title: S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Vered
authors.initials: V
authors.lastname: Ben-Hur
authors.forename: Polina
authors.initials: P
authors.lastname: Denichenko
authors.forename: Zahava
authors.initials: Z
authors.lastname: Siegfried
authors.forename: Avi
authors.initials: A
authors.lastname: Maimon
authors.forename: Adrian
authors.initials: A
authors.lastname: Krainer
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.forename: Rotem
authors.initials: R
authors.lastname: Karni
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002448:Cell Adhesion; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012315:RNA Caps / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics* / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D007527:Isoenzymes; C579094:Mcl1 protein, mouse; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012315:RNA Caps; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D018631:ras Proteins