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Misactivation of Hedgehog signaling causes inherited and sporadic cancers
David R. Raleigh, Jeremy F. Reiter
David R. Raleigh, Jeremy F. Reiter
Published February 1, 2019
Citation Information: J Clin Invest. 2019;129(2):465-475. https://doi.org/10.1172/JCI120850.
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Review Series

Misactivation of Hedgehog signaling causes inherited and sporadic cancers

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Abstract

The Hedgehog pathway is critical for the development of diverse organs. Misactivation of the Hedgehog pathway can cause developmental abnormalities and cancers, including medulloblastoma, the most common pediatric brain tumor, and basal cell carcinoma, the most common cancer in the United States. Here, we review how basic, translational, and clinical studies of the Hedgehog pathway have helped reveal how cells communicate, how intercellular communication controls development, how signaling goes awry to cause cancer, and how to use targeted molecular agents to treat both inherited and sporadic cancers.

Authors

David R. Raleigh, Jeremy F. Reiter

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Figure 1

A model of ciliary Hedgehog signaling.

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A model of ciliary Hedgehog signaling.
(A) In the absence of Hedgehog li...
(A) In the absence of Hedgehog ligands such as SHH, PTCH1 localizes to the primary cilium and, through an unknown mechanism, prevents SMO from entering the cilium. GLI proteins bind SUFU, a negative regulator, and are phosphorylated by kinases, such as PKA, to generate transcriptional repressors that enter the nucleus and silence the Hedgehog transcriptional program. (B) In the presence of SHH, PTCH1 leaves the cilium, allowing SMO to accumulate at the primary cilium membrane. At the cilium, SMO inhibits the formation of GLI3 repressor and activates GLI2, which enters the nucleus to promote transcription of Hedgehog target genes. (C) Inactivating mutations in PTCH1, PTCH2, or SUFU; activating mutations in SMO (denoted here as an asterisk); or amplification of GLI2 can activate expression of Hedgehog target genes in an unregulated way, leading to cancer.
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