title: Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs.
abstract: The signal transducer and activator of transcription 1 (Stat1) functions as a tumor suppressor via immune regulatory and cell-autonomous pathways. Herein, we report a previously unidentified cell-autonomous Stat1 function, which is its ability to exhibit both antiproliferative and prosurvival properties by facilitating translation of mRNAs encoding for the cyclin-dependent kinase inhibitor p27(Kip1) and antiapoptotic proteins X-linked inhibitor of apoptosis and B-cell lymphoma xl. Translation of the select mRNAs requires the transcriptional function of Stat1, resulting in the up-regulation of the p110γ subunit of phosphoinositide 3-kinase (PI3K) class IB and increased expression of the translational repressor translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). Increased PI3Kγ signaling promotes the degradation of the eIF4A inhibitor programmed cell death protein 4, which favors the cap-independent translation of the select mRNAs under conditions of general inhibition of protein synthesis by up-regulated eIF4E-binding protein 1. As such, Stat1 inhibits cell proliferation but also renders cells increasingly resistant to antiproliferative effects of pharmacological inhibitors of PI3K and/or mammalian target of rapamycin. Stat1 also protects Ras-transformed cells from the genotoxic effects of doxorubicin in culture and immune-deficient mice. Our findings demonstrate an important role of mRNA translation in the cell-autonomous Stat1 functions, with implications in tumor growth and treatment with chemotherapeutic drugs.
authors: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada;
authors: Shuo
authors: S
authors: Wang
authors: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada; Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada; and.
authors: Christos
authors: C
authors: Patsis
authors: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada; Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec H2W 1S6, Canada antonis.koromilas@mcgill.ca.
authors: Antonis E
authors: AE
authors: Koromilas
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058544:Class Ib Phosphatidylinositol 3-Kinase; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects* / Q000502:physiology; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; C493961:Cdkn1b protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D012315:RNA Caps; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004317:Doxorubicin; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse
keywords: Stat1; eIF4E-binding protein 1; mRNA translation; phosphoinositide 3-kinase; programmed cell death protein 4