Alternate Splicing Transforms Tumor Suppressor into Tumor Promoter

Short isoforms of the signaling molecule ribosomal S6 kinase 1 (S6K1), which are produced by the process of alternative RNA splicing, have been found to be tumorigenic and overexpressed in breast cancer cell lines and tumors.

S6K1 is an important signaling molecule downstream from the mTOR complex that regulates cell size and translation efficiency. MTOR (mammalian target of rapamycin) is itself a master regulator of protein synthesis that under ordinary conditions induces cells to grow and divide. In cancer cells, the mTOR pathway is deregulated and signals tumor cells to grow, divide, undergo metastasis, and invade new, healthy tissues.

Investigators at the Hebrew University of Jerusalem (Israel) reported in the December 27, 2012, online edition of the journal Cell Reports that overexpression of S6K1 short isoforms induced transformation of human breast epithelial cells. The long S6K1 variant (Iso-1) induced opposite effects. It inhibited Ras-induced transformation and tumor formation, while its knockdown or knockout induced transformation, suggesting that Iso-1 had a tumor-suppressor activity.

Results additionally showed that S6K1 short isoforms bound and activated mTORC1, elevating 4E-BP1 (eukaryotic translation initiation factor 4E binding protein 1) phosphorylation, cap-dependent translation, and Mcl-1 (induced myeloid leukemia cell differentiation protein) levels. Both a phosphorylation-defective 4E-BP1 mutant and the mTORC1 inhibitor rapamycin partially blocked the oncogenic effects of S6K1 short isoforms.

Taken together, the results suggest that S6K1 alternative splicing acts as a switch between a tumor suppressor protein and a tumorigenic one, which is deregulated in breast cancer and modulates mTORC1 activity. Potential practical implications of these findings were recently submitted as a patent application by Yissum, the technology transfer company of the Hebrew University.

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