TRIM27 (tripartite motif containing 27)

2014-07-01   Georgia Zoumpoulidou , Sibylle Mittnacht 

UCL Cancer Institute, University College London, 72 Huntley Street, WC1E 6DD, London, UK

Identity

HGNC
LOCATION
6p22.1
LOCUSID
ALIAS
RFP,RNF76
FUSION GENES

DNA/RNA

Description

The unprocessed TRIM27 transcript spans 20.990 kb and is organised in 8 exons. Reporter construct studies suggest the presence of elements between -365 and -68 relative to the transcription start point to be sufficient to drive basal gene transcription. This promoter region is GC rich and has no typical TATA and CAAT boxes (Iwata et al., 1999).

Transcription

Alternative splicing of the human locus may generate 7 or more processed alternative transcripts. Three of these transcripts contain open reading frames and presumably give rise to protein products (Ensembl).
Transcript 1: 2969 bps (transcript ID ENST00000377199, protein encoding, protein ID ENSP00000366404);
Transcript 2: 2704 bps (transcript ID ENST00000377194, protein encoding, protein ID ENSP00000366399);
Transcript 3: 1813 bps (transcript ID ENST00000414543, protein encoding, protein ID ENSP00000400058);
Transcript 4: 7006 bps (transcript ID ENST00000481474, processed transcript without open reading frame);
Transcript 5: 687 bps (transcript ID ENST00000496091, processed transcript without open reading frame);
Transcript 6: 541 bps (transcript ID ENST00000467742, processed transcripts without open reading frame);
Transcript 7: 7006 bps (transcript ID ENST00000481474, retains intronic sequence relative to other coding transcripts, without open reading frame).

Pseudogene

There are no reported pseudogenes of TRIM27.

Proteins

Atlas Image
Schematic diagram of TRIM27 protein. The domain structure of the three TRIM27 protein isoforms (i-iii) and a ribbon diagram of the structure of TRIM27 domains which represents a high confidence model generated by Phyre2 (http://www.sbg.bio.ic.ac.uk/phyre2/html/page.cgi?id=index). NH2, Amino-terminal region; COOH, Carboxyl-terminal region.

Description

The longest isoform 1 of TRIM27 (protein ID ENSP00000366404) encodes a 513 amino acids protein with a molecular weight of 58 KDa; displaying the so-called tripartite/RBCC motif within its N-terminal region, composed of a RING type zinc finger (InterPro ID IPR001841) (aa 16-57), a B-box type zinc finger (InterPro ID001841) (aa 96-127) and coiled-coil domains (aa 132-172 and aa 282-311), and a B30.2/PRY-SPRY domain (InterPro ID IPR001870) within its C-terminal region (aa 298-492). The RING finger may be involved in mediating protein-protein interactions and may confer ubiquitin family ligase activity. TRIM27 can form homo and hetero-oligomeric assemblies mediated by the centrally located coiled-coil domain (Cao et al., 1997). Isoform 2 (protein ID ENSP00000366399) lacks the C-terminal SPRY domain. Isoform 3 (protein ID ENSP00000400058) encodes the B30.2/PRY-SPRY domain only. The diagram above is a scheme of the protein isoforms and their domains.

Expression

TRIM27 transcripts and protein is ubiquitous in day 10.5-13.5 mouse embryos. Expression is restricted in adult mice, with the highest level of expression in pachytene spermatocytes and round spermatids of differentiating sperm (Cao et al., 1996; Tezel et al., 1999). TRIM27 is also expressed in mouse spleen, thymus, cerebrum and cerebellum. TRIM27 is expressed in various human and rodent cell lines. Based on RNAseq., TRIM27 mRNA is detected widely in human tissues, with no evidence for absence. Expression levels between tissues are similar, including testes, with comparative expression rating of low to medium across tissues (Human Protein Atlas).

Localisation

The protein localizes to the nucleus, cytoplasm and in nuclear bodies (NB) associated with the nuclear matrix (Isomura et al., 1992). Nuclear export of RFP is dependent on a functional NES, which can be activated by protein kinase C (PKC) (Harbers et al., 2001). Hetero-oligomerization has been observed between TRIM27 and TRIM19 with the recruitment of TRIM27 to the promyelocytic leukaemia nuclear bodies (PMLs) (Cao et al., 1998). Furthermore, interaction with members of the protein inhibitors of activated STAT (PIAS) family targets TRIM27 to subnuclear compartments/NBs, involving TRIM27 sumoylation (Matsuura et al., 2005). Nuclear or cytoplasmic localisation depends on the cell type or tissue.

