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Small Molecule Intervention in a Protein Kinase C–Gli Transcription Factor Axis

Tran, UyenPhuong and Zhang, Grace C. and Eom, Ryan and Billingsley, Kelvin L. and Ondrus, Alison E. (2020) Small Molecule Intervention in a Protein Kinase C–Gli Transcription Factor Axis. ACS Chemical Biology, 15 (6). pp. 1321-1327. ISSN 1554-8929. https://resolver.caltech.edu/CaltechAUTHORS:20200602-071011767

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Abstract

Aberrations in the Hedgehog (Hh) signaling pathway are responsible for a broad range of human cancers, yet only a subset rely on the activity of the clinical target, Smoothened (Smo). Emerging cases of cancers that are insensitive to Smo-targeting drugs demand new therapeutic targets and agents for inhibition. As such, we sought to pursue a recently discovered connection between the Hedgehog pathway transcription factors, the glioma-associated oncogene homologues (Glis), and protein kinase C (PKC) isozymes. Here, we report our assessment of a structurally diverse library of PKC effectors for their influence on Gli function. Using cell lines that employ distinct mechanisms of Gli activation up- and downstream of Smo, we identify a PKC effector that acts as a nanomolar Gli antagonist downstream of Smo through a mitogen-activated protein kinase kinase (MEK)-independent mechanism. This agent provides a unique tool to illuminate crosstalk between PKC isozymes and Hh signaling and new opportunities for therapeutic intervention in Hh pathway-dependent cancers.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acschembio.0c00355DOIArticle
ORCID:
AuthorORCID
Zhang, Grace C.0000-0002-2044-9230
Billingsley, Kelvin L.0000-0001-9071-5170
Ondrus, Alison E.0000-0002-6023-3290
Alternate Title:Small Molecule Intervention in a PKC-Gli Axis
Additional Information:© 2020 American Chemical Society. Received: May 6, 2020; Accepted: June 1, 2020; Published: June 1, 2020. We thank J. K. Chen (Stanford University) for Shh-LIGHT2, Sufu-KO-LIGHT, C3H10T1/2, and TM3-Gli-Luc cells and S. X. Atwood (UC Irvine) for ASZ001 mBCC cells. We thank N. V. Patel (CSU Fullerton) for use of a GloMax luminometer. G.C.Z. was supported through a training grant (NIH GM07616) provided by the National Institutes of Health. This research was supported by start up funds granted by the College of Natural Sciences and Mathematics at California State University, Fullerton (K.L.B.), and the Division of Chemistry and Chemical Engineering at the California Institute of Technology (A.E.O.). The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
NIH Predoctoral FellowshipGM07616
California State University, FullertonUNSPECIFIED
Caltech Division of Chemistry and Chemical EngineeringUNSPECIFIED
Issue or Number:6
Record Number:CaltechAUTHORS:20200602-071011767
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200602-071011767
Official Citation:Small Molecule Intervention in a Protein Kinase C–Gli Transcription Factor Axis. UyenPhuong Tran, Grace C. Zhang, Ryan Eom, Kelvin L. Billingsley, and Alison E. Ondrus. ACS Chemical Biology 2020 15 (6), 1321-1327; DOI: 10.1021/acschembio.0c00355
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103627
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:02 Jun 2020 16:06
Last Modified:01 Jul 2020 16:28

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