1. Center for Cancer Research, Department of Biology and
2. Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
3. Department of Biochemistry, McGill Cancer Centre, McGill University, Montreal, Quebec, H3G 1Y6, Canada

Correspondence to: Michael B. Yaffe^1,2 Correspondence and requests for materials should be addressed to M.B.Y. (Email: myaffe@mit.edu).

Abstract

14-3-3 proteins are crucial in a wide variety of cellular responses including cell cycle progression, DNA damage checkpoints and apoptosis. One particular 14-3-3 isoform, , is a p53-responsive gene, the function of which is frequently lost in human tumours, including breast and prostate cancers as a result of either hypermethylation of the 14-3-3 promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3 for proteasomal degradation^{1, 2, 3, 4, 5, 6, 7, 8, 9}. Loss of 14-3-3 protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3 might have an important tumour suppressor function that becomes lost early in the process of tumour evolution^{3, 9}. The molecular basis for the tumour suppressor function of 14-3-3 is unknown. Here we report a previously unknown function for 14-3-3 as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B in a stoichiometric manner. Cells lacking 14-3-3, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3-depleted cells can be rescued by forced expression of p58 PITSLRE or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Our findings show how aberrant mitotic translation in the absence of 14-3-3 impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3-deficient cells may progress on the path to aneuploidy and tumorigenesis.

1. Center for Cancer Research, Department of Biology and
2. Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
3. Department of Biochemistry, McGill Cancer Centre, McGill University, Montreal, Quebec, H3G 1Y6, Canada

Correspondence to: Michael B. Yaffe^1,2 Correspondence and requests for materials should be addressed to M.B.Y. (Email: myaffe@mit.edu).

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.