Thyroid Stem Cell Speciation—a Major Role for PKC

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Abstract

Instructive signals that delineate the formation of thyroid follicles by thyrotropin (TSH) in stem cells are complex. Here, we have examined the role of protein kinase C (PKC) by using a unique Gαq/11 biased small molecule (MSq1) to develop thyroid progenitor cells. Mouse embryonic stem cells (mESCs) were differentiated into anterior endoderm cells and treated with either TSH or MSq1 in the presence or absence of PKC inhibitors. The transcriptional and translational response of key thyroid markers—sodium iodide symporter (NIS), thyroglobulin (TG), and thyrotropin receptor (TSHR) as well as potential signaling molecules—were then analyzed. The data confirmed that MSq1 is a potent Gαq/11 activator with a major increase in Gαq/11 signaling when compared to TSH. MSq1 activation resulted in an increase in thyroid-specific genes, demonstrating that enhanced PKC signaling was able to induce their expression. The specificity of the PKC signals over the protein kinase A (PKA) pathway in regulating thyroid gene expression was shown by using a specific PKC enzyme inhibitor. The data revealed that TG and NIS expression were suppressed in the presence of the PKC inhibition but, in contrast, were not influenced by PKA inhibition. This indicated that PKC activation was the dominant pathway in the inductive process for thyroid hormone production. Furthermore, by examining PKC isoforms we found that PKCξ was the predominant form in the ES cells that mediated the effects. Since PKCξ can lead to activation of transforming growth factor-β–activated kinase (pTAK1), and its downstream effector nuclear factor κB (NFκB) complex, this demonstrated the involvement of the TAK1/NFκB pathway in thyroid speciation.

Original languageEnglish
Article numberbqad067
JournalEndocrinology
Volume164
Issue number6
DOIs
StatePublished - 2023

Keywords

  • PKC
  • stem cells
  • thyroid

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