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primary topic: Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming

Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming
type: Article
abstract: Aberrations in signaling networks have long been studied for their contribution to tissue degeneration and cancer. Chemical modulation of such pathways provides an excellent opportunity to fine-tune their activity, owing to the rapid and dose-dependent effects of small molecules. The results of the presented thesis demonstrate the application of small molecules in: (i) studying one of the key pathways in cancer and development–TGFb/Smad signaling; and (ii)modulation of cellular fate towards stemness via targeting self-renewal- and pluripotency-associated signaling molecules. In the first chapter, I describe the use of newly-synthesized molecules derived from the indirubin family of natural compounds in the regulation of R-Smad signaling, with a focus on TGFb-related Smad2/3. Using a large screen encompassing cell lines of various cancerous- and non-cancerous tissue origins, I show that indirubin derivatives (IRDs) collectively, and the IRD E738 analogue specifically, interfere with TGFb/Smad signaling via a profound reduction in steady-state R-Smad levels. My analyses illustrate that this effect is not only due to reduced R-Smad gene transcription by E738, but also a result of protein degradation, demonstrating that the IRD modulates the TGFb/Smad pathway through different mechanisms. Further investigation by transient over-expression of wild-type-, truncated-, and phosphorylation-defective mutant forms of Smad2 and Smad3 reveals the significance of the "linker domain", in particular its phosphorylation status, in the small molecule's regulation of basal Smad stability. Given the role of Smad linker phosphorylation–referred to as "phospho-Smad signaling"–in the malignant switch of TGFb in some tumor types, the potential connection between E738's regulation of steady-state Smad2/3 stability and the phospho-Smad pathway is explored. Using patient-derived cholangiocarcinoma (CCA) cell lines, I show that IRD E738 inhibits oncogenic phospho-Smad isoforms (linker region s…
date: 2020
author list: authors
type: EPrint
type: DoctoralThesisEPrint
is part of: repository
has document: Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming (PDF)
has document: Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming (Other)
subject: 500 Naturwissenschaften und Mathematik
subject: 570 Biowissenschaften, Biologie
subject: 610 Medizin

Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming (PDF)
type: Document
has file: 2020_Thesis_Dabiri.pdf
has part: 2020_Thesis_Dabiri.pdf

Yasamin Dabiri
type: Person
given name: Yasamin
family name: Dabiri

Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming (Other)
type: Document
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Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming (Other)
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Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming (Other)
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Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming (Other)
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Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming (Other)
type: Document
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HTML Summary of #28984 Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming
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primary topic: Small Molecule Approaches for Targeting Signaling Networks in Cancer and Cellular Reprogramming

500 Naturwissenschaften und Mathematik
type: Concept
preferred label: 500 Natural sciences and mathematics @en

570 Biowissenschaften, Biologie
type: Concept
preferred label: 570 Life sciences @en

610 Medizin
type: Concept
preferred label: 610 Medical sciences Medicine @en