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A Pair of Gene Splice Isoforms Has Opposite Effects on Cancer Development

By BiotechDaily International staff writers
Posted on 21 Apr 2014
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Two distinct splice isoforms of the MAP kinase interacting serine/threonine kinase 2 (MKNK2) gene have dramatically different roles in cancer development and growth.

It is known that the protein products of MKNK2 phosphorylate the eukaryotic initiation factor 4E (eIF4E), thus playing important roles in the initiation of mRNA translation, oncogenic transformation, and malignant cell proliferation. However, it has come to light that MKNK2 is alternatively spliced with the two splicing isoforms having different last exons: Mnk2a, which contains a MAPK-binding domain, and Mnk2b, which lacks it.

Investigators at the Hebrew University of Jerusalem (Israel) reported in the April 10, 2014, online edition of the journal Cell Reports that the Mnk2a isoform was a tumor suppressor that was downregulated in human cancers. This isoform interacted with, phosphorylated, and activated p38-MAPK, leading to activation of its target genes and to p38alpha-mediated cell death. Thus, Mnk2a downregulation by alternative splicing was a tumor suppressor mechanism that was lost in some breast, lung, and colon tumors.

On the other hand, the Mnk2b isoform was found to be pro-oncogenic and did not activate p38-MAPK, while still enhancing eIF4E phosphorylation.

These results suggested that Mnk2 alternative splicing served as a switch in several cancers to downregulate a tumor suppressor isoform (Mnk2a) that activates the p38-MAPK stress pathway and to induce an isoform (Mnk2b) that does not activate this pathway and is pro-oncogenic.

"The mechanism we discovered explains how cancer cells eliminate the anticancer form of Mnk2 without changing their DNA, and how they become resistant to anticancer treatments—a problem which exists for almost every cancer treatment today," said senior author Dr. Rotem Karni, senior lecturer of biochemistry and molecular biology at the Hebrew University of Jerusalem.

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