Background: Retinoblastoma protein (RB) is frequently targeted for proteasomal degradation by oncoproteins. Results: NRBE3 promotes RB degradation as an E3 and is transcriptionally activated by E2F1. Conclusion: NRBE3 is an E3 ubiquitin ligase for RB and regulates the cell cycle. Significance: This study identified a novel E3 ubiquitin ligase for RB that might be a potential oncoprotein in human cancers.

Serum deprivation response (SDPR) gene has been recently characterized as a gene signature marker or serving a tumor suppressor role in specific types of cancer. However, gene expression alterations of SDPR in various types of cancer and their relevance to clinical outcomes remain unclear. In the present study, SDPR expression was profiled using the Oncomine database, and SDPR downregulation was indicated in most types of cancer. In agreement with previously reported breast cancer cases, downregulation of SDPR was indicated to be significantly associated with poor survival in patients with lung cancer, glioma and sarcoma. To clarify why SDPR expression was altered in these types of cancer, both DNA methylation patterns and potential transcriptional factors of SDPR were analyzed. Altered DNA methylation levels of SDPR were found in 17/18 cancer types using MethHC. To the best of our knowledge, the present study for the first time, identified the CpG site (cg10082589) as one of the best survival methylation markers for lung adenocarcinoma, and the CpG site (cg07488576) for sarcoma using Methsurv. In addition, GATA binding protein 2 was identified as a potential transcription factor for SDPR, by integrating and analyzing both the co-expressed genes and the potential transcription factor binding sites of SDPR. In the present study, the systematic analysis of SDPR provided insight for the underlying molecular mechanisms in cancer progression, revealing novel perspectives for the clinical prognostic evaluation of lung adenocarcinoma and sarcoma.

BackgroundNIR was identified as an inhibitor of histone acetyltransferase and it represses transcriptional activation of p53. NIR is predominantly localized in the nucleolus and known as Noc2p, which is involved in the maturation of the 60S ribosomal subunit. However, how NIR functions in the nucleolus remains undetermined. In the nucleolus, a 47S ribosomal RNA precursor (pre-rRNA) is transcribed and processed to produce 18S, 5.8S and 28S rRNAs. The 18S rRNA is incorporated into the 40S ribosomal subunit, whereas the 28S and 5.8S rRNAs are incorporated into the 60S subunit. U3 small nucleolar RNA (snoRNA) directs 18S rRNA processing and U8 snoRNA mediates processing of 28S and 5.8 S rRNAs. Functional disruption of nucleolus often causes p53 activation to inhibit cell proliferation.Methodology/Principal FindingsWestern blotting showed that NIR is ubiquitously expressed in different human cell lines. Knock-down of NIR by siRNA led to inhibition of the 18S, 28S and 5.8S rRNAs evaluated by pulse-chase experiment. Pre-rRNA particles (pre-rRNPs) were fractionated from the nucleus by sucrose gradient centrifugation and analysis of the pre-RNPs components showed that NIR existed in the pre-RNPs of both the 60S and 40S subunits and co-fractionated with 32S and 12S pre-rRNAs in the 60S pre-rRNP. Protein-RNA binding experiments demonstrated that NIR is associated with the 32S pre-rRNA and U8 snoRNA. In addition, NIR bound U3 snoRNA. It is a novel finding that depletion of NIR did not affect p53 protein level but de-repressed acetylation of p53 and activated p21.ConclusionsWe provide the first evidence for a transcriptional repressor to function in the rRNA biogenesis of both the 40S and 60S subunits. Our findings also suggested that a nucleolar protein may alternatively signal to p53 by affecting the p53 modification rather than affecting p53 protein level.

No abstract