Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human PTCH2 gene is highly similar to PTCH1, a tumour suppressor gene frequently mutated in basal cell carcinoma and several other tumour types. PTCH1 is a transmembrane protein believed to inhibit another transmembrane protein SMO (Smoothened), which mediates HH (Hedgehog) signalling. In this study, we analysed the biological properties of several PTCH2 splice variants. An mRNA form that lacked the last exon was abundantly expressed in all tissues examined, in contrast with the one that included it. Moreover, a transcript lacking exon 9, which is a part of a conserved sterol-sensing domain, was identified in intestine, prostate and cerebellum. In ovary, spleen, testis, cerebellum and skin, an mRNA lacking both exons 9 and 10 could also be observed. The different PTCH2 isoforms localized in the cytoplasm were capable of internalizing the N-terminal fragment of Sonic HH (Shh-N). Additionally, the PTCH2 gene was found to be a target of HH signalling. PTCH2 promoter regulation assays demonstrated that only one of the PTCH2 variants could inhibit the activity of SHH-N, whereas none was capable of inhibiting the activated form of SMO (SMO-M2) and this contrasts with PTCH1. Despite the fact that the PTCH2 isoforms lacked the ability to inhibit SMO-M2 activity, all PTCH2 variants as well as PTCH1, on co-transfection with Smo, were able to change Smo localization from being largely dispersed in the cytoplasm to the juxtanuclear region. Furthermore, the PTCH2 isoforms and PTCH1 co-localized in doubly transfected cells and an interaction between them was confirmed using immunoprecipitation assays. Using Ptch1-/- mouse cells, it was shown that the PTCH2 variants and PTCH1 differentially act to reconstitute not only the SHH but also the Desert HH-dependent transcriptional response. We conclude that in spite of their structural similarities, the PTCH2 isoforms have distinct functional properties when compared with PTCH1.
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PMID:Distinct roles of PTCH2 splice variants in Hedgehog signalling. 1461 84

Patched1 (PTCH1) is a human tumour suppressor that acts as an HH (Hedgehog) receptor protein and is important for embryonic patterning. PTCH1 mediates its effects through SMO (Smoothened) and represses the expression of HH target genes such as the transcription factor GLI1 (glioma 1) as well as PTCH1. Up-regulation of these genes has been observed in several cancer forms, including basal cell carcinoma, digestive track tumours and small cell lung cancer. The fact that PTCH1 down-regulates its own expression via 'negative feedback' is an important feature in HH signalling, as it keeps the balance between HH and PTCH1 activities that are essential for normal development. In the present study, we provide evidence that a novel mechanism allowing PTCH1 to maintain this balance may also exist. We show that gene activation by GLI1, the transcriptional effector of the pathway, can be down-regulated by PTCH1 without involvement of the canonical cascade of HH signalling events. Specifically, the SMO antagonist cyclopamine has no appreciable effects in blocking this PTCH1-mediated inhibition. Moreover, the negative GLI1 regulator SUFU (Suppressor of Fused) was also found to be dispensable. Additionally, deletion mapping of PTCH1 has revealed that the domains encompassed by amino acids 180-786 and 1058-1210 are of highest significance in inhibiting GLI1 gene activation. This contrasts with the importance of the PTCH1 C-terminal domain for HH signalling.
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PMID:Inhibition of GLI1 gene activation by Patched1. 1622 83

The purpose of this paper is to review the features and behaviour of the odontogenic keratocyst (OKC), now officially known as the keratocystic odontogenic tumour (KCOT); to analyze a series of histologically confirmed KCOT cases; and to review and discuss the redesignation of KCOT and the implications for treatment. Redesignation of the OKC as the KCOT by the World Health Organization (WHO) is based on the well-known aggressive behaviour of this lesion, its histology and new information regarding its genetics. Abnormal function of PTCH, a tumour suppressor gene, is noted to be involved in both nevoid basal cell carcinoma syndrome and sporadic KCOTs. Normally, PTCH forms a receptor complex with the oncogene SMO for the SHH ligand. PTCH binding to SMO inhibits growth-signal transduction. SHH binding to PTCH releases inhibition of the signal transduction pathway. If normal functioning of PTCH is lost, the proliferation-stimulating effects of SMO are permitted to predominate. A review of the literature was conducted and results were tabulated to determine whether treatment modality is related to recurrence rate. More aggressive treatment - resection or enucleation supplemented with Carnoy"s solution with or without peripheral ostectomy - results in a lower recurrence rate than enucleation alone or marsupialization. Notably, the recurrence rate after marsupialization followed by enucleation is not significantly higher than that following the so-called aggressive modalities. Our case series consists of 21 patients treated for KCOTs. Results were organized to demonstrate recurrence as it relates to size of lesion and time since treatment and incidence as it relates to patient age and location in the jaws. In our series, the average KCOT surface area measured radiographically was 14 cm<sup>2</sup>. Most lesions were within the 0-15 cm<sup>2</sup> range and lesions in this range resulted in the greatest number and proportion of recurrences. The recurrence rate of 29% in our case series was consistent with previously established data; all recurrences occurred within 2 years post-intervention. The incidence of primary lesions was highest in the age group 70-79 years; most lesions occurred in the posterior mandible. WHO"s reclassification of the OKC as the KCOT based on behaviour, histology and genetics underscores the aggressive nature of the lesion and should motivate clinicians to manage the disease in a correspondingly aggressive manner. The most effective interventions for the KCOT are either enucleation with Carnoy"s solution, or marsupialization with later cystectomy. Future treatment may involve molecular-based modalities, which may reduce or eliminate the need for aggressive surgical management.
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PMID:Keratocystic odontogenic tumour: reclassification of the odontogenic keratocyst from cyst to tumour. 1856