title: The effect of p-4E-BP1 and p-eIF4E on cell proliferation in a breast cancer model.
abstract: Cell signaling pathways and protein translation are crucial for understanding malignant transformation. 4E-BP1 and the eIF4F complex regulate cap-dependent translation. We investigated how 4E-BP1 and eIF4E phosphorylation status affects in vitro and in vivo cell proliferation in a breast cancer model. Cells from 2 breast carcinoma lines (MDA-MB 231 and MDA-MB 468) and human fibroblasts (IMR90 cells) were infected in vitro with a retrovirus carrying a wild-type 4E-BP1 or a mutant 4E-BP1 unable to hyperphosphorylate. Overexpression of the mutant 4E-BP1 induced a significant decrease in cell proliferation in IMR90 and MDA-MB 468 cells, but not in MDA-MB 231 cells. A correlation was observed between baseline-phosphorylated eIF4E (p-eIF4E) levels and sensitivity to 4E-BP1 transduction. By co-immunoprecipitation, p-eIF4E seemed to present lower affinity for 4E-BP1 than total eIF4E in MDA-MB 468 cells. After treatment with CGP57380, the MAP kinase-interacting kinase (MNK) inhibitor, downregulation of p-eIF4E levels was associated with an increase of E-cadherin and β-catenin protein expression. These results provide evidence that 4E-BP1 transduction leads to a decrease in cell proliferation, and that high p-eIF4E levels may counteract the suppressor effect of 4E-BP1. We propose that high p-4E-BP1 and p-eIF4E levels are central factors in cell signaling and reflect the oncogenic potential of cell signaling pathways in breast cancer.
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Pons
authors.forename: Vicente
authors.initials: V
authors.lastname: Peg
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Vázquez-Sánchez
authors.forename: Laura
authors.initials: L
authors.lastname: López-Vicente
authors.forename: Elisabet
authors.initials: E
authors.lastname: Argelaguet
authors.forename: Laura
authors.initials: L
authors.lastname: Coch
authors.forename: Alba
authors.initials: A
authors.lastname: Martínez
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández-Losa
authors.forename: Gemma
authors.initials: G
authors.lastname: Armengol
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramon Y Cajal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D046912:Multiprotein Complexes; D050505:Mutant Proteins; D010750:Phosphoproteins