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Metabolic regulation and anticancer drug resistance in the yeast Saccharomyces cerevisiae

Carlsson, Mattias (2014). Metabolic regulation and anticancer drug resistance in the yeast Saccharomyces cerevisiae. Diss. (sammanfattning/summary) Uppsala : Sveriges lantbruksuniv., Acta Universitatis agriculturae Sueciae, 1652-6880 ; 2014:55
ISBN 978-91-576-8058-7
eISBN 978-91-576-8059-4
[Doctoral thesis]

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Abstract

Cancer is a malignant neoplastic tissue. The pyrimidine analogue 5-fluorouracil is an anticancer drug used against several types of cancer. It owes its specificity against neoplasms due to the higher rate of nutrient uptake, RNA and DNA synthesis, and in particular the higher rate of nucleobase scavenging and salvage of neoplastic cells. However, tumours can develop resistance to 5-fluorouracil and other anticancer drugs, rendering the therapy useless. Due to genetic variation, humans can also be inherently more or less sensitive to 5-fluorouracil and other anticancer drugs such as the purine analogue mercaptopurine.

In this thesis I have investigated the mechanisms of resistance to 5-fluorouracil and the model purine analogue 6-N-hydroxylaminopurine in the budding yeast Saccharomyces cerevisiae. The mechanisms found to confer resistance in S. cerevisiae to 5-fluorouracil and 6-N-hydroxylaminopurine included both deregulation of the de novo synthesis of nucleotides, and detoxification of non-canonical nucleotides. I proceeded to study genetic interactions between genes involved in resistance to both 5-fluorouracil and 6-N-hydroxylaminopurine by using plasmid overexpression in yeast strains knocked out for different resistance genes and other genes involved in nucleotide metabolism.

HAM1 is a yeast gene coding for a nucleotide pyrophosphatase, the overexpression of which we found to confer resistance to both 5-fluorouracil and 6-N-hydroxylaminopurine. HAM1 has a human homologue called ITPA. We proceeded to test if a known genetic polymorphism in ITPA could help predict toxicity in patients receiving a chemotherapeutic regimen including 5-fluorouracil. Our results suggest that loss of ITPA function may lead to increased sensitivity to 5-fluorouracil.

We have also investigated the mechanism of transcriptional regulation by the yeast Rph1p protein, a zinc finger transcription factor which also contains a jmjC domain with histone demethylase activity. Rph1p functions downstream of the RAS-cAMP-PKA pathway and several other nutrient sensing pathways. We found, surprisingly, that the histone demethylase activity of Rph1p is largely dispensable for its role in transcriptional regulation.

Authors/Creators:Carlsson, Mattias
Title:Metabolic regulation and anticancer drug resistance in the yeast Saccharomyces cerevisiae
Series/Journal:Acta Universitatis agriculturae Sueciae (1652-6880)
Year of publishing :19 August 2014
Volume:2014:55
Number of Pages:91
Papers/manuscripts:
NumberReferences
I.Carlsson, M., Gustavsson, M., Hu, G-Z., Murén, E., Ronne, H. (2013). A Ham1p-dependent mechanism and modulation of the pyrimidine biosynthetic pathway can both confer resistance to 5-fluorouracil in yeast. PloS One 8: e52094. doi:10.1371/journal.pone.0052094.
II.Nordberg, N., Olsson, I., Carlsson, M., Hu, G-Z., Orzechowski Westholm, J., Ronne, H., (2014). The histone demethylase activity of Rph1 is not essential for its role in the transcriptional response to nutrient signaling. PloS One 9(7): e95078. doi: 10.1371/journal.pone.0095078.
III.Mattias Carlsson, Mia Wadelius, Hugo Kohnke, Bengt Glimelius, Hans Ronne, 2014. Genetic variant of inosine triphosphate pyrophosphatase (ITPA) predicts toxicity of 5-fluorouracil and irinotecan in patients with metastatic colorectal cancer. (manuscript).
IV.Mattias Carlsson, Guo-Zhen Hu, Hans Ronne, 2014. Cloning of genes that confer resistance to 6-N-hydroxylaminopurine when overexpressed in yeast and their interaction with genes that confer resistance to 5-fluorouracil. (manuscript).
Place of Publication:Uppsala
Publisher:Department of Microbiology, Swedish University of Agricultural Sciences
ISBN for printed version:978-91-576-8058-7
ISBN for electronic version:978-91-576-8059-4
ISSN:1652-6880
Language:English
Publication Type:Doctoral thesis
Full Text Status:Public
Agris subject categories.:X Agricola extesions > X30 Life sciences
X Agricola extesions > X38 Human medicine, health, and safety
Subjects:(A) Swedish standard research categories 2011 > 1 Natural sciences > 106 Biological Sciences (Medical to be 3 and Agricultural to be 4) > Genetics (medical genetics to be 30107 and agricultural genetics to be 40402)
(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 302 Clinical Medicine > Cancer and Oncology
Agrovoc terms:neoplasms, fluorouracil, antineoplastic agents, saccharomyces cerevisiae, drug resistance, nucleotides, gene expression
Keywords:5-fluorouracil, 6-N-hydroxylaminopurine, drug resistance, saccharomyces, cerevisiae, histone demethylase, ITPA, cancer, toxicity
URN:NBN:urn:nbn:se:slu:epsilon-e-2063
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-e-2063
ID Code:11415
Faculty:NJ - Fakulteten för naturresurser och jordbruksvetenskap
Department:(NL, NJ) > Dept. of Microbiology (until 161231)
External funders:Cancerfonden / Swedish Cancer Society and Swedish Research Council
Deposited By: Mattias Carlsson
Deposited On:20 Aug 2014 14:53
Metadata Last Modified:02 Dec 2014 11:08

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