Impact Of Patient-derived Suppressor Of Fused Mutations In Hedgehog Signaling

Hh gene has been found as a segment polarity gene in Drosophila.Hedgehog pathway is one of the main signaling pathway of vertebrate embryonic development.It can regulator of determine cellular growth fate and specify tissue pattern.The mutation of signaling pathway can cause dysregulation which lead to developmentaal malformations,and plays a central role in the development of a serise of cancers including basal cell carcinoma,medulloblastoma,rhabdosarcoma,pancreatic cancer and so on.In early 2012,american FDA approval Shh pathway-specific inhibitor apply to clinical Shh-basal cell carcinoma treatment,imply the center role of Shh pathway in developmental genetics.Thererfore,having a detailed understanding of the Shh signaling pathway transduction mechanisms will help us to know Shh signaling bettwer,let us to regulate it better.To understand the occurrence of cancer development and also search for new cancer treatment has very significance to the clinic.There are three Hh genes in vertebrates,there are Sonic Hedgehog,Indian Hedgehog,and Desert Hedgehog.Sonic Hedgehog pathway have pecision and complex conduction mechanisms and is most wildly studied.Patched(Ptch)and Smoothened(Smo)is two transmembrane receptors which can mediated Shh sigaling.Shh can directly binding to Ptch,lead to Smo release its activation.then,downstream target genes began to express.At the downstream of Shh pathway,Shh signaling is mediated by Gli protein family.which containing three members,they are Glil,Gli2,Gli3.Glil is an activator that only has full length,it cannot undergo the proteolytic processing event.but Gli2 and Gli3 go through a proteasome-mediated proteolytic coursing.which can disassemble them into truncated transcription repressors as Gli2R and Gli3R.Which can inhibit Shh target gene expression.To the contrary,full length Gli2 and Gli3 as a transcription activation stimulus Shh pathway downstream target genes expression.Sufu(Supressor of Fused)is at downstream of Shh sigaling pathway,and it plays a significant inhibitor role in the sigaling.Sufu usually can bind to a amino-terminal region of Gli protein which where contain highly conservered SYGH motif.To forative Sufu-Gli compound in the cytoplasm inhibit Hedgehog target genes expression.Under the condition of the existence of the Shh ligand,along with the activation of pathway,Gli proteins locate into nucleus,Shh target genes began to expression.At the same time,Sufu can not bind to Gli protein,suggesting that the ability of Sufu to anchor Gli in the cytoplasm is somehow relived.However Sufu mediated Gli protein the detail mechanism is not clear enough.In order to know the abnormal Shh sigaling,i focused my resreach on the patient-derived Suppressor of Fused(Sufu)Mutations.Sufu as a portant downstream inhibitor of Shh sigaling pathway,and mutation of Sufu the relation with cancer devlopment.The majority of medulloblastoma arise from activation of the aberrant Hedgehog sigaling pathay,the mutations contain Patched and smoothed receptor and Sufu protein.among them,Patched and smoothed receptor mutations had already reported,but Sufu is rarely described.Whole genome sequencing of tumor-normal patients with early sporadic medulloblastoma.This resulted in the discovery of mutations in Sufu,which were functionally investigated to determine whether they help drive medulloblastoma formation.Our results show that four of the Sufu mutations inappropriately activate the Hedgehog pathway,suggesting they act as driver mutations for medulloblastoma development.Indeed,all four of the activating variants were found to disrupt Sufu’s binding to Gli,leading to constitutive pathway activation.Our results from functional characterization of these mutations shed light on Sufu’s role in Hedgehog signaling,tumor progression,and present a novel way in which medulloblastoma can arise.Validation of Shh mutations provides valable information on which variants serve as drivers of suppressors of cancer progression and help tailor personalized cancer therapy for Hedgehog-driven cancers.