Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells

By Christine Mayr, David P. Bartel. Cell, 2009

1,660 citations recorded by the source corpus.

Summary In cancer cells, genetic alterations can activate proto-oncogenes, thereby contributing to tumorigenesis. However, the protein products of oncogenes are sometimes over-expressed without alteration of the proto-oncogene. Helping to explain this phenomenon, we found that when compared to similarly proliferating non-transformed cell lines, cancer cell lines often expressed substantial amounts of mRNA isoforms with shorter 3′ untranslated regions (UTRs). These shorter isoforms usually resulted from alternative cleavage and polyadenylation (APA). The APA had functional consequences, with the shorter mRNA isoforms exhibiting increased stability and typically producing ten-fold more protein, in part through the loss of microRNA-mediated repression. Moreover, expression of the shorter mRNA isoform of the proto-oncogene IGF2BP1/IMP-1 led to far more oncogenic transformation than did expression of the full-length, annotated mRNA. The high incidence of APA in cancer cells, with consequent loss of 3′UTR repressive elements, suggests a pervasive role for APA in oncogene activation without genetic alteration.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1db433a3c137e63dd476168761a54a9aa87962dc

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Citations in the corpus

Predicting effective microRNA target sites in mammalian mRNAs (2015, methodology): “To remove biases afflicting y i , y i was predicted from X (cid:1) i using partial least squares regression, as implemented in the plsr function in the ‘pls’ R package ( Mevik and Wehrens, 2007 ).”
RNA-Binding Proteins in Cancer: Old Players and New Actors. (2017, background): “Cancer cells express widespread amounts of mRNA isoforms with shorter [539_TD$DIFF] 0-UTRs [87,88].”
Analysis and design of RNA sequencing experiments for identifying isoform regulation (2010, background): “, and it would be of interest to determine whether hnRNP H1 contributes to the widespread '3′ UTR shortening' (preferential expression of upstream PASs) that occurs in cancer cell”
MicroRNA and cancer (2012, background): “Functionally, the truncated isoform of the proto-oncogene IGF2BP1was shown to increase the frequency of oncogenic transformationmore than expression of the full-length isoform (Mayr and Bartel, 2009).”
MicroRNAs in development and disease. (2011, background): “It is now realized that this phenomenon occurs on a much broader scale in cancer through selective cleavage and polyadenylation of mRNAs that leads to elimination of their miRNA-targeted sites and, thereby, higher translational output (410).”
MicroRNAs in human cancer. (2013, background): “Shortening of the 3 ¢ UTR through alternative polyadenylation can relax miRNA mediated regulation of known oncogenes, such as IGF2BP1 / IMP1 , and lead to oncogenic transformation [ 127 ] , as does use of decoy pseudogenes, as in the case of PTEN , by saturating miRNA binding sites [ 128 ] .”