title: Rapamycin-induced G1 cell cycle arrest employs both TGF-β and Rb pathways.
abstract: The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of G1 cell cycle progression. Two key substrates of mTORC1 are ribosomal subunit S6 kinase (S6K) and eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4E-BP1). We reported previously that simultaneous knockdown of S6K and eIF4E causes a transforming growth factor-β (TGF-β)-dependent G1 cell cycle arrest in MDA-MB-231 human breast cancer cells. Rapamycin inhibits the phosphorylation of S6K at nano-molar concentrations in MDA-MB-231 cells; however, micro-molar concentrations of rapamycin are required to inhibit phosphorylation of 4E-BP1 - the phosphorylation of which liberates eIF4E to initiate translation. Micro-molar doses of rapamycin are required for complete G1 cell cycle arrest - indicating that 4E-BP1 is a critical target of mTOR for promoting cell cycle progression. Data are provided demonstrating that G1 cell cycle arrest induced by rapamycin is due to up-regulation of TGF-β signaling and down-regulation of Rb phosphorylation via phosphorylation of the mTORC1 substrates S6K and 4E-BP1 respectively. These findings enhance the current understanding of the cytostatic effects of mTORC1 suppression with therapeutic implications.
authors: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA.
authors: Amrita
authors: A
authors: Chatterjee
authors: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA.
authors: Suman
authors: S
authors: Mukhopadhyay
authors: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA.
authors: Kaity
authors: K
authors: Tung
authors: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA.
authors: Deven
authors: D
authors: Patel
authors: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA. Electronic address: foster@genectr.hunter.cuny.edu.
authors: David A
authors: DA
authors: Foster
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; C530104:CCND1 protein, human; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D020123:Sirolimus
keywords: Rapamycin; Rb; TGF-β; eIF4E; mTOR