Functionally conserved effects of rapamycin exposure on zebrafish

Date
2016-03
Authors
Sucularli, C.
Shehwana, H.
Kuscu, C.
Dungul, D. C.
Ozdag, H.
Konu, O.
Advisor
Supervisor
Co-Advisor
Co-Supervisor
Instructor
Source Title
Molecular Medicine Reports
Print ISSN
1791-2997
Electronic ISSN
Publisher
Spandidos Publications
Volume
13
Issue
5
Pages
4421 - 4430
Language
English
Type
Article
Journal Title
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Abstract

Mechanistic target of rapamycin (mTOR) is a conserved serine/threonine kinase important in cell proliferation, growth and protein translation. Rapamycin, a well-known anti-cancer agent and immunosuppressant drug, inhibits mTOR activity in different taxa including zebrafish. In the present study, the effect of rapamycin exposure on the transcriptome of a zebrafish fibroblast cell line, ZF4, was investigated. Microarray analysis demonstrated that rapamycin treatment modulated a large set of genes with varying functions including protein synthesis, assembly of mitochondrial and proteasomal machinery, cell cycle, metabolism and oxidative phosphorylation in ZF4 cells. A mild however, coordinated reduction in the expression of proteasomal and mitochondrial ribosomal subunits was detected, while the expression of numerous ribosomal subunits increased. Meta-analysis of heterogeneous mouse rapamycin microarray datasets enabled the comparison of zebrafish and mouse pathways modulated by rapamycin, using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathway analysis. The analyses demonstrated a high degree of functional conservation between zebrafish and mice in response to rapamycin. In addition, rapamycin treatment resulted in a marked dose-dependent reduction in body size and pigmentation in zebrafish embryos. The present study is the first, to the best of our knowledge, to evaluate the conservation of rapamycin-modulated functional pathways between zebrafish and mice, in addition to the dose-dependent growth curves of zebrafish embryos upon rapamycin exposure.

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Keywords
Meta-analysis, Microarray, Mouse, mTOR, Rapamycin, Real-time qPCR, Zebrafish, ZF4, Aromatic levo amino acid decarboxylase, Cytochrome P450, Cytochrome P450 26B1, Dickkopf 1 protein, Dickkopf 1b protein, Messenger RNA, Phenylalanine 4 monooxygenase, Proteasome, Protein, Rapamycin, Transcription factor, Transcription factor FOXM1, Transcriptome, Unclassified drug, WNT inhibitory factor 1, Rapamycin, Target of rapamycin kinase, Zebrafish protein, Animal cell, Animal cell culture, Animal experiment, Apoptosis, Article, Body size, Cell cycle, Cell metabolism, Cell proliferation, Cell viability, Controlled study, DNA synthesis, Down regulation, Drug effect, Drug exposure, Embryo, Embryo growth, Endoplasmic reticulum, Fibroblast culture, Gene expression, Genetic conservation, Microarray analysis, Mitochondrion, Mouse, Nonhuman, Oxidative phosphorylation, Pigmentation, Protein synthesis, Ribosome subunit, Steady state, Upregulation, Zebra fish, Animal, Cell line, Comparative study, Drug effects, Gene expression regulation, Metabolism, Species difference, Zebra fish, Animals, Cell Line, Gene Expression Regulation, Mice, Sirolimus, Species Specificity, TOR Serine-Threonine Kinases, Zebrafish, Zebrafish Proteins
Citation
Published Version (Please cite this version)