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Basal Cell and Squamous Cell Carcinomas
Published in Dongyou Liu, Tumors and Cancers, 2017
The PTCH1 gene encodes a receptor for a protein called Sonic Hedgehog (SHH), which is involved in embryonic development. When SHH binds to PTCH, it releases smoothened (SMOH), a transmembrane signalling protein, from inhibition by PTCH. SMOH in turn signals to GSK3b, which phosphorylates GLI3 (a human ortholog of the Drosophila gene cubitus interruptus), leading to subsequent activity of target genes such as WNT and NFkB genes. The development of BCC in the context of PTCH1 as well as SMOH mutations may represent uncontrolled hair follicle morphogenesis. Although p53 mutations are often observed in BCC, they appear to be secondary events that may have insignificant contribution to the tumorigenesis of BCC [5].
Hedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia
Published in Expert Review of Anticancer Therapy, 2019
Rory M. Shallis, Jan Philipp Bewersdorf, Prajwal C. Boddu, Amer M. Zeidan
The Hedgehog (HH) proteins are a collection of small molecules which participate in intercellular signaling pathways responsible for embryogenesis and maintenance of adult stem cells [1–3]. The primitive differentiation into definitive cell types is a result of cellular response to heterogeneous concentrations and gradients of HH ligands [2]. The canonical HH pathway is dependent upon the three human HH ligand homologs Sonic HH (SHH), Indian HH (IHH), and Desert HH (DHH) which recognize, bind to, and inactivate Patched-1 (PTCH-1) and Patched-2 (PTCH-2), the 12-pass transmembrane proteins which act as HH ligand receptors [4,5]. PTCH-1/2 constitutively suppresses Smoothened (SMO), a 7-pass transmembrane HH-related, G-protein-like signal transducer protein whose activation culminates in the downstream phosphorylation of the glioma (GLI) family zinc finger activating transcription factors GLI1 and GLI2 (oncogene homologs of the cubitus interruptus transcription factor) [4–6]. Thus, HH ligand inactivation of PTCH-1/2 abolishes its repression of SMO which can, in turn, activate and lead to the transport of GLI1 and GLI2 into the nucleus of target cells; this leads to the expression of target HH pathway-related genes responsible for inciting cell cycling, anti-apoptotic mechanisms, and cellular differentiation [3–5]. Conversely, the absence of HH ligand, its receptor or signaling transduction, or the alternative cleaving (and resultant full-length) of the HH-related transcription factor GLI3 assumes the role of a transcriptional repressor and halts the downstream gene transcription that was predestined by canonical HH pathway activation [7,8] (Figure 1).