Protein phosphatase 2A and rapamycin regulate the nuclear localization and activity of the transcription factor GLI3.
Gain-of-function alterations to the sonic hedgehog (SHH) signaling cascade have been found in a wide range of tumors. Three SHH effectors, GLI1, GLI2, and GLI3, regulate transcription of diverse genes involved in cell growth and cell proliferation. Here, we show that protein phosphatase 2A (PP2A), its regulatory subunit, alpha4, and rapamycin, an inhibitor of the mammalian target of rapamycin kinase complex 1 (mTORC1), regulate the nuclear localization and transcriptional activity of GLI3. An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. Conversely, inhibition of PP2A results in increased expression of cyclin D1. In summary, our findings reveal the existence of a hitherto unrecognized molecular cross-talk between the oncogenic SHH pathway and the tumor suppressor PP2A and suggest a novel mechanism underlying the anticancerogenic effects of rapamycin.
Charité University Hospital, Department of Dermatology and Max-Planck Institute for Molecular Genetics, Berlin, Germany.
Sybille
S
Krauss
John
J
Foerster
Rainer
R
Schneider
Susann
S
Schweiger
D048868:Adaptor Proteins, Signal Transducing; D002467:Cell Nucleus / Q000378:metabolism*; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000494:pharmacology*; D021381:Protein Transport; D011506:Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D013347:Subcellular Fractions; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D000098706:Taste Receptors, Type 2
D048868:Adaptor Proteins, Signal Transducing; D056741:Cyclin D; D016213:Cyclins; C400551:GLI1 protein, human; C082593:GLI2 protein, human; C065683:GLI3 protein, human; D053823:Hedgehog Proteins; C490467:IGBP1 protein, human; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; C485184:enhanced green fluorescent protein; D000098706:Taste Receptors, Type 2; D049452:Green Fluorescent Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D054648:Protein Phosphatase 2; D020123:Sirolimus