Projects per year
Abstract
The signalling pathways initiated by members of the transforming growth factor-β (TGFβ) family of cytokines control many metazoan cellular processes, including proliferation and differentiation, epithelial-mesenchymal transition (EMT) and apoptosis. TGFβ signalling is therefore strictly regulated to ensure appropriate context-dependent physiological responses. In an attempt to identify novel regulatory components of the TGFβ signalling pathway, we performed a pharmacological screen by using a cell line engineered to report the endogenous transcription of the TGFβ-responsive target gene PAI-1. The screen revealed that small molecule inhibitors of salt-inducible kinases (SIKs) attenuate TGFβ-mediated transcription of PAI-1 without affecting receptor-mediated SMAD phosphorylation, SMAD complex formation or nuclear translocation. We provide evidence that genetic inactivation of SIK isoforms also attenuates TGFβ-dependent transcriptional responses. Pharmacological inhibition of SIKs by using multiple small-molecule inhibitors potentiated apoptotic cell death induced by TGFβ stimulation. Our data therefore provide evidence for a novel function of SIKs in modulating TGFβ-mediated transcriptional and cellular responses.
Original language | English |
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Article number | 49 |
Number of pages | 17 |
Journal | Cell Death and Disease |
Volume | 11 |
DOIs | |
Publication status | Published - 22 Jan 2020 |
Keywords
- Apoptosis
- Cell signaling
ASJC Scopus subject areas
- Immunology
- Cellular and Molecular Neuroscience
- Cell Biology
- Cancer Research
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- 1 Finished
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Elucidation of Mechanisms that Restrict Activation of the Innate Immune System to Prevent Inflammatory and Autoimmune Diseases
Arthur, S. (Investigator) & Cohen, P. (Investigator)
1/04/18 → 31/03/23
Project: Research