Post-transcriptional control of C/EBPα and C/EBPβ proteins: Insights into their role in energy homeostasis and diseases

Zaini, M. A., 2017, [Groningen]: University of Groningen. 199 p.

Research output: ThesisThesis fully internal (DIV)

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  • Title and contents

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  • Chapter 1

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  • Chapter 2

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  • Chapter 3

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  • Chapter 4

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  • Chapter 5

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  • Chapter 6

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  • Samenvatting

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  • Acknowledgements

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  • Curriculum Vitae

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  • Complete Thesis

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  • Propositions

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  • Mohamad Amr Zaini
C/EBPα and C/EBPβ proteins are transcription factors playing important roles in the control of cellular proliferation, differentiation and metabolism of different tissues. Their expression and function are strictly regulated at the translational and post-translational levels.
In this thesis we show that C/EBPα is acetylated by p300 lysine acetyl transferase and deacetylated by SIRT1 lysine deacetylase. SIRT1 is activated in times of energy demand by high levels of nicotinamide adenine dinucleotide (NAD+) and controls mitochondrial biogenesis and function. A hypoacetylated mutant of C/EBPα induces the transcription of mitochondrial genes and results in increased mitochondrial respiration. This study identifies C/EBPα as a key mediator of SIRT1-controlled adaption of energy homeostasis to changes in nutrient supply. In a previous study we showed that a cis-regulatory upstream open reading frame (uORF) in the C/EBPβ-mRNA is required for expression of the protein isoform C/EBPβ-LIP. Experimental elimination of the uORF in C/EBPβΔuORF mice results in constitutive low levels of C/EBPβ-LIP and an increase in health- and lifespans with a reduction in tumor incidence. In this thesis we present a luciferase-based cellular reporter system that acts as a surrogate for C/EBPβ-mRNA translation under different conditions. By using this system in a high-throughput screening strategy we identified drugs that suppress translation into C/EBPβ-LIP and potentially exhibit calorie restriction mimetic properties. Finally, in this thesis we show that function of the ribosome maturation protein SBDS is specifically required for efficient uORF-dependent expression of the protein isoforms C/EBPα-p30 and C/EBPβ-LIP. Genetic mutations in SBDS that result in the Shwachman-Diamond syndrome (SDS) causes deregulation of C/EBPα and C/EBPβ translation and a decrease in MYC expression. This study provides the first indication that disturbance of specific translation by loss of SBDS function may contribute to the development of the SDS phenotype.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
Award date11-Dec-2017
Place of Publication[Groningen]
Print ISBNs978-94-034-0282-6
Electronic ISBNs978-94-034-0281-9
Publication statusPublished - 2017

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