Function

A role for TRIM27 has been reported in transcriptional regulation through interaction with retinoblastoma protein (RB1) and the Mi-2b-containing histone deacetylase complex in the nucleus (Krutzfeldt et al., 2005; Shimono et al., 2005), in transcriptional repression through interaction with the enhancer of polycomb protein (EPC) (Shimono et al., 2000; Bloor et al., 2005) and MBD proteins (Fukushige et al., 2006), in the negative regulation of NF-kB and IFN-signaling pathways (Zha et al., 2006), in the positive regulation of apoptosis through activation of Jun N-terminal kinase (JNK) (Dho and Kwon, 2003) and augmentation of TNF alpha receptor activation (Zaman et al., 2013), and in cell cycle regulation (Patel and Ghiselli, 2005) suggesting that TRIM27 is involved in the control of multiple cellular processes. TRIM27 has been shown to confer E3 ubiquitin ligase activity with the enzymes UBE2D1 and UBE2D3 (Napolitano et al., 2011) and to possess SUMO E3 ligase activity (Chu and Yang, 2011). TRIM27 regulates innate immune responses by physical interaction with NOD2. So, TRIM27 mediates K48-linked ubiquitination and subsequent proteasomal degradation of NOD2 (Zurek et al., 2012). TRIM27 has a critical role in regulating PTEN phosphatase activity through ubiquitination which inhibits PTEN increasing AKT signalling (Lee et al., 2013). TRIM27 functions as an E3 ligase to ubiquitinate and inhibit PI3K-C2betas kinase activity and negatively regulates CD4 T cells (Cai et al., 2011). TRIM27 also negatively regulates IgE receptor activation and downstream signalling by the same mechanism (Srivastava et al., 2012). TRIM27 interacts with MAGE-L2 protein and ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport (Hao et al., 2013). MRTF-B/TRIM27 complex plays a role in the regulation of integrin b1 expression via Rho and miR-124 in Leading Cells (LCs) among migrating cancer cell groups following loss of intracellular adhension (Kato et al., 2014).

Homology

H. sapiens, TRIM27 tripartite motif containing 27, 513 aa.
P. troglodytes (chimpanzee), TRIM27 tripartite motif containing 27, 513 aa (XP_001140726.2).
M. mulatta, TRIM27 tripartite motif containing 27, 513 aa (XP_001094465.2).
C. lupus, TRIM27 tripartite motif containing 27, 487 aa (XP_005642504.1).
B. taurus, TRIM27 tripartite motif containing 27, 513 aa (XP_001069267.1).
M. musculus, Trim27 tripartite motif containing 27, 513 aa (NP_033080.2).
R. norvegicus, Trim27 tripartite motif containing 27, 513 aa (NP_001128446.1).
G. gallus, TRIM27 tripartite motif containing 27, 505 aa (NP_001092824.1).
With other RING finger/B box proteins.

Mutations

Atlas Image
TRIM27 mutations identified in cancer.

Germinal

No germinal mutations described for TRIM27.

Somatic

TRIM27 have been identified in cancer tissues by large scale tumour genome sequencing at low frequency (see table above). COSMIC lists 26 mutations from sequence analysis of 8960 cancers (mutation rate 0.29%). Mutation spectrum: one nonrecurrent, 8 synonymous substitutions, one nonsense mutation, 16 nonsynonymous missense substitutions mostly leading to conservative aminoacid changes. Evidence is not available at present whether these observed mutations affect function of TRIM27 or confer selective advantage to tumour cells (COSMIC).

