Tripartite Motif Proteins - A Protein Family Strongly Linked to Cancer

Cancer is a highly prevalent genetic disease and it is estimated that almost every second person will suffer from the disease during his or her life-time. Despite intensive research over the last 50 years, the development and progression of the disease is, in many cases, still incompletely understood. In the past few years, a distinctive family of proteins called the TRIM (tripartite motif), or RBCC (RING, B-box, coiled-coil region) protein family came into the focus of cancer research. The TRIM protein family is a very large family of proteins with more than 70 members in humans. All proteins of this family have a tripartite motif in their N-terminus consisting of a RING (really interesting new gene) domain, one or two B-boxes and a coiled-coil region. The RING domain within their N-terminal RBCC motif is in most cases functional and used by the individual TRIM proteins to polyubiquitinate target proteins followed by their degradation in 26S proteasomes. About half of the members of this large protein family are connected with the development, progression or metastasis of tumors (Figure 1). Many TRIM proteins are overexpressed or down regulated in the different cancers (Figure 1) and some TRIM proteins have even been postulated to be prognostic factors or potential therapeutic targets. Despite their widespread association with carcinogenesis, the individual TRIM proteins may differ in the way they exert their effects in cancer. Several TRIM proteins are part of chromosomal rearrangements. For example, TRIM19, also known as PML (promyelocytic leukemia), is fused to the retinoic acid receptor-α in acute promyelocytic leukemia [1] and TRIM24, TRIM27 or TRIM33 are fused to the RET (rearranged during transfection) protein in papillary thyroid carcinoma [2,3]. TRIM24 is also found fused to the fibroblast growth factor receptor 1 in the myeloproliferative syndrome or to the B-Raf protein in hepatocarcinomas [3]. Other chromosomal rearrangements that involve TRIM proteins are the fusion of TRIM4 to the MET kinase in melanomas and the fusion of TRIM46 to MUC1 (Mucin glycoprotein 1) and KRTCAP2 (keratinocyte associated protein 2) in high-grade serous ovarian cancer [4,5].