ArticleCell death and differentiation2013
PCAF ubiquitin ligase activity inhibits Hedgehog/Gli1 signaling in p53-dependent response to genotoxic stress.
Article in Cell death and differentiation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 93 citations in OpenAlex.
- TheiScience · 2025Article
- SMURF1 and SMURF2 directly target GLI1 for ubiquitination and proteasome-dependent degradation.Cell death discovery · 2024Article
- Daunorubicin induces GLI1‑dependent apoptosis in colorectal cancer cell lines.International journal of oncology · 2024Article
- The histone lysine acetyltransferase KAT2B inhibits cholangiocarcinoma growth: evidence for interaction with SP1 to regulate NF2-YAP signaling.Journal of experimental & clinical cancer research : CR · 2024Article
- USP5 promotes tumorigenesis by activating Hedgehog/Gli1 signaling pathway in osteosarcoma.American journal of cancer research · 2024Article
- Sonic hedgehog signaling: Alternative splicing and pathogenic role in medulloblastoma.Genes & diseases · 2023Review
- Review
- Antitumor activity and mechanism of cucurbitacin B in A549/DDP cells.Naunyn-Schmiedeberg's archives of pharmacology · 2023Article
- The post-translational modification of Fascin: impact on cell biology and its associations with inhibiting tumor metastasis.Amino acids · 2022Review
- Multiprotein GLI Transcriptional Complexes as Therapeutic Targets in Cancer.Life (Basel, Switzerland) · 2022Review
- A gene dosage-dependent effect unveils NBS1 as both a haploinsufficient tumour suppressor and an essential gene for SHH-medulloblastoma.Neuropathology and applied neurobiology · 2022Article
- Hedgehog signaling activates a mammalian heterochronic gene regulatory network controlling differentiation timing across lineages.Developmental cell · 2022Article
- The crosstalk between long non-coding RNAs and the hedgehog signaling pathway in cancer.Medical oncology (Northwood, London, England) · 2022Review
- Regulation of Hedgehog Signal Transduction by Ubiquitination and Deubiquitination.International journal of molecular sciences · 2021Review
- P300/CBP-associated factor (PCAF)-mediated acetylation of Fascin at lysine 471 inhibits its actin-bundling activity and tumor metastasis in esophageal cancer.Cancer communications (London, England) · 2021Article
- Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease.Cancers · 2021Review
- Keratin 17 regulates nuclear morphology and chromatin organization.Journal of cell science · 2020Article
- Crystal structure of GCN5 PCAF N-terminal domain reveals atypical ubiquitin ligase structure.The Journal of biological chemistry · 2020Article
- Basal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches.Biomedicines · 2020Review
- Dynamic modules of the coactivator SAGA in eukaryotic transcription.Experimental & molecular medicine · 2020Review
3 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Hedgehog (Hh) signaling regulates tissue development, and its aberrant activation is a leading cause of malignancies, including medulloblastoma (Mb). Hh-dependent tumorigenesis often occurs in synergy with other mechanisms, such as loss of p53, the master regulator of the DNA damage response. To date, little is known about mechanisms connecting DNA-damaging events to morphogen-dependent processes. Here, we show that genotoxic stress triggers a cascade of signals, culminating with inhibition of the activity of Gli1, the final transcriptional effector of Hh signaling. This inhibition is dependent on the p53-mediated elevation of the acetyltransferase p300/CBP-associated factor (PCAF). Notably, we identify PCAF as a novel E3 ubiquitin ligase of Gli1. Indeed PCAF, but not a mutant with a deletion of its ubiquitination domain, represses Hh signaling in response to DNA damage by promoting Gli1 ubiquitination and its proteasome-dependent degradation. Restoring Gli1 levels rescues the growth arrest and apoptosis effect triggered by genotoxic drugs. Consistently, DNA-damaging agents fail to inhibit Gli1 activity in the absence of either p53 or PCAF. Finally, Mb samples from p53-null mice display low levels of PCAF and upregulation of Gli1 in vivo, suggesting PCAF as potential therapeutic target in Hh-dependent tumors. Together, our data define a mechanism of inactivation of a morphogenic signaling in response to genotoxic stress and unveil a p53/PCAF/Gli1 circuitry centered on PCAF that limits Gli1-enhanced mitogenic and prosurvival response.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.