Implicated in

Entity name
Thyroid papillary carcinoma (TPC)
Disease
A chromosomal translocation involving TRIM27/RFP is found in human thyroid papillary carcinomas. TPC is the most common cancer of the thyroid gland that usually begins as a small irregular solid lump (nodule) in the thyroid gland. Classical papillary carcinoma is characterised by the formation of papillae and a set of distinctive nuclear features (optically clear appearance, overlapping, pseudo-inclusions and nuclear grooves) (Rosai et al., 1992).
Cytogenetics
t(6;10)(p21.3;q11.2)
Hybrid gene
TRIM27-RET; deltaTRIM27-RET.
Fusion protein
Fusion of the N-terminus tripartite motif of TRIM27 with the truncated C-terminus tyrosine kinase domain of the c-ret proto-oncogene result in production of the ret transforming protein (Hasegawa et al., 1996; Saenko et al., 2003). The level of catalytic activity of the hybrid TRIM27-RET protein is higher than that of RET alone (Kato et al., 2000).
Entity name
Lung cancer
Note
TRIM27 mRNA or protein is highly expressed in human lung cancers. In a study that uses a cancer-profiling array containing tumour cRNA alongside cRNA from paired tissue, TRIM27 expression was found to be significantly increased in lung cancers versus normal tissue (Zoumpoulidou et al., 2012). TRIM27 expression is associated with poor prognosis of lung cancers with EGFR mutations suggesting that TRIM27 status might be associated with response to anticancer therapy in EGFR-mutated lung cancers (Iwakoshi et al., 2012).
Entity name
Endometrial cancer
Note
Positive TRIM27 expression in human endometrial cancer cells is correlated with poor clinical outcome in patients (Tsukamoto et al., 2009). Immunohistochemical analysis of TRIM27 expression in non-neoplastic endometrium samples as well as type I endometrial cancer in comparison to type II endometrial cancer has shown that TRIM27 positive expression was strongly correlated with serous carcinoma morphology (Tezel et al., 2012).
Entity name
Breast cancer
Note
Analysis of TRIM27 expression by Townson et al. revealed TRIM27 is expressed in breast cancer derived cell lines regardless of estrogen receptor (ER) status. However, it is not clear to what extend TRIM27 is involved in breast tumorigenesis (Townson et al., 2006). In a tissue microarray (TMA) study, TRIM27 protein expression was found in breast carcinomas but not in benign breast tissues. TRIM27 expression also correlates with ERBB2 protein expression and ERBB2 gene amplification, which is a marker for poor prognosis in breast cancer (Tezel et al., 2009). However, the biological significance of this correlation is not known.
Entity name
Ovarian cancer
Note
Immunohistochemical analysis of TRIM27 expression in epithelial ovarian cancer shows that TRIM27 expression significantly correlates with chemoresistance in ovarian cancer patients. In addition, positive TRIM27 staining was increased in recurrent ovarian cancer, correlating with a poor outcome of the patients. TRIM27 protein expression was significantly higher in platinum-resistant than in platinum-sensitive patients (Horio et al., 2012). Recombinant TRIM27 expression enhances chemoresistance of ovarian cancer cells to carboplatin and paclitaxel in culture and xenografts (Horio et al., 2012).
Entity name
Murine squamous carcinoma of the skin
Note
TRIM27 is highly expressed in chemically induced squamous cell carcinomas (SCC) in the mouse after exposure of the skin to the carcinogen 7, 12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA), as part of a two-step carcinogenesis model. Trim27 expression peaks in early mouse cancer development (Zoumpoulidou et al., 2012). Moreover, mice with TRIM27 deletion are resistant to development of chemically induced SSC (Zoumpoulidou et al., 2012).

