Investigating the Molecular Regulation of PDX-1 in the Generation of New Insulin-Producing β-Cells from Stem Cells/Progenitor Cells

Student thesis: Doctoral ThesisDoctor of Philosophy


Diabetes mellitus is categorized based on the dysfunction (type 2) or loss (type 1) of beta cells. Central to understanding diabetes is the transcription factor PDX-1, which is crucial for pancreas development and beta cell function in adults. Gaining insight into PDX-1's molecular regulation could aid in producing induced pluripotent stem cell-derived mature beta-cells and facilitate the transdifferentiation of various cell types into beta cells. This research explores the post-translational regulation of endogenous or overexpressed PDX-1 via proteasomal or lysosomal machinery.

Using Mass Spectrometry, ISG15 was identified as a novel PDX-1 interactor. The study then delved into the impact of ISG15 on PDX-1's stability and function across cell lines and iPSC-derived beta cells. High-throughput imaging of human tissues illuminated their association in type 2 diabetes and cancer. Key findings included the proteasomal degradation of PDX-1 in specific cell lines and human pancreatic progenitors. Also, the influence of ISG15 on PDX-1 stability varied based on its origin (overexpressed vs. endogenously induced). Increased levels of ISG15 and nuclear PDX-1 proteins were observed in PDAC, while type 2 diabetic cells had elevated ISG15 and insulin.

In summary, this study sought to uncover new PDX-1 regulatory pathways in mature and iPSCs, aiming to advance cell therapies for diabetes and shed light on PDX-1's role in type 2 diabetes and cancer. The results indicate that ISG15's effects on PDX-1 are context-dependent and may play a role in pancreatic diseases.
Date of Award1 Nov 2023
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorRocio Sancho (Supervisor), Karen Liu (Supervisor) & Nikolay N Ninov (Supervisor)

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