Regulation of the Ets transcription factor Tel
Roukens, M.G.
Citation
Roukens, M. G. (2010, April 15). Regulation of the Ets transcription factor Tel. Retrieved from https://hdl.handle.net/1887/15226
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Regulation of the Ets transcription factor Tel
Regulation of the Ets transcription factor Tel
Proefschrift
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus prof. Mr. P.F. van der Heijden, volgens besluit van het College voor Promoties
te verdedigen op donderdag 15 April 2010 klokke 11.15 uur
door
Mark Guido Roukens
geboren te Bleiswijk
in 1979
Promotiecommissie
Promotor: Prof. Dr. P. ten Dijke Co-promotor: Dr. D.A. Baker
Overige leden: Prof. Dr. L.H. Mullenders
Prof. Dr. C.P. Verrijzer (Erasmus University Rotterdam)
Dr. A.C. Vertegaal
The studies described in this thesis were performed at the department of Molecular and Cellular Biology, Leiden University Medical Center.
Cover: Branching in Elswout. Photographed by Swie Yin Oei.
This thesis was printed by Gildeprint Drukkerijen, Enschede.
Table of contents
Outline of the thesis 7
Chapter 1 General Introduction 9
Chapter 2 Identification of a new site of sumoylation on Tel (ETV6) uncovers a PIAS-dependent mode of regulating Tel function. 45
Roukens MG, Alloul-Ramdhani M, Vertegaal AC, Anvarian Z, Balog CI, Deelder AM, Hensbergen PJ, Baker DA. Mol Cell Biol. 2008 Apr;28(7):2342-57. Chapter 3 Downregulation of vertebrate Tel (ETV6) and Drosophila Yan is facilitated by an evolutionarily conserved mechanism of F-box-mediated ubiquitination. 63
Roukens MG, Alloul-Ramdhani M, Moghadasi S, Op den Brouw M, Baker DA. Mol Cell Biol. 2008 Jul;28(13):4394-406. Chapter 4 An Evolutionarily Conserved Mechanism of the Control of Endothelial Sprouting by a Tel:CtBP Complex 79
Roukens MG, Alloul-Ramdhani M, Baan B, Kobayashi K, Peterson-Maduro J, Schulte-Merker S, Baker DA. Submitted for publication in Nat Cell Biol. Chapter 5 General Discussion 131
Chapter 6 Summary 145
Nederlandse Samenvatting 149
Curriculum Vitae 153
Appendix: List of abbreviations 155
Outline of the thesis
In this thesis we report novel studies on the molecular regulation of the transcriptional repressor Tel (Translocation Ets Leukemia). Tel is highly evolutionarily conserved, is indispensable for development and is of major importance in leukemogenesis. However, its mechanism of action remains poorly understood. The aim of this thesis was to gain more insight in the mechanisms that underlie the regulation of cell fate by Tel.
The work in this thesis is presented as follows:
Chapter 1 is an introduction which summarizes the literature about Tel and its Drosophila orthologue Yan as it was known prior to the work presented here.
Chapter 2 shows that Tel is modified by SUMO (Small Ubiquitin-like Modifier) on the highly conserved lysine 11 (K11), which serves to inhibit DNA binding of Tel.
Chapter 3 describes the regulation of Tel and Yan by the F-box protein Fbl6, which mediates ubiquitination and subsequent degradation of Tel/Yan.
Chapter 4 reports that Tel regulates angiogenesis through recruitment of the generic corepressor C-terminal Binding Protein (CtBP). This complex integrates intracellular Vascular Endothelial Growth Factor (VEGF) signaling and intercellular Delta-like 4 (Dll4)/Notch signaling. The impact of these findings is discussed in the general discussion in Chapter 5. Taken together the work in this thesis provides significant advances in the molecular details of Tel regulation. Furthermore, the work in chapter 4 should be of considerable importance to the field of angiogenesis.