Bibliography

Pubmed IDLast YearTitleAuthors
160071602005RFP represses transcriptional activation by bHLH transcription factors.Bloor AJ et al
221283292011Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β.Cai X et al
92471901997Involvement of the rfp tripartite motif in protein-protein interactions and subcellular distribution.Cao T et al
95707501998Ret finger protein is a normal component of PML nuclear bodies and interacts directly with PML.Cao T et al
90239831996Mouse ret finger protein (rfp) proto-oncogene is expressed at specific stages of mouse spermatogenesis.Cao T et al
209724562011SUMO E3 ligase activity of TRIM proteins.Chu Y et al
128078812003The Ret finger protein induces apoptosis via its RING finger-B box-coiled-coil motif.Dho SH et al
170494872006RET finger protein enhances MBD2- and MBD4-dependent transcriptional repression.Fukushige S et al
234528532013Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination.Hao YH et al
115917182001Intracellular localization of the Ret finger protein depends on a functional nuclear export signal and protein kinase C activation.Harbers M et al
87538101996A RING finger motif regulates transforming activity of the rfp/ret fusion gene.Hasegawa N et al
233422712012Expression of RET finger protein predicts chemoresistance in epithelial ovarian cancer.Horio M et al
14375491992RFP is a DNA binding protein associated with the nuclear matrix.Isomura T et al
225246602012RET finger protein expression is associated with prognosis in lung cancer with epidermal growth factor receptor mutations.Iwakoshi A et al
104251941999Characterization of the promoter region of the human RFP gene.Iwata Y et al
112134882000Molecular mechanism of activation and superactivation of Ret tyrosine kinases by ultraviolet light irradiation.Kato M et al
247944332014TRIM27/MRTF-B-dependent integrin β1 expression defines leading cells in cancer cell collectives.Kato T et al
158374242005Selective ablation of retinoblastoma protein function by the RET finger protein.Krützfeldt M et al
234195142013RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation.Lee JT et al
159078352005PIAS proteins are involved in the SUMO-1 modification, intracellular translocation and transcriptional repressive activity of RET finger protein.Matsuura T et al
211431882011Functional interactions between ubiquitin E2 enzymes and TRIM proteins.Napolitano LM et al
157812692005The RET finger protein interacts with the hinge region of SMC3.Patel CA et al
127879162003Novel tumorigenic rearrangement, Delta rfp/ret, in a papillary thyroid carcinoma from externally irradiated patient.Saenko V et al
161861062005Microspherule protein 1, Mi-2beta, and RET finger protein associate in the nucleolus and up-regulate ribosomal gene transcription.Shimono K et al
109761082000RET finger protein is a transcriptional repressor and interacts with enhancer of polycomb that has dual transcriptional functions.Shimono Y et al
226453152012Phosphatidylinositol-3-kinase C2β and TRIM27 function to positively and negatively regulate IgE receptor activation of mast cells.Srivastava S et al
124451332002Differential expression of RET finger protein in testicular germ cell tumors.Tezel G et al
230118232012The selective expression of ret finger protein in endometrial cancer: can RFP be a marker of serous carcinomas?Tezel GG et al
192328402009RET finger protein expression in invasive breast carcinoma: relationship between RFP and ErbB2 expression.Tezel GG et al
169453322006Novel role of the RET finger protein in estrogen receptor-mediated transcription in MCF-7 cells.Townson SM et al
196508602009Expression of Ret finger protein correlates with outcomes in endometrial cancer.Tsukamoto H et al
241449792013Ubiquitination-deubiquitination by the TRIM27-USP7 complex regulates tumor necrosis factor alpha-induced apoptosis.Zaman MM et al
163939952006The Ret finger protein inhibits signaling mediated by the noncanonical and canonical IkappaB kinase family members.Zha J et al
225562692012Role of the tripartite motif protein 27 in cancer development.Zoumpoulidou G et al
228299332012TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation.Zurek B et al

Other Information

Locus ID:

NCBI: 5987
MIM: 602165
HGNC: 9975
Ensembl: ENSG00000204713

Variants:

dbSNP: 5987
ClinVar: 5987
TCGA: ENSG00000204713
COSMIC: TRIM27

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000204713ENST00000377194P14373
ENSG00000204713ENST00000377199P14373
ENSG00000204713ENST00000377199A0A1U9X8R9
ENSG00000204713ENST00000414543H0Y551

Expression (GTEx)

0
10
20
30
40
50
60
70

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
234528532013Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination.75
198514452009High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions.51
228299332012TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation.36
163939952006The Ret finger protein inhibits signaling mediated by the noncanonical and canonical IkappaB kinase family members.30
145302592003Mi-2 beta associates with BRG1 and RET finger protein at the distinct regions with transcriptional activating and repressing abilities.29
234195142013RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation.25
161861062005Microspherule protein 1, Mi-2beta, and RET finger protein associate in the nucleolus and up-regulate ribosomal gene transcription.23
221283292011Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β.19
158374242005Selective ablation of retinoblastoma protein function by the RET finger protein.18
247944332014TRIM27/MRTF-B-dependent integrin β1 expression defines leading cells in cancer cell collectives.15

Citation

Georgia Zoumpoulidou ; Sibylle Mittnacht

TRIM27 (tripartite motif containing 27)

Atlas Genet Cytogenet Oncol Haematol. 2014-07-01

Online version: http://atlasgeneticsoncology.org/gene/42092/trim27