestinal stem cells
dct.subject nutrients
ethesis.language englanti fi
ethesis.language English en
ethesis.language engelska sv
ethesis.supervisor Jaakko Mattila und
ethesis.thesistype pro gradu -tutkielmat fi
ethesis.thesistype master's thesis en
ethesis.thesistype pro gradu-avhandlingar sv
dct.identifier.ethesis E-thesisID:302ce3ff-d68c-4ac4-a0a5-21896f31c7bb
ethesis-internal.timestamp.reviewStep 2022-03-25 10:46:39:445
ethesis.principalprofessor Per-Erik Saris und
dct.identifier.urn URN:NBN:fi:hulib-202205101857
dct.alternative ATF4:n rooli heksosamiini biosynteesireitin välittäjänä suoliston kantasoluissa fi
ethesis.facultystudyline ei opintosuuntaa fi
ethesis.facultystudyline no specialization en
ethesis.facultystudyline ingen studieinriktning sv
ethesis.mastersdegreeprogram Mikrobiologian ja mikrobibiotekniikan maisteriohjelma fi
ethesis.mastersdegreeprogram Master 's Programme in Microbiology and Microbial Biotechnology en
ethesis.mastersdegreeprogram Magisterprogrammet i mikrobiologi och mikrobiell bioteknik sv

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