Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells.
Common human malignancies acquire derangements of the translation initiation complex, eIF4F, but their functional significance is unknown. Hypophosphorylated 4E-BP proteins negatively regulate eIF4F assembly by sequestering its mRNA cap binding component eIF4E, whereas hyperphosphorylation abrogates this function. We found that breast carcinoma cells harbor increases in the eIF4F constituent eIF4GI and hyperphosphorylation of 4E-BP1 which are two alterations that activate eIF4F assembly. Ectopic expression of eIF4E in human mammary epithelial cells enabled clonal expansion and anchorage-independent growth. Transfer of 4E-BP1 phosphorylation site mutants into breast carcinoma cells suppressed their tumorigenicity, whereas loss of these 4E-BP1 phosphorylation site mutants accompanied spontaneous reversion to a malignant phenotype. Thus, eIF4F activation is an essential component of the malignant phenotype in breast carcinoma.
Avdulov
Svetlana
S
Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
Li
Shunan
S
Michalek
Van
V
Burrichter
David
D
Peterson
Mark
M
Perlman
David M
DM
Manivel
J Carlos
JC
Sonenberg
Nahum
N
Yee
Douglas
D
Bitterman
Peter B
PB
Polunovsky
Vitaly A
VA
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D001665:Binding Sites; D001943:Breast Neoplasms / Q000473:pathology; D002277:Carcinoma / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000096:biosynthesis; D042361:Mammary Glands, Human / Q000473:pathology*; D009154:Mutation; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039562:Eukaryotic Initiation Factor-4F; D019394:Ki-67 Antigen; D010750:Phosphoproteins; D004247:DNA