RESEARCH OF NOVEL COMPONENTS OF SONIC HEDGEHOG/GLI TRANSDUCTION PATHWAY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。Sonic hedgehog(Shh)是一种分泌分子，通过促进颗粒细胞前体(GCPs)的增殖来调节小脑的出生后发育。Shh结合修补的受体并激活平滑。这触发了一系列涉及几种细胞质蛋白(FUSED、SUFU、PKA、Costal、GSK3)的事件，最终导致GLI转录因子(GLI1、GLI2和GLI3)的激活。Shh途径的解除调控与几个组织的肿瘤转化有关，包括小脑、胰腺、前列腺和皮肤。阻断Shh转导途径的化合物，如环多巴胺，在体外和体内都是肿瘤生长的抑制因子。因此，对Shh激活和抑制机制的完整了解是开发能够抑制肿瘤生长的药物的关键方面。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sonic hedgehog (Shh) is a secreted molecule that regulates the postnatal development of the cerebellum, by promoting the proliferation of granule cell precursors (GCPs). Shh binds the patched receptor and activates smoothened. This triggers a cascade of events that involves several cytoplasmic proteins (Fused, SUFU, PKA, Costal, GSK3) and culminates with the activation of the GLI trancription factors (GLI1, GLI2 and GLI3). Deregulation of the Shh pathway is linked to neoplastic transformation of several tissues, including cerebellum, pancreas, prostate and skin. Compounds that block Shh transduction pathway, such as cyclopamine, are suppressors of neoplastic growth in vitro and in vivo. Therefore, the complete knowledge of the mechanisms of activation and repression of Shh represents a key aspect to generate drugs able to suppress tumor growth.