A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

By L. Poliseno, L. Salmena, Jiangwen Zhang, B. Carver, W. Haveman, P. Pandolfi. Nature, 2010

2,272 citations recorded by the source corpus.

The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory role that relies on their ability to compete for microRNA binding, independently of their protein-coding function. As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1 locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active. These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6684b2760aac99366a9f2a9bbf2b2a63331928b4

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Citations in the corpus

Long noncoding RNA in prostate, bladder, and kidney cancer. (2014, background): “Excess levels of miR-106b93-25 can be sequestered by the miRNA sponge structure formed by two lncRNAs (PTENP1-ASb and PTENP1-C) produced from the pseudogene PTENP1 highly homologous to PTEN [28,29], as well as by at least two other proteincoding RNAs [30].”
Roles for microRNAs in conferring robustness to biological processes. (2012, positive): “Recently there have been reports of endogenous transcripts that appear to act as natural miRNA decoys, called ‘‘competitive endogenous RNAs’’ (ceRNAs) (Poliseno et al., 2010; Cesana et al., 2011; Karreth et al., 2011; Sumazin et al., 2011; Tay et al., 2011).”
miRNA‐dependent gene silencing involving Ago2‐mediated cleavage of a circular antisense RNA (2011, background): “One hypothesis could be that the abundance of CDR1 NAS antisense may titrate an miRNA from acting on the CDR1 mRNA, that is a sponge model (Poliseno et al, 2010).”
Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types (2012, background): “. A role in regulating the pool of RNA binding proteins or small RNAs capable of interacting with the conventional linear RNA counterpart is another possibility”
Natural RNA circles function as efficient microRNA sponges (2013, methodology): “The specificity of the signal was tested by hybridizing parallel sections with: (1) 100-fold excess of unlabelled probe, (2) pre-treatment with RNase A (Pharmacia Biotech), (3) buffer alone, or (4) Cy5-labelled miR-449 probe.”
Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. (2012, background): “Other lncRNAs may act as decoys in the sequestration of miRNAs (Poliseno et al. 2010), transcription factors (Hung et al. 2011), or other proteins (Tripathi et al. 2010).”