title: Inhibition of GLI1 gene activation by Patched1.
abstract: 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.
authors.affiliation: Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden. fahimeh.rahnama@cnt.ki.se
authors.forename: Fahimeh
authors.initials: F
authors.lastname: Rahnama
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimokawa
authors.forename: Matthias
authors.initials: M
authors.lastname: Lauth
authors.forename: Csaba
authors.initials: C
authors.lastname: Finta
authors.forename: Priit
authors.initials: P
authors.lastname: Kogerman
authors.forename: Stephan
authors.initials: S
authors.lastname: Teglund
authors.forename: Rune
authors.initials: R
authors.lastname: Toftgård
authors.forename: Peter G
authors.initials: PG
authors.lastname: Zaphiropoulos
mesh_terms: D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002454:Cell Differentiation; D002460:Cell Line; D002522:Chlorocebus aethiops; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D000071676:Zinc Finger Protein GLI1
chemical_list: D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1