S6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1

Vered Ben-Hur, Polina Denichenko, Zahava Siegfried, Avi Maimon, Adrian Krainer, Ben Davidson, Rotem Karni*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


Ribosomal S6 kinase 1 (S6K1) is a major mTOR downstream signaling molecule that regulates cell size and translation efficiency. Here, we report that short isoforms of S6K1 are overproduced in breast cancer cell lines and tumors. Overexpression of S6K1 short isoforms induces transformation of human breast epithelial cells. The long S6K1 variant (Iso-1) induced opposite effects. It inhibits Ras-induced transformation and tumor formation, while its knockdown or knockout induces transformation, suggesting that Iso-1 has a tumor-suppressor activity. Furthermore, we found that S6K1 short isoforms bind and activate mTORC1, elevating 4E-BP1 phosphorylation, cap-dependent translation, and Mcl-1 protein levels. Both a phosphorylation-defective 4E-BP1 mutant and the mTORC1 inhibitor rapamycin partially blocked the oncogenic effects of S6K1 short isoforms, suggesting that these are mediated by mTORC1 and 4E-BP1. Thus, alternative splicing of S6K1 acts as a molecular switch in breast cancer cells, elevating oncogenic isoforms that activate mTORC1.

Original languageAmerican English
Pages (from-to)103-115
Number of pages13
JournalCell Reports
Issue number1
StatePublished - 31 Jan 2013

Bibliographical note

Funding Information:
The authors wish to thank Nahum Sonenberg and Jerry Pelletier (McGill University) for 4E-BP1 mutant constructs; Orna Elroy-Stein for the bi-cistronic Cap-Renilla-IRES-firefly luciferase reporter gene construct; Mario Pende (INSERM, Paris) for the S6K1/2 DKO MEF’s; Oded Meyuhas and Ittai Ben Porath for comments on the manuscript; members of the Ben Porath lab for technical help, and members of the Karni lab for discussions. This study was supported by the US-Israel Bi-national Science Foundation (BSF) (grant no. 2009026 to R.K. and A.K.) and Israel Science Foundation (ISF) (grant no. 780/08 to R.K.). V.B.-H. and R.K. designed the experiments, V.B.-H., P.D., Z.S., and A.M. performed experiments, B.D. provided breast tumor samples, A.K. provided reagents and comments on the manuscript, and V.B.-H. and R.K. wrote the manuscript.


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