Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1

Annie Tan, Peter Bitterman, Nahum Sonenberg, Mark Peterson, Vitaly Polunovsky

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

Ectopically expressed eukaryotic translation initiation factor 4E (eIF4E) stimulates cell proliferation, suppresses apoptosis in growth factor restricted cells, and induces malignant transformation in primary rodent fibroblasts when coexpressed with protooncogene myc. We report here that eIF4E rescued rat embryo fibroblasts ectopically expressing c-Myc (REF/Myc) from genotoxic and non-genotoxic cytostatic drugs and identify cyclin D1 as a downstream effector in the antiapoptotic mechanism. In clones of REF/Myc ectopically expressing eIF4E, resistance to apoptosis paralleled steady state levels of cyclin D1. Stable expression of cyclin D1 in REF/Myc inhibited apoptosis in response to a broad range of cell cycle specific cytostatic agents. Partial loss-of-cyclin D1 function in REF/Myc ectopically expressing eIF4E (REF/Myc/4E) significantly increased chemosensitivity; either soluble antisense cyclin D1 oligomers or transfection with a dominant negative cyclin D1 mutant that prevents translocation of cyclin D-dependent kinases to the nucleus, significantly blunted the antiapoptotic effect of eIF4E. These data directly link eIF4E rescue from cytostatic drugs to cyclin D1. Since overexpression of eIF4E and cyclin D1 is observed in many aggressive forms of chemoresistant cancers, these findings provide insight into possible mechanisms responsible for this biological behavior.

Original languageEnglish (US)
Pages (from-to)1437-1447
Number of pages11
JournalOncogene
Volume19
Issue number11
DOIs
StatePublished - Mar 9 2000

Bibliographical note

Funding Information:
This work was supported by a grant from the NIH SCOR 2P50-HL50152. We are grateful to R Weinberg, P Leboulch and C Sherr for cell lines and constructs, and to I Rosenwald for valuable discussion. We thank J Murray and P Jung for technical assistance.

Keywords

  • Apoptosis
  • Cyclin D1
  • Myc
  • Translation
  • eIF4E

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