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A novel regulatory mechanism of the oncogenic transcription factor GLI3 through toll-like receptor signaling

Gli3 mediates TLR-induced inflammation. Credit: Matissek et al.

A new research article has been published in Oncotarget on August 3, 2022, entitled, “A Novel Mechanism of Regulation of the Oncogenic Transcription Factor GLI3 by Toll-Like Receptor Signaling.”

The transcription factor GLI3 is a member of the GLI family and has been shown to be regulated by canonical hedgehog (HH) signaling via smoothened (SMO). Little is known about SMO-independent regulation of GLI3.

Hedgehog (HH) signaling is known for its role in embryonic development, cancer and inflammation. At the center of HH signaling, the 2 receptors are patched (PTCH1) and smoothed (SMO) along with GLI transcription factors. In the absence of HH ligand, PTCH1 inhibits SMO.”

In this study, researchers (Stephan J. Matissek, Mona Karbalivand, Weiguo Han, Ava Boutilier, Estefania Yzar-Garcia, Laura L. Kehoe, Devin Storm Gardner, Adam Hage, Krista Fleck, Vicki Jeffers, Ricardo Rajsbaum, and Sherine F. Elsawa ) from the University of New Hampshire and University of Texas Medical Branch identified toll-like receptor (TLR) signaling as a novel pathway that regulates GLI3 expression.

The researchers showed that GLI3 expression is induced by LPS/TLR4 in human monocyte cell lines and CD14+ cells in peripheral blood. Further analysis identified TRIF, but not MyD88, which signals as the adapter used by TLR4 to regulate GLI3. Using pharmacological and genetic tools, they identified IRF3 as the transcription factor that regulates GLI3 downstream of TRIF.

“In addition, using additional TLR ligands that signal via TRIF, such as the TLR4 ligand, MPLA and the TLR3 ligand, Poly(I:C), we confirm the role of TRIF-IRF3 in the regulation of GLI3.”

They found that IRF3 binds directly to the GLI3 promoter region and this binding was increased upon stimulation of TRIF-IRF3 with Poly(I:C). Using Irf3−/− MEFs, the researchers found that Poly(I:C) stimulation no longer induced GLI3 expression. Finally, using macrophages from mice lacking Gli3 expression in myeloid cells (M-Gli3−/−), they found that in the absence of Gli3, LPS-stimulated macrophages secrete less CCL2 and TNF-α compared to macrophages from mice. wild-type (WT) mice.

Taken together, these results identify a novel TLR-TRIF-IRF3 pathway that regulates the expression of GLI3 that regulates inflammatory cytokines and increases our understanding of the non-canonical signaling pathways involved in the regulation of GLI transcription factors.

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More information:
Stephan J. Matissek et al, A novel mechanism of regulation of the oncogenic transcription factor GLI3 by toll-like receptor signaling, Oncotarget (2022). DOI: 10.18632/oncotarget.28261

Provided by Impact Journals LLC

Quote: A novel regulatory mechanism of the oncogenic transcription factor GLI3 by toll-like receptor signaling (2022, August 9,), retrieved August 10, 2022 from https://phys.org/news/2022-08-mechanism-oncogenic-transcription-factor-gli3 .html

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