Genetic mutation, chromosomal rearrangement and copy number amplification are common mechanisms responsible for generating gain-of-function, cancer-causing alterations. Here we report a new mechanism by which premature cleavage and polyadenylation (pPA) of RNA can produce an oncogenic protein. We identify a pPA event at a cryptic intronic poly(A) signal in MAGI3, occurring in the absence of local exonic and intronic mutations. The altered mRNA isoform, called MAGI3pPA, produces a truncated protein that acts in a dominant-negative manner to prevent full-length MAGI3 from interacting with the YAP oncoprotein, thereby relieving YAP inhibition and promoting malignant transformation of human mammary epithelial cells. We additionally find evidence for recurrent expression of MAGI3pPA in primary human breast tumors but not in tumor-adjacent normal tissues. Our results provide an example of how pPA contributes to cancer by generating a truncated mRNA isoform that encodes an oncogenic, gain-of-function protein.
Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to the animal protocol approved by the Tufts University Institutional Animal Care and Use Committee. The approval number for animal research is A-3775-01.
Human subjects: Disease-free human breast tissue was obtained in compliance with the laws and institutional guidelines as approved by the Tufts Medical Center Institutional Review Board Committee. The approval number for human subject research is 00004517. The tissue was obtained from patients undergoing elective reduction mammoplasty. De-identified breast tissue was utilized for this study, and for this reason informed consent was not required.
- Jonathan A Cooper, Fred Hutchinson Cancer Research Center, United States
© 2016, Ni & Kuperwasser
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