Effect of the sonic hedgehog inhibitor GDC-0449 on an in vitro isogenic cellular model simulating odontogenic keratocysts.

07:00 EST 5th January 2019 | BioPortfolio

Summary of "Effect of the sonic hedgehog inhibitor GDC-0449 on an in vitro isogenic cellular model simulating odontogenic keratocysts."

Odontogenic keratocysts (OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome (NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations (at ∼80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog (SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1 cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403C>T (p.R135X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1 heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.


Journal Details

This article was published in the following journal.

Name: International journal of oral science
ISSN: 2049-3169
Pages: 4


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Medical and Biotech [MESH] Definitions

A frizzled-like, G-protein-coupled receptor that associates with PATCHED RECEPTORS to transduce signals from HEDGEHOG PROTEINS and initiate hedgehog signaling to ZINC FINGER PROTEIN GLI1. It may normally inhibit signaling in the absence of SONIC HEDGEHOG PROTEIN binding to PATCHED RECEPTOR-1.

A transcriptional activator and oncogene protein that contains two CYS2-HIS2 ZINC FINGERS. Two isoforms are expressed; both regulate the expression of specific genes during development of craniofacial features, digits, the CENTRAL NERVOUS SYSTEM; and the GASTROINTESTINAL TRACT. They also regulate SONIC HEDGEHOG PROTEIN signaling and cell proliferation.

A zinc finger transcription factor that contains five CYS2-HIS2 ZINC FINGERS and binds to the GLI consensus sequence 5'-GGGTGGTC-3'. The full-length protein functions as a transcriptional activator whereas the truncated C-terminal form functions as a transcriptional repressor of the Sonic Hedgehog (Shh) signaling pathway; a balance between these two forms is critical for limb and digit development. GLI3 also plays a critical role in the differentiation and proliferation of CHONDROCYTES.

A family of intercellular signaling proteins that play and important role in regulating the development of many TISSUES and organs. Their name derives from the observation of a hedgehog-like appearance in DROSOPHILA embryos with genetic mutations that block their action.

A potent inhibitor of the high affinity uptake system for CHOLINE. It has less effect on the low affinity uptake system. Since choline is one of the components of ACETYLCHOLINE, treatment with hemicholinium can deplete acetylcholine from cholinergic terminals. Hemicholinium 3 is commonly used as a research tool in animal and in vitro experiments.

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