The interrelationship between Nucleophosmin and STAT3/5 in cancer

Abstract

The development and progression of cancer require the concerted activationand participation of a pool of different oncogenic signal pathways. Some ofthese oncogenic pathways converge at a nuclear phosphoprotein namednucleophosmin (NPM). NPM transcriptionally regulates p53 gene, andstabilizes its expression. It is also an important ubiquitination target ofBRCA1-BARD1 complex, where cancer predisposing mutations occur leadingto development of hereditary breast cancer. Moreover, genetic mutations onNPM gene were found to be associated with haematological malignanciesincluding acute myeloid leukemia (AML) and anaplasitic large T celllymphoma (ALCL). In the development of ALCL, fusion protein NPM-ALKdrives transformation of CD4+ T cells by phosphorylating members of signaltransducer and activator of transcription (STAT) family. However, little isknown how wild type NPM interacts with the signal pathways mentionedabove in cancers.The present thesis dissected this fundamental question into three morespecific questions : (1) whether wild type NPM is functionally related toSTAT3 in cancers; (2) whether there is a potentially regulatory relationshipbetween NPM and STAT5 in cancers; (3) whether there is any cancerpredisposing mutation in NPM gene in breast cancers bearing no BRCA1/2mutation.The first section of the thesis demonstrated that tyrosine 705phosphorylated STAT3 (P-STAT3) physically interacts with NPM, andtranscriptionally regulates the expression level of NPM gene. The secondsection further explored the relationship between STAT5 and NPM in cancers,and unveiled that phosphorylated STAT5 regulates p53 expression viaBRCA1/BRAD1-NPM1 and MDM2 in cancers. The third section identified agenetic variation, c.772-46 C>A, among 198 high risk breast cancer familiesin which BRCA1/2 mutation was found negative. Though this mutation is notcancer predisposing, its in vitro expression accelerate the turnover of NPMprotein, leading to its destabilization.

Date of Award	12 Dec 2016
Original language	English
Awarding Institution	Vrije Universiteit Brussel
Supervisor	Jacques De Grève (Promotor), Karine Breckpot (Co-promotor), Joeri Aerts (Co-promotor), Karin Vanderkerken (Jury), Christian Demanet (Jury), Kris Thielemans (Jury), Johan Swinnen (Jury), Kim De Keersmaecker (Jury) & Richard Moriggi (Jury)