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Study of STAT3 interactions with DNA as a target for anticancer drug discovery

Yang, Yiwen; (2021) Study of STAT3 interactions with DNA as a target for anticancer drug discovery. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

STAT3 is a transcription factor involved in the regulation of many cellular functions including proliferation, differentiation, apoptosis, migration and immune response. It has great biological value in understanding the regulation system from genes to cellular activities. STAT3, is one transcriptional activator, but is involved in multiple cellular activities in different cells. It is regarded as an important anti-cancer drug target and a biomarker for tumour growth. Understanding the detailed biological activity of STAT3 can lead to the discovery of mechanisms of regulation of different cellular functions. In this thesis, we reveal more detailed biological activities of STAT3 with three different in vitro methods: protein electrophoresis mobility shift assay (PEMSA), fluorescent polarization (FP) and fluorescent resonance energy transfer (FRET). The development of in vitro methods not only provide more direct visualization of STAT3 biological functions such as DNA binding activity, dimerization, and aggregation, but also can be easily developed into inhibitor screening methods. We successfully created and purified different STAT3 mutations that provide different STAT3 functional domains to detect detailed STAT3 domain functions. Both PEMSA assay and FP assay suggest that STAT3 binds to dsDNA without a requirement for the SH2 domain, which emphasis the possibility of STAT3 binding to dsDNA as a monomer. The PEMSA assay provided an intuitive and orthogonal method to detect STAT3 DNA binding activity while the FP assay is very highthroughput. The developed FRET assay can not only be used to study the DNA binding activity of STAT3 but also be used to detect STAT3 dimerization.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Study of STAT3 interactions with DNA as a target for anticancer drug discovery
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
URI: https://discovery.ucl.ac.uk/id/eprint/10126550
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