Circular RNAs (circRNAs) represent a class of widespread and diverse endogenous RNAs that may regulate gene expression in eukaryotes. However, the regulation and function of human circRNAs remain largely unknown. Here we generate ribosomal-depleted RNA sequencing data from six normal tissues and seven cancers, and detect at least 27,000 circRNA candidates. Many of these circRNAs are differently expressed between the normal and cancerous tissues. We further characterize one abundant circRNA derived from Exon2 of the HIPK3 gene, termed circHIPK3. The silencing of circHIPK3 but not HIPK3 mRNA significantly inhibits human cell growth. Via a luciferase screening assay, circHIPK3 is observed to sponge to 9 miRNAs with 18 potential binding sites. Specifically, we show that circHIPK3 directly binds to miR-124 and inhibits miR-124 activity. Our results provide evidence that circular RNA produced from precursor mRNA may have a regulatory role in human cells.

Exosomes, which are nanosized endocytic vesicles that are secreted by most cells, contain an abundant cargo of different RNA species that can modulate the behavior of recipient cells and may be used as circulating biomarkers for diseases. Here, we develop a web-accessible database (http://www.exoRBase.org), exoRBase, which is a repository of circular RNA (circRNA), long non-coding RNA (lncRNA) and messenger RNA (mRNA) derived from RNA-seq data analyses of human blood exosomes. Experimental validations from the published literature are also included. exoRBase features the integration and visualization of RNA expression profiles based on normalized RNA-seq data spanning both normal individuals and patients with different diseases. exoRBase aims to collect and characterize all long RNA species in human blood exosomes. The first release of exoRBase contains 58 330 circRNAs, 15 501 lncRNAs and 18 333 mRNAs. The annotation, expression level and possible original tissues are provided. exoRBase will aid researchers in identifying molecular signatures in blood exosomes and will trigger new exosomal biomarker discovery and functional implication for human diseases.

Apoptosis is critical for embryonic development, tissue homeostasis, and tumorigenesis and is determined largely by the Bcl-2 family of antiapoptotic and prosurvival regulators. Here, we report that glycogen synthase kinase 3 (GSK-3) was required for Mcl-1 degradation, and we identified a novel mechanism for proteasome-mediated Mcl-1 turnover in which GSK-3beta associates with and phosphorylates Mcl-1 at one consensus motif ((155)STDG(159)SLPS(163)T; phosphorylation sites are in italics), which will lead to the association of Mcl-1 with the E3 ligase beta-TrCP, and beta-TrCP then facilitates the ubiquitination and degradation of phosphorylated Mcl-1. A variant of Mcl-1 (Mcl-1-3A), which abolishes the phosphorylations by GSK-3beta and then cannot be ubiquitinated by beta-TrCP, is much more stable than wild-type Mcl-1 and able to block the proapoptotic function of GSK-3beta and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by beta-TrCP is an essential mechanism for GSK-3beta-induced apoptosis and contributes to GSK-3beta-mediated tumor suppression and chemosensitization.