A PTCH1 Homolog Transcriptionally Activated by p53 Suppresses Hedgehog Signaling

The p53-mediated responses to DNA damage and the Hedgehog (Hh) signaling pathway are each recurrently dysregulated in many types of human cancer. Here we describe PTCH53, a p53 target gene that is homologous to the tumor suppressor gene PTCH1 and can function as a repressor of Hh pathway activation....

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Bibliographic Details
Published in:The Journal of biological chemistry 2014-11, Vol.289 (47), p.33020-33031
Main Authors: Chung, Jon H., Larsen, Andrew R., Chen, Evan, Bunz, Fred
Format: Article
Language:English
Subjects:
Binding Sites - genetics
Cell Line, Tumor
Colorectal Neoplasms - genetics
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
DNA Damage Response
Down-Regulation
HCT116 Cells
Hedgehog Proteins - genetics
Hedgehog Proteins - metabolism
HEK293 Cells
Humans
Molecular Sequence Data
Mutation
p53
Promoter Regions, Genetic - genetics
Protein Binding
Repressor Proteins - genetics
Repressor Proteins - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA Interference
Signal Transduction
Signal Transduction - genetics
Sonic Hedgehog (SHH)
Transcriptional Activation
Tumor Cell Biology
Tumor Suppressor Gene
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:The p53-mediated responses to DNA damage and the Hedgehog (Hh) signaling pathway are each recurrently dysregulated in many types of human cancer. Here we describe PTCH53, a p53 target gene that is homologous to the tumor suppressor gene PTCH1 and can function as a repressor of Hh pathway activation. PTCH53 (previously designated PTCHD4) was highly responsive to p53 in vitro and was among a small number of genes that were consistently expressed at reduced levels in diverse TP53 mutant cell lines and human tumors. Increased expression of PTCH53 inhibited canonical Hh signaling by the G protein-coupled receptor SMO. PTCH53 thus delineates a novel, inducible pathway by which p53 can repress tumorigenic Hh signals. Background: p53 activates transcription of downstream target genes that contribute to tumor suppression. Results: The expression of PTCH53, a structural and functional homolog of PTCH1, is highly responsive to p53 in diverse cells and tissues. Conclusion: p53 can suppress canonical Hedgehog signaling via induction of PTCH53. Significance: PTCH53 is a new mediator by which p53 can suppress oncogenic Hedgehog signals.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.597203