A coding-independent function of gene and pseudogene mRNAs regulates tumour biology
Authors: William J Haveman
Pier Paolo Pandolfi
Laura Poliseno
Leonardo Salmena
Brett Carver
Jiangwen Zhang
Journal: Nature (2010)
Discipline: Multidisciplinary
Keywords: mRNA; microRNAs; RNAs; protein-coding; PTEN
Affiliations: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

Abstract:  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. 

Retracted: No

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 Results of the Cancer Biology Reproducibility Project are now published in eLife From the abstract: As part of the Reproducibility Project: Cancer Biology we published a Registered Report (Khan et al., 2015), that described how we intended to replicate selected experiments from the paper  A coding-independent function of gene and pseudogene mRNAs regulates tumour biology (Poliseno et al., 2010). **Here we report the results. We found PTEN depletion in the prostate cancer cell line DU145 did not detectably impact expression of the corresponding pseudogene PTENP1. Similarly, depletion of PTENP1 did not impact PTEN mRNA levels. The original study reported PTEN or PTENP1 depletion statistically reduced the corresponding pseudogene or gene (Figure 2G; Poliseno et al., 2010). PTEN and or PTENP1 depletion in DU145 cells decreased PTEN protein expression, which was similar to the original study (Figure 2H; Poliseno et al., 2010). Further, depletion of PTEN and or PTENP1 increased DU145 proliferation compared to non-targeting siRNA, which was in the same direction as the original study (Figure 2F; Poliseno et al., 2010), but not statistically significant. We found PTEN 3 UTR overexpression in DU145 cells did not impact PTENP1 expression, while the original study reported PTEN 3 UTR increased PTENP1 levels (Figure 4A; Poliseno et al., 2010). Overexpression of PTEN 3 UTR also statistically decreased DU145 proliferation compared to controls, which was similar to the findings reported in the original study (Figure 4A; Poliseno et al., 2010). Differences between the original study and this replication attempt, such as level of knockdown efficiency and cellular confluence, are factors that might have influenced the results. Finally, where possible, we report meta-analyses for each result**. ,