The Function And Mechanism Of PHLPP2 Regulating Expression Of FBW7 In A CeRNA Manner

The non-coding RNA is the pervasive transcription that does not encode protein-coding genes,which comprised about 70%?90%of human genome.There are two major classes of non-coding transcripts according to their size,1)Small non-coding RNAs,including miRNA,piRNA,snoRNA;2)large non-coding RNA.Non-coding RNA plays an important role in tumorigenesis,the pluripotency and immune response.In recent years,there are emerging role of other non-coding transcription such as ceRNA(competition endogeneous RNA).The hypothesis of ceRNA is based on the RNA-RNA crosstalk.As our knowledge of miRNA,many transcripts have the same miRNA binding sites;as a result the transcripts that contain the same miRNA-binding sites could communicate with and regulate each other by competing specifically for shared miRNAs,thus acting as competing endogenous RNAs and forming a network of trancriptome via miRNA.However,until now there are so few ceRNA that have been reported,new ceRNA need to be further identified.Moreover,we learned little about this type of regulation in vivo.The emergency,mechanism as well as the implications of ceRNA in vivo need to be further investigated,thus provide novel insight into the biological function of ceRNA regulation.PHLPPs are membrane-associated phosphatases,which specifically dephosphorylate AKT,MST1,and S6K and regarded as a tumor suppressor.The PHLPP family comprises three isozymes,the alternatively spliced PHLPP1?,PHLPP1? and PHLPP2.We have observed that there are difference in the miRNA binding sites and the legth of 3'UTR between PHLPP1 and PHLPP2.Meanwhile,we have observed that many homologous genes have difference in the legth and sequence between 3'UTR and 5'UTR across the transcriptome.But we are not very clear whether these differences are closely related to their biological function.In the current study,we find that PHLPP2 could regulate the stability of c-Myc via its 3'UTR.Furthermore,we identified PHLPP2 could act as a ceRNA of FBW7.FBW7 is the substrate binding component of SCF-FBW7 E3 ubiquitin ligase and involved in many biological processes,such as tumorigenesis,pluripotency and drug resistance.The function of FBW7 is tightly regulated at both transcriptional and posttranslational level.We have identified that PHLPP2 could regulate the stability of c-Myc via FBW7.NF-?B pathway may regulate the PHLPP2-FBW7 axis,thus involved in the inflammation inducing tumorigenesis.Analysis of patient gene expression data reveals that PHLPP2 and FBW7 are coordinately regulated in patient material,a vital corollary to ceRNA function.Meanwhile,we use TALEN to construct PHLPP2 polyA polyadenylation signal knockout mice and investigate the regulation in vivo.Taken together,our findings highlighted the regulation of ceRNA in vivo for the first time.Meanwhile,we have uncovered a new function of PHLPP2 in a phosphatase independent manner and identified a new regulation mechanism of FBW7.These will provide us a new vision about the regulation mechanism of FBW7,PHLPP2 and ceRNA function.