University of Groningen Probing the ligand receptor interface of TNF ligand family members RANKL and TRAIL Wang, Yizhou

University of Groningen

Probing the ligand receptor interface of TNF ligand family members RANKL and TRAIL

Wang, Yizhou

DOI:

10.33612/diss.127959201

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Publication date: 2020

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Wang, Y. (2020). Probing the ligand receptor interface of TNF ligand family members RANKL and TRAIL. University of Groningen. https://doi.org/10.33612/diss.127959201

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Probing the ligand-receptor interface

of TNF ligand family members

RANKL and TRAIL

The research described in this thesis was carried out in the Department of Chemical and Pharmaceutical Biology (Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands) and was financially supported by the China Scholarship Council, the Dutch Top Institute Pharma project TNF-ligands in cancer (project nr. T3-112) and the Dutch Science Foundation (NWO/STW) (grant 11056).

The research work was carried out according to the requirements of the Graduate School of Science, Faculty of Science and Engineering, University of Groningen, The Netherlands.

Printing of this thesis was financially supported by the University Library and the Graduate School of Science, Faculty of Science and Engineering, University of Groningen, The Netherlands.

ISBN: 978-94-034-2667-9 (printed version) ISBN: 978-94-034-2666-2 (electronic version) Printing: Ridderprint BV, www.ridderprint.nl

Probing the ligand-receptor

interface of TNF ligand family

members RANKL and TRAIL

PhD thesis

to obtain the degree of PhD at the

University of Groningen

on the authority of the

Rector Magnificus Prof. C. Wijmenga

and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Tuesday 30 June 2020 at 12.45 hours

by

Yizhou Wang

born on 22 April 1990

in Hebei, China

Supervisors

Prof. W.J. Quax

Prof. H.J. Haisma

Assessment Committee

Prof. R.A. Bank

Prof. B.N. Melgert

Table of Contents

Chapter 1

General introduction and scope of the thesis

7

Chapter 2

TNF-family member Receptor Activator of NF-κB

(RANK) and RANK-Ligand (RANKL) in bone

remodeling

19

Chapter 3

Novel RANKL DE-loop mutants antagonize

RANK-mediated osteoclastogenesis

33

Chapter 4

Creation of RANKL mutants with low affinity for

decoy receptor OPG and their potential anti-fibrosis

activity

59

Chapter 5

Long term secretion of adenovirally-expressed

RANKL WT/ Q236D for treatment of fibrosis

83

Chapter 6

Overcoming senescent cancer cell resistance to

extrinsic apoptosis using a death receptor 5 (DR5)

selective TNF-related apoptosis inducing ligand

(TRAIL) variant

105

Chapter 7

Novel TRAIL variants with reduced binding to decoy

receptor OPG overcome TRAIL resistance in breast

cancers

131

Chapter 8

Summary and future perspectives

151

Samenvatting Nederlandse Samenvatting

159

Appendices

Acknowledgements

168

List of publications

173