TRIM37 (tripartite motif-containing 37)

2006-06-01   Elif Ayse Erson , .M Elizabeth Petty 

Biology Department, Room: 141, Middle East Technical University, Ankara 06531, TURKEY

Identity

HGNC
LOCATION
17q22
LOCUSID
ALIAS
MUL,POB1,TEF3
FUSION GENES

DNA/RNA

Description

The TRIM37 gene spans 106.9 kb. Promoter prediction and reporter constructs suggest the presence of elements sufficient for strong basal activity between -591 and -246 relative to the translation initiation site. This region is GC rich (70%) and TATA-less.

Transcription

RIM37 has two major well-described transcript variants: TRIM37a (4488 bp, 24 exons) and TRIM37b (3588 bp, 25 exons). The cDNA and genomic DNA alignments and boundaries of exons are determined by the mRNA-to-genomic alignment tool Spidey.
Both of these variants encode an identical protein product but they use different termination codons and have different 3 untranslated sequences. In the first transcript, all of the exon 24 sequence is included, whereas in the second one, only the first 79 nucleotides of exon 24 are included followed by nucleotides of exon 25, resulting in a shorter transcript.
A third "TRIM37adel23" transcript is detected as an alternatively spliced transcript of TRIM37a. This transcript lacks exon 23 (only 117 bp) with an in frame deletion of 39 amino acids that span the evolutionarily conserved DES (aspartate-glutamate-serine) rich motif at the C-terminus.
A 4.4 kb band representing the full-length transcript of TRIM37 is detected in RNA representing brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, ovary, small intestine, colon and leukocyte samples by hybridization of several PCR-generated TRIM37 cDNA probes on a multi-tissue Northern blot. In addition, a strong signal of 3.9 kb is detected in the testis sample and a 2.6 kb band is noted in the heart sample.

In situ hybridization suggests TRIM37 expression patterns in multiple tissues during mouse and human embryogenesis. No Trim37 expression is detected up to E9.5. At E11.5, Trim37 expression is detected in cells lining the esophagus and bronchias well as the innermost cells of the optic cup adjacent to the lens. Between E12.5 and E14.5, TRIM37 is detected in different parts of ganglia and throughout liver. Intense expression is seen in gut epithelium of the midgut, stomach, esophagus and in the primitive seminiferous tubules of the developing testis at E14.5. Expression is also evident in the olfactory epithelium, epithelial lining of the bronchioles, surface ectoderm and in the developing eye lens epithelium, neural layer of the retina (but not in the optic nerve), epithelium of developing nephron, mesonephric duct, and epithelial pancreas cells. Similar to the E14.5 mouse, in 7 week old human embryos, TRIM37 expression can be detected in similar tissues including dorsal root ganglia, liver, submandibular gland and epithelial lining of the gut lumen. At 10 weeks, intense TRIM37 expression can be detected in dorsal root and trigeminal ganglia, epithelia in multiple tissues and liver. However, no TRIM37 transcript can be detected in migrating neural crest cells.

In another study, TaqMan PCR results suggest expression of TRIM37a and TRIM37b to be the highest in testis. In the brain, TRIM37a expression is 15-fold higher in adult and 20-fold higher in fetal tissue compared to the expression in heart as a reference. The lowest TRIM37a expression is detected in skeletal muscle with 0.3 and 0.8 times the expression of heart in adult and in fetal tissues.

Pseudogene

There are no reported pseudogenes of TRIM37.

Proteins

Atlas Image
  • RING (14th-58th aa) : RING-finger (Really Interesting New Gene) domain that has the cross-brace motif C-X2-C-X(9-39)-C-X(1-3)- H-X(2-3)-(N/C/H)-X2-C-X(4-48) C-X2-C. This domain is believed to be involved in mediating protein-protein interactions and also found in ubiquitin ligases. Ubiquitin ligases attach ubiquitin to target proteins during a cascade of enzymatic reactions. RING finger domains are present in a variety of proteins (e.g. Anaphase promoting complex, APC, Cbl family proteins, MDM2) implicated in cancer.
  • Zf-B Box (90th-132th aa) : B-box zinc finger. Function is largely unknown.
  • BBC (132th-254th aa) : B-Box C-terminal domain; Coiled coil region C-terminal to (some) B-Box domains.
  • MATH (278th-403th aa) : Meprin and TRAF-C homology domains. Meprins are extracellular membrane metalloproteases that can cleave biologically active peptides, growth factors, extracellular matrix proteins, etc. Math domains can form hetero- and homo-oligomeric enzymes formed from dimers of disulfide-linked dimers. TRAFs are adapter proteins that link cell surface receptors (Tumor Necrosis Factor like) to downstream kinases during activation of transcription factors and regulation of cell survival, growth and stress response in the immune and inflammatory systems.
  • In addition, a nuclear coil localization signal (NLS) and two aspartate-glutamate serine (DES) rich sequences at the C terminus are found.
  • Description

