A PTCH1 Homolog Transcriptionally Activated by p53 Suppresses Hedgehog Signaling

Chung, Jon; Larsen, Andrew R.; Chen, Evan; Bunz, Fred

doi:10.1074/jbc.m114.597203

Cited by 33 publications

(31 citation statements)

References 36 publications

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“…PTCHD4 suppresses sonic hedgehog (SHH) signaling in colorectal cancers (Chung et al, 2014) and SHH signaling is important in liver regeneration. SHH pathway gene expression was significantly upregulated in low p53 signature tumors by GSEA analysis.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Ally¹,

Balasundaram²,

Carlsen³

et al. 2017

Cell

1,874

1,195

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SUMMARY Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

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Section: Resultsmentioning

confidence: 99%

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Ally¹,

Balasundaram²,

Carlsen³

et al. 2017

Cell

1,874

1,195

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show abstract

“…In mammals, PTCHD1 belongs to a gene family including PTCHD2 (also known as DISP3 ), 14 testis-specific PTCHD3 15 and PTCHD4 (also known as PTCH53 ). 16 Little is known regarding the specific function of the respective encoded proteins; however, they display secondary structures similar to the Patched (PTCH1) receptor, including 12 predicted transmembrane domains and a sterol-sensing domain. 9 In vitro studies have therefore suggested a possible role of the PTCHD proteins in the regulation of sonic hedgehog (SHH) signalling pathway, as well as their likely localization at cell plasma membrane.…”

Section: Introductionmentioning

confidence: 99%

Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse

et al. 2017

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Synapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked ID and/or ASD. The structure of PTCHD1 protein is similar to the Patched (PTCH1) receptor; however, the cellular mechanisms and pathways associated with PTCHD1 in the developing brain are poorly determined. Here we show that PTCHD1 displays a C-terminal PDZ-binding motif that binds to the postsynaptic proteins PSD95 and SAP102. We also report that PTCHD1 is unable to rescue the canonical sonic hedgehog (SHH) pathway in cells depleted of PTCH1, suggesting that both proteins are involved in distinct cellular signalling pathways. We find that Ptchd1 deficiency in male mice (Ptchd1−/y) induces global changes in synaptic gene expression, affects the expression of the immediate-early expression genes Egr1 and Npas4 and finally impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity. Thus our results support that PTCHD1 deficiency induces a neurodevelopmental disorder causing excitatory synaptic dysfunction.

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“…For example, oncogenic Hh signaling can be suppressed by p53-mediated responses to DNA damage (116). Thus, p53 inactivating mutations may account for the enhancement or activation of Hh signaling in basal cells.…”

Section: Introductionmentioning

confidence: 99%

Ionizing Radiation Exposure and Basal Cell Carcinoma Pathogenesis

Athar

2016

Radiation Research

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This commentary summarizes studies showing risk of basal cell carcinoma (BCC) development in relationship to environmental, occupational and therapeutic exposure to ionizing radiation (IR). BCC, the most common type of human cancer, is driven by the aberrant activation of hedgehog (Hh) signaling. Ptch, a tumor suppressor gene of Hh signaling pathway, and Smoothened play a key role in the development of radiation-induced BCCs in animal models. Epidemiological studies provide evidence that humans exposed to radiation as observed among the long-term, large scale cohorts of atomic bomb survivors, bone marrow transplant recipients, patients with tinea capitis and radiologic workers enhances risk of BCCs. Overall, this risk is higher in Caucasians than other races. People who were exposed early in life develop more BCCs. The enhanced IR correlation with BCC and not other common cutaneous malignancies is intriguing. The mechanism underlying these observations remains undefined. Understanding interactions between radiation-induced signaling pathways and those which drive BCC development may be important in unraveling the mechanism associated with this enhanced risk. Recent studies showed that Vismodegib, a Smoothened inhibitor, is effective in treating radiation-induced BCCs in humans, suggesting that common strategies are required for the intervention of BCCs development irrespective of their etiology.

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A PTCH1 Homolog Transcriptionally Activated by p53 Suppresses Hedgehog Signaling

Cited by 33 publications

References 36 publications

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse

Ionizing Radiation Exposure and Basal Cell Carcinoma Pathogenesis

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