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Translational control of cell growth and malignancy by the CPEBs

Nature Reviews Cancer volume 13, pages 283–290 (2013)Cite this article

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Abstract

The cytoplasmic polyadenylation element binding proteins (CPEBs) associate with specific sequences in mRNA 3′ untranslated regions to promote translation. They do so by inducing cytoplasmic polyadenylation, which requires specialized poly(A) polymerases. Aberrant expression of these proteins correlates with certain types of cancer, indicating that cytoplasmic RNA 3′ end processing is important in the control of growth. Several CPEB-regulated mRNAs govern cell cycle progression, regulate senescence, establish cell polarity, and promote tumorigenesis and metastasis. In this Opinion article, we discuss the emerging evidence that indicates a key role for the CPEBs in cancer biology.

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Figure 1: Model for CPEB1 regulation of polyadenylation-induced translation.
Figure 2: The CPEB and GLD family members in cancer.
Figure 3: CPEB1 control of cellular senescence.
Figure 4: CPEB1 and the control of cell polarity.

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Acknowledgements

The authors thank O. Rando for help with the bioinformatic analysis. K.N. was supported by JSPS postdoctoral fellowships for Research Abroad. Work in the authors' laboratory was supported by grants from the US National Institutes of Health.

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Authors and Affiliations

  1. Andrea D'Ambrogio and Joel D. Richter are at The Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.,

    Andrea D'Ambrogio & Joel D. Richter

  2. Department of Veterinary Medicine, Kentaro Nagaoka is at The Laboratory of Veterinary Physiology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183–8509, Japan.,

    Kentaro Nagaoka

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Supplementary information

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Glossary

Cytoplasmic polyadenylation element binding protein

(CPEB). All CPEB proteins contain two RNA recognition motifs and two zinc fingers. CPEB1 binds to the cytoplasmic polyadenylation element, a U-rich structure in mRNA 3′ untranslated regions and recruits a complex of proteins that mediate polyadenylation and translation. CPEB24 may also bind U-rich structures, but probably with different affinities from those of CPEB1.

Eukaryotic translation initiation factor 4F

(eIF4F). A protein complex composed of eIF4A, eIF4E and eIF4G. eIF4A is an RNA helicase, eIF4E binds the cap, and eIF4G, through interaction with the multisubunit initiation factor eIF3, recruits the 40S ribosomal subunit to the 5′ end of the mRNA.

Germline development 2

(GLD2). A non-canonical poly(A) polymerase that associates with CPEB1 to polyadenylate mRNAs in the cytoplasm. Independently from CPEBs, GLD2 also 3′ monoadenylates and stabilizes specific miRNAs.

GLD4

A paralogue of GLD2. In human fibroblasts, it associates with CPEB1 to polyadenylate TP53 mRNA.

m7GpppG

Also known as the cap. The structure found at the 5′ end of all nuclear-encoded eukaryotic mRNAs. It consists of a 7-methyl-guanine nucleotide connected to the mRNA via an unusual 5′ to 5′ linkage. The cap ensures mRNA stability and is essential for translation except for those messengers that use an internal ribosome entry site.

Senescence

A phenomenon by which primary cells exit the cell cycle and undergo several biochemical and morphological changes. Senescence can be induced by oncogenes, changes in substrate adhesion, alterations in oxygen tension and many other parameters; it is a mechanism of tumour suppression.

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D'Ambrogio, A., Nagaoka, K. & Richter, J. Translational control of cell growth and malignancy by the CPEBs. Nat Rev Cancer 13, 283–290 (2013). https://doi.org/10.1038/nrc3485

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