    TRIM37 has 964 amino acids with a predicted molecular weight of 108kDa. TRIM37 antibodies (against an internal (490-513) region and a C terminal (942-964) region) recognize a 130 kDa band in TRIM37 transfected COS-1 cells. TRIM37 has the following domains 5. See above.

    Expression

    In mouse embryonic tissues, Trim37 protein is detected in epithelia of ducts of developing pancreas, of the midgut and in nasal epithelium. In adult mice, Trim37 immunoreactivity is detected in central and peripheral nervous systems, including retina, enteric ganglia and the adrenal medulla and in subset of cells in the adenohypophysis (endocrine part of the pituitary gland).

    In post-pubertal testis, a stage-specific cytoplasmic Trim37 staining of germ cells can be detected. Developing sperm from type B spermatogonia to early round spermatids show immunoreactivity. In post-pubertal ovary, intense Trim37 staining is observed in maturing oocytes as well as in the granulosa cells, luteal gland, and in the epithelium of the fallopian tubes.

    Localisation

    peroxisome

    Function

    Evidence suggest that TRIM37 can auto ubiquitinate itself and therefore is believed to function as an E3 ubiquitin ligase due to its RING domain that is found in ubiquitin ligases.

    Homology

    H.sapiens , TRIM37 tripartite motif-containing 37, 964 aa.
    P.troglodytes , LOC455163 similar to POB1, 705 aa.
    C.familiaris , LOC480575 similar to tripartite motif protein 37, 962 aa.
    M.musculus , Trim37 tripartite motif protein 37, 961 aa.
    R.norvegicus , Trim37_predicted, 1075 aa.
    G.gallus , TRIM37, 983 aa.
    A.gambiae , ENSANGG00000009789, 153 aa.

    Mutations

    Germinal

    1. c.493-497 : This "Finmajor" mutation co-segregates with the Finnish ancestral MUL haplotype. Finmajor mutation is found in 98 of 100 Finnish MUL chromosomes. This mutation is a 5-bp deletion at nucleotides 493-497 of the TRIM37 cDNA. Sequencing of genomic DNA suggets an A-to-G transition altering the consensus dinucleotide sequence of the 3 splice site (AG) at position c.493_2 and this results in aberrant splicing at the next AG site. The cDNA deletion causes a frameshift and predicts a stop codon ten codons downstream. This mutation is predicted to generate a truncated 174 aa protein.

    2. c.2212delG : This "Finminor" mutation is a 1-bp deletion of a G at nucleotide c.2212 and results in a frameshift that predicts a stop codon 30 codons downstream. Finminor is found to be associated with a distinct haplotype that is found in 2 of 100 Finnish MUL chromosomes. This mutation is predicted to generate a truncated 767 aa protein. Two patients were found to be compound heterozygotes for the Finmajor and Finminor mutations.

    3. c.838delACTTT : This homozygous "Czech" mutation found in a Czech patient is a 5-bp deletion of ACTTT at nucleotides c.838_842 leading to a frameshift that results in a stop codon 55 codons downstream. This mutation is predicted to generate a truncated 334 aa protein.

    4. c.134insA : this "American" mutation is a homozygous 1-bp insertion of an A nucleotide after c.1346 in an American patient. The mutation disrupts the reading frame and results in a stop codon eight codons downstream. This mutation is predicted to generate a truncated 334 aa protein.

    5. c.855_862delTGAATTAG : This mutation detected in a Turkish family is an 8-bp deletion. On the genomic level, aberrant splicing was implicated due to a transition at the splice acceptor (AG) at position c.855 1G>A. A cryptic splice site (AG, c.860) 8-bp downstream is activated, which leads to disruption of the open reading frame (ORF) through a premature stop codon (PTC, TGA) at position c.1045 1047 that translates into a truncated protein.

    6. c.745C>T : This mutