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  • Review Article
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TRIM proteins and cancer

Nature Reviews Cancer volume 11, pages 792–804 (2011)Cite this article

Subjects

Key Points

  • The family of tripartite motif (TRIM)-containing proteins is defined as a subfamily of the RING type E3 ubiquitin ligase family and contains more than 70 members in humans and mice. TRIM family proteins are involved in a broad range of biological processes, including transcriptional regulation, cell growth, apoptosis, development and tumorigenesis.

  • Several TRIM proteins are involved in the regulation of nuclear receptors. The promyelocytic leukaemia (PML) gene encodes TRIM19 and is involved in the t(15;17) translocation that is specific for acute promyelocytic leukaemia (APL). TRIM19 is localized in PML-nuclear bodies (PML-NBs) in the nucleus and regulates the response to various cellular stresses, DNA repair and viral infection.

  • TRIM24 (also known as TIF1α) regulates several nuclear receptors, including, retinoic acid receptor-α (RARα), the thyroid receptor and the oestrogen receptors (ERs). TRIM24 is a potent liver-specific tumour suppressor in mice and attenuates RARα-mediated transcription. TRIM28 (also known as TIF1β and KAP1) is highly expressed in many cancers and contributes to p53 inactivation.

  • TRIM proteins, including TRIM24 and TRIM22, are also involved in p53 regulation. TRIM13 overexpression causes increased expression of p53, resulting in the induction of apoptosis. TRIM29 (also known as ATDC) regulates p53 through its interaction with TIP60. TRIM29 expression correlates with a poor prognosis in gastric cancer.

  • Other TRIMs, such as TRIM32, TRIM8 and TRIM40, have been associated with specific tumorigenic pathways.

  • Further work using biochemical approaches as well as genetic knock-in and knockout experiments in mice are needed to understand the full contribution of specific TRIM proteins to tumour development and progression.

Abstract

Emerging clinical evidence shows that the deregulation of ubiquitin-mediated degradation of oncogene products or tumour suppressors is likely to be involved in the aetiology of carcinomas and leukaemias. Recent studies have indicated that some members of the tripartite motif (TRIM) proteins (one of the subfamilies of the RING type E3 ubiquitin ligases) function as important regulators for carcinogenesis. This Review focuses on TRIM proteins that are involved in tumour development and progression.

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Figure 1: Diversity of the TRIM protein family.
Figure 2: Chromosome mapping of human TRIM family genes.
Figure 3: Roles of PML in carcinogenesis.
Figure 4: Roles of TIF1 family in carcinogenesis.
Figure 5: Role of TRIM proteins in regulation of p53.
Figure 6: Oncogenic activity of TRIM32.

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Acknowledgements

The author wishes to thank all members of his laboratory for their comments and Y. Soida for help in preparing the manuscript. This work was in part supported by grants for science research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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  1. Department of Biochemistry, Institute for Animal Experimentation, and Central Institute of Isotope Science, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, 060-8638, Hokkaido, Japan

    Shigetsugu Hatakeyama

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Supplementary information S1 (table)

List of TRIM proteins: classifications, functions and related diseases. (PDF 841 kb)

Glossary

Ubiquitin

A small protein, highly conserved among eukaryotic species, that consists of 76 amino acids.

Proteasome

Protein degradative machinery that is found in the nucleus and cytoplasm. It is present in all eukaryotic organisms and also in archaebacteria.

Ubiquitin ligases

Enzymes that cause the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond in combination with an E2 ubiquitin-conjugating enzyme.

RING-finger domain

A protein structural domain of zinc finger type that contains a Cys3HisCys4 amino acid motif that binds two zinc cations. Many proteins containing a RING finger have a key role in the ubiquitylation pathway.

Ubiquitin-activating enzyme

Enzyme responsible for the first step in ubiquitin–protein isopeptide bond formation. E1 activates ubiquitin by first adenylating with ATP the carboxyl group of ubiquitin and linking a C-terminal glycine of ubiquitin to the sulphydryl side chain moiety of a cysteine of E1.

Ubiquitin-conjugating enzyme

Enzyme that possesses a core catalytic domain required for ubiquitin conjugation by transfer from E1 and forms a thioester bond with ubiquitin.

Nucleolar caps

Unique structures surrounding a central body in the nucleus. The dark nucleolar caps appear to be pressed onto the surface of the nucleolar body, and the light nucleolar caps have a convex appearance without a clear margin between them and the nucleolar body.

TRIM motif

Protein structure comprising a RING-finger domain, a B-box type 1 and/or a B-box type 2 domain, and a coiled-coil region.

Limb-girdle muscular dystrophy type 2H

A myopathy with a predominant involvement of the pelvic or shoulder girdle musculature.

Bardet–Biedl syndrome

A syndrome characterized by retinal degeneration, genito-urinary tract malformations, cognitive impairment, obesity and polydactyly.

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Hatakeyama, S. TRIM proteins and cancer. Nat Rev Cancer 11, 792–804 (2011). https://doi.org/10.1038/nrc3139

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