Báo cáo sinh học: Research news Agonizing.

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Báo cáo sinh học: "Research news Agonizing." Journal BioMed Central of BiologyResearch newsAgonizing HedgehogJonathan B WeitzmanPublished: 6 November 2002Journal of Biology 2002, 1:7The electronic version of this article is thecomplete one and can be found online athttp://jbiol.com/content/1/2/7© 2002 BioMed Central Ltd ISSN 1475-4924An approach using ‘chemical genetics’ has identified small-molecule agonists of the Hedgehogsignaling pathway that may lead the way to drugs for chronic degenerative diseases.It is a rare treat when a drug discovery segmentation, and it was subsequently events in a range of developing tissuesprogram teaches us something about found to control patterning of struc- (see the ‘Background’ box) [2,3].the biology of the process that it tures such as the eye and the abdominal Recently, signaling by Hh has beenattempts to modulate. The paper by cuticle. In mammals there are three hh shown to be important for patterningMaria Frank-Kamenetsky and col- homologs, called Sonic Hedgehog, of the cerebellum, where it promotesleagues in this issue of the Journal of Indian Hedgehog and Desert Hedgehog the proliferation of granule neuronBiology [1] presents a compelling (Shh, Ihh and Dhh, respectively), which precursors. A link between Hh proteinsexample of how the search for thera- have been implicated in patterning and stem-cell proliferation has raisedpeutics can provide powerful experi-mental tools and insights intofundamental biology, blurring the dis- The bottom linetinction between applied and basicresearch. By characterizing a small • Frank-Kamenetsky and colleagues designed a cell-based, high-throughputgroup of chemically similar agonists of assay to screen 140,000 compounds to find modulators of the Hedgehogthe Hedgehog signaling pathway, signaling pathway.Frank-Kamenetsky et al. have been ableto propose a new model for how the • They identified a small group of related synthetic non-peptidyl moleculesSmoothened component of the that can act as agonists of Hedgehog signals at nanomolar concentra-Hedgehog-receptor complex works, tions, having previously identified small-molecule Hedgehog antagonists.and to hint at the existence of natural-ligand agonists of the Hedgehog • A range of in vitro and in vivo assays were used to show that thesignaling pathway (see ‘The bottom agonists can be used as drugs to overcome Hedgehog-signaling defectsline’ box for a summary of their work). and to promote cell proliferation.Hedgehog history • The action of the agonist compounds is independent of the HedgehogSignaling by the Hedgehog (Hh) ligand and the inhibitory receptor Patched. Further characterizationfamily of secreted proteins plays a revealed that the agonists bind directly to the receptor Smoothened.central role in regulating cell differenti-ation and tissue patterning during • These data give new insights into the nature of Hedgehog-Smootheneddevelopment [2]. The hedgehog gene signaling and raise the possibility of analogous endogenous modulators(hh) was first identified by virtue of its of Hh signaling.role in the specification of positionalidentity during Drosophila embryonic Journal of Biology 2002, 1:77.2 Journal of Biology 2002, Volume 1, Issue 2, Article 7 Weitzman http://jbiol.com/content/1/2/7 the enticing possibility that modulating a proto-oncogene and activates signal- (Johns Hopkins University School of Hh signaling might be relevant for the ing in response to Hh ligand. The Smo Medicine, Maryland, USA). “The previ- clinical management of certain degener- protein is a seven-transmembrane ous models are not tenable,” and he ative diseas ...