14-3-3sigma controls mitotic translation to facilitate cytokinesis.
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, sigma, 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 14-3-3sigma promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3sigma for proteasomal degradation. Loss of 14-3-3sigma protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3sigma might have an important tumour suppressor function that becomes lost early in the process of tumour evolution. The molecular basis for the tumour suppressor function of 14-3-3sigma is unknown. Here we report a previously unknown function for 14-3-3sigma 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 14-3-3sigma, 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 14-3-3sigma-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 14-3-3sigma impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3sigma-deficient cells may progress on the path to aneuploidy and tumorigenesis.
Wilker
Erik W
EW
Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
van Vugt
Marcel A T M
MA
Artim
Steven A
SA
Huang
Paul H
PH
Petersen
Christian P
CP
Reinhardt
H Christian
HC
Feng
Yun
Y
Sharp
Phillip A
PA
Sonenberg
Nahum
N
White
Forest M
FM
Yaffe
Michael B
MB
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor / Q000172:deficiency / Q000378:metabolism*; D045744:Cell Line, Tumor; D048749:Cytokinesis; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D005092:Exonucleases / Q000172:deficiency / Q000378:metabolism*; D005095:Exoribonucleases; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008938:Mitosis; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D039642:Eukaryotic Initiation Factors; D009363:Neoplasm Proteins; D012315:RNA Caps; C031799:eIF-4B; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human