Disease relevance of SHH

• SUFU is a newly identified tumor-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway through a newly identified mechanism [1].
• Individuals with germline mutations of the SHH receptor gene PTCH are at high risk of developmental anomalies and of basal-cell carcinomas, medulloblastomas and other cancers (a pattern consistent with nevoid basal-cell carcinoma syndrome, NBCCS) [1].
• Our data demonstrate the dependence of prostate cancer on SHH-GLI function and suggest a novel therapeutic approach [2].
• In contrast, only one BCC and one PNET expressed SHH mRNA at levels detectable by reverse transcription-PCR, and no SHH gene mutations were found [3].
• In ameloblastomas, these SHH signaling molecules were expressed more intensely in peripheral columnar or cuboidal cells than in central polyhedral cells; keratinizing cells and granular cells showed no or little reactivity [4].

Psychiatry related information on SHH

• Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly [5].
• Motor neuron generation depends on two critical periods of SHH signaling: an early period during which naive neural plate cells are converted into ventralized progenitors and a late period that extends well into S phase of the final progenitor cell division, during which SHH drives the differentiation of ventralized progenitors into motor neurons [6].
• There was, however, an approximately 30% improvement in both motor disability and locomotor activity following the first administration of high dose SHH (1.0 microg) [7].
• Two families were initially ascertained because of microcephaly in combination with developmental delay and/or mental retardation and SMMCI, the latter being a frequent finding in patients with an identified SHH mutation [8].

High impact information on SHH

• Several of these mutations encode truncated proteins that are unable to export the GLI transcription factor from nucleus to cytoplasm, resulting in the activation of SHH signaling [1].
• We report here that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele [1].
• The sonic hedgehog (SHH) signaling pathway directs the embryonic development of diverse organisms and is disrupted in a variety of malignancies [1].
• BMP7 acts directly on neural cells, modifying their response to SHH so that they differentiate into rostral diencephalic ventral midline cells rather than floor plate cells [9].
• However, prechordal mesoderm also expresses BMP7 whose function is required coordinately with SHH to induce rostral diencephalic ventral midline cells [9].

Chemical compound and disease context of SHH

• 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 [10].

Biological context of SHH

• Inversely, SHH can potentiate tumor cell proliferation, suggesting that autocrine signaling may often sustain tumor growth [2].
• These results indicated a connection between alterations of PTCH/SHH genes and abnormalities of chromosome 17 [11].
• In order to delineate the phenotype of specific SHH mutations, we described the expression of the SHH gene during early human embryogenesis and investigated the phenotype of novel SHH mutations [5].
• This study confirms the genetic heterogeneity of HPE, and further demonstrates that SHH mutations are associated with a broad spectrum of cerebral midline defects [5].
• Although a number of missense mutations in SHH have been identified in patients with HPE, the functional significance of these mutations has not yet been determined [12].

Anatomical context of SHH

• SHH is implicated in stem/progenitor cell restitution of damaged gastric mucosa during chronic infection with Helicobacter pylori [13].
• These studies show that SHH is expressed in the notochord, the floorplate, the brain, the zone of polarizing activity and the gut [5].
• We suggest that SHH signaling in inflammatory diseases of the gut acts to ensure stem cell restitution of damaged mucosal epithelium [14].
• SHH mediates a number of processes in central nervous system development and is required for the normal induction of ventral cell types in the brain and spinal cord [12].
• SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature [15].

Associations of SHH with chemical compounds

• This is the first instance in humans where SHH mutations in the domain responsible for autocatalytic cleavage and cholesterol modification of the N-terminal signaling domain of the protein have been observed [16].
• The results revealed that cyclopamine, alone or at a lower concentration in combination with gefitinib, inhibited the growth of sonic hedgehog- (SHH), epidermal growth factor- (EGF) and serum-stimulated androgen-sensitive LNCaP-C33 and LNCaP-LN3 and androgen-independent LNCaP-C81, DU145 and PC3 cells [17].
• The SHH signaling pathway is an important developmental pathway, and ptc protein (PTC) is a suppressive component serving as a receptor for the secreted SHH [18].
• Immunohistochemical studies showed intact dopaminergic pathways in the mesencephalon, suggesting that midbrain dopamine neuron induction appears to require only one functioning SHH allele [19].
• Sonic hedgehog (SHH) is a secreted glycoprotein that has a major role in the developing cerebellum [20].

Physical interactions of SHH

• This repression is relieved when SHH binds to PTCH [21].
• Patched (PTCH) combines with Smoothened (SMO) to form a receptor complex for SHH ligand [22].
• Perlecan forms complexes with increasing amounts of SHH that correlate with increasing metastatic potential of the prostate cancer cell line [23].

Regulatory relationships of SHH

• However, SHH induced GLI-dependent promoter activity in normal urothelial cells [24].
• SHH regulates growth and differentiation within gastric mucosa through autocrine loop and FOXL1-mediated epithelial-mesenchymal interaction [13].
• Sonic hedgehog (SHH) is expressed throughout axial mesoderm and is required for the induction of both rostral diencephalic ventral midline cells and floor plate [9].
• FOXM1 gene is up-regulated in pancreatic cancer and basal cell carcinoma due to the transcriptional regulation by Sonic Hedgehog (SHH) pathway [25].
• Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions [23].

Other interactions of SHH

• CONCLUSION: Both SHH and DHH signaling components were detected during human fetal prostate development [26].
• They include Sonic hedgehog (SHH), ZIC2, and SIX3 [27].
• We noted that high levels of SHH appear almost regularly, especially in dermoids, usually accompanied by increased expression of SMO [28].
• We identified three novel mutations: two were missense mutations of the SHH gene (Cys183-->Phe; His140-->Pro); the third mutation was a 2-bp deletion in the zinc-finger region of the ZIC2 gene [29].
• Differential epithelial expression of SHH and FOXF1 in usual and nonspecific interstitial pneumonia [30].

Analytical, diagnostic and therapeutic context of SHH

• SHH, DHH, and GLI1 expression was also analyzed in ten snap-frozen specimens by Western blot [26].
• The supernatants from these cell cultures showed no significant SHH-signaling activity in a reporter cell-based assay [31].
• Archived healthy gut and inflammatory gut diseased tissues were analyzed by RNA in situ hybridization and immunohistochemistry to describe location and levels of SHH signaling [14].
• In addition, animal models have shown that SHH is involved in face development [32].
• In basal cell nevus syndrome (BCNS) patients, mutations of a gene, patched (ptc), which encodes a putative signal transducer of sonic hedgehog protein (SHH), were found and are thought to be one of the major causes of BCNS [18].

References