Sci. Signal., 6 July 2010
Cancer Decoyed from Tumorigenesis
Science Signaling, AAAS, Washington, DC 20005, USA
PTEN (phosphatase and tensin homolog deleted on chromosome 10) acts as a tumor suppressor by opposing mitogenic signaling mediated by phosphatidylinosinol 3-kinase (PI3K) and downstream effectors such as AKT. One mechanism by which PTEN abundance is regulated is through microRNAs (miRNAs), small noncoding RNAs that posttranscriptionally regulate target genes by preventing mRNA translation or decreasing mRNA stability (or both) (see Rigoutsos and Furnari). Noting that the sequence of the pseudogene PTENP1 is homologous to the coding sequence and a portion of the 3' untranslated region (UTR) of PTEN, Poliseno et al. found that the seed matches for miR-17, miR-214, miR-19, and miR-26 in the 3'UTR region of PTEN were also present in PTENP1. In DU145 prostate cancer cells, the mRNA abundance of PTEN and PTENP1 decreased with transfection of miR-19b and miR-20a and increased with treatment with antisense inhibitors of PTEN-targeting miRNAs. Overexpression of the PTENP1 3'UTR increased the mRNA and protein abundance of PTEN and, accordingly, promoted the tumor-suppressive activities of PTEN, such as decreasing the activation of AKT in response to growth factor stimulation, inhibiting cellular proliferation, and promoting anchorage-independent growth. In contrast, small interfering RNAs (siRNAs) selectively directed against PTENP1 decreased the mRNA and protein abundance of PTEN and increased cellular proliferation. In samples of normal tissue or prostate tumor, the abundance of PTENP1 correlated with that of PTEN. Furthermore, copy number losses occurred at the PTENP1 locus in sporadic colon cancer and correlated with PTEN abundance in two patient populations. Sequence analysis revealed that miRNA binding sites were conserved between other genes and their respective pseudogenes, including the proto-oncogene KRAS and its pseudogene KRAS1P. Overexpression of the 3'UTR of KRAS1P increased the mRNA and protein abundance of KRAS and promoted cellular proliferation. Thus, these results suggest that in acting as decoys for miRNA binding, pseudogenes have similar biological roles as their cognate genes and are more than just nonfunctional "junk" DNA.
L. Poliseno, L. Salmena, J. Zhang, B. Carver, W. J. Haveman, P. P. Pandolfi, A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033–1038 (2010). [PubMed]
I. Rigoutsos, F. Furnari, Decoy for microRNAs. Nature 465, 1016–1017 (2010). [PubMed]
Citation: W. Wong, Decoyed from Tumorigenesis. Sci. Signal. 3, ec202 (2010).
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