Disease relevance of SMO

• Patched (ptch)-associated preferential expression of smoothened (smoh) in human basal cell carcinoma of the skin [1].
• Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system [2].
• According to this model, the inhibition of SMO signalling is relieved following mutational inactivation of PTCH in basal-cell nevus syndrome [3].
• Furthermore, skin abnormalities similar to BCCs developed in transgenic murine skin overexpressing mutant SMO [3].
• Mutant SMO, unlike wild type, can cooperate with adenovirus E1A to transform rat embryonic fibroblast cells in culture [3].

High impact information on SMO

• Pathway activation is triggered by binding of hedgehog proteins to the multipass Patched-1 (PTCH) receptor, which in the absence of hedgehog suppresses the activity of the seven-pass membrane protein Smoothened (SMOH) [4].
• De-repression of SMOH culminates in the activation of one or more of the GLI transcription factors that regulate the transcription of downstream targets [4].
• We report here the identification of activating somatic missense mutations in the SMO gene itself in sporadic BCCs from three patients [3].
• These findings support the role of SMO as a signalling component of the SHH-receptor complex and provide direct evidence that mutated SMO can function as an oncogene in BCCs [3].
• Cyclopamine had particularly potent effects of inhibiting the growth of cell lines that expressed high levels of SMO [5].

Chemical compound and disease context of SMO

• In our study, we evaluate, for the first time, the antiproliferative and cytotoxic effects induced by a combination of selective SMO inhibitor, cyclopamine and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib on metastatic prostate cancer (PC) cells [6].
• The objective of this paper is to investigate the protein distribution of SHH and its receptor PTC, SMO and transcription factor GLI1 in various odontogenic tumors [7].
• Interestingly, the deduced amino acid sequence of Gx alpha predicts that the Gx alpha protein may be refractory to modification by pertussis toxin since the cysteine residue in the fourth position from the C terminus of pertussis toxin-sensitive G alpha is replaced by isoleucine [8].

Biological context of SMO

• Mutational analysis identified four BCCs with somatic missense mutations in SMOH affecting codon 535 (TGG==>TTG: Trp==>Leu) in three tumors and codon 199 (CGG==>TGG: Arg==>Trp) in one tumor [2].
• We demonstrate that SMO agonist Ag-1.4 mediates activation of extracellular signal-regulated kinase (Erk) phosphorylation, which is abrogated by IFNalpha in sonic hedgehog responsive C3H10T1/2 cells [9].
• Specific inhibition of hedgehog signaling in these three cell lines by smoothened (SMO) antagonist, KAAD-cyclopamine, or with Shh neutralizing antibodies decreases expression of hedgehog target genes, inhibits cell growth and results in apoptosis [10].
• We determined the methylation status and screened the gene encoding the Hedgehog receptor-associated protein Smoothened (SMO) for putative mutations [11].
• Short tandem-repeat molecular analysis at the PTCH locus and sequencing of PTCH and SMO genes is performed [12].

Anatomical context of SMO

• SHH was expressed at the top of the crypts and in a few basally located cells, while PTCH was detected in the neuroendocrine cells and SMOH at the brush border of superficial epithelium [13].
• Expression of an activated SMO mutant in keratinocytes appears to be insufficient for the development and/or maintenance of full-blown BCCs [14].
• Fas expression is low in human and murine basal cell carcinomas but is up-regulated in the presence of the smoothened (SMO) antagonist, cyclopamine, both in vitro in the mouse basal cell carcinoma cell line ASZ001 and in vivo after acute treatment of mice with basal cell carcinomas [15].
• SHH, PTC, SMO and GLI1 were detected more in the cytoplasm of the epithelial cells than in stromal cells [7].
• A number of osteoblast genes were also identified as 'roughness' genes on the basis of their similar response on SLA and TPS, compared with SMO [16].

Associations of SMO with chemical compounds

• Another transmembrane protein, smoothened (SMO), forms a complex with PTC and regulates this signaling pathway [17].
• The data are consistent with a model that directly links inflammation and DNA damage through the production of H(2)O(2) by SMO/PAOh1 [18].
• SMO/PAOh1 oxidizes spermine into spermidine, 3-aminopropanal, and H(2)O(2) [18].
• The present study has therefore examined the effects of a moderately rough (sand-blasted, acid-etched; SLA) Ti surface, a highly rough (plasma-sprayed; TPS) surface, and a smooth surface (SMO) on bone cells in vitro [16].
• Postoperative analgesia, including non-steroidal anti-inflammatory drugs, was provided using either pethidine patient-controlled epidural analgesia (group PCEA) or subarachnoid morphine 200 microg, the latter supplemented as required with patient-controlled intravenous pethidine (group SMPCIA) or oral paracetamol and codeine (group SMO) [19].

Physical interactions of SMO

• Patched (PTCH) combines with Smoothened (SMO) to form a receptor complex for SHH ligand [20].

Regulatory relationships of SMO

• Two additional cell lines both having one methylated SMO allele and expressing mutant SMO did not express GLI3 [11].
• It now appears that constitutive activation of Hedgehog signalling, by inactivating mutations in PTCH1 or activating mutations in the coreceptor SMOH, is required and possibly sufficient for basal cell carcinoma development and also contributes to the formation of a variety of other tumour types, including medulloblastoma and rhabdomyosarcoma [21].

Other interactions of SMO

• Small-molecule inhibitors for SMO or STK36 are suitable to be used for treatment of Hedgehog-dependent cancer [22].
• We noted that high levels of SHH appear almost regularly, especially in dermoids, usually accompanied by increased expression of SMO [23].
• Our results suggest that expression of wild-type SMO is required for expression of GLI3 by a mechanism that is independent of conventional Hedgehog signalling [11].
• SMOH mutations were identified in four of the 42 BCCs (10%) while two tumours demonstrated mutations in SUFUH, including one missense mutation and one silent mutation [24].
• Indian hedgehog (IHH) and its receptors patched (PTC) and smoothened (SMO) belong to the hedgehog family of signaling molecules, which are essential for a variety of patterning events during mammalian tIssue development [25].

Analytical, diagnostic and therapeutic context of SMO

• In addition, we fine-mapped the SMOH gene locus by fluorescence in situ hybridization to chromosomal band 7q32 [2].
• Odontogenic tumor tissues including 34 epithelial derived, 24 epithelial-mesenchymal derived, and 26 mesenchymal derived were examined by immunohistochemistry for SHH, PTC, SMO and GLI1 [7].
• Chromosomal localization of the human smoothened gene (SMOH) to 7q32. 3 by fluorescence in situ hybridization and radiation hybrid mapping [26].
• OBJECTIVES: To assess the knowledge of pulse oximetry of senior (SMO) and junior medical officers (JMO) in a tertiary paediatric hospital [27].
• A mathematical model was used in the development of the Sarns/3M SMO oxygenator, as presented at the 1985 ASAIO meeting [28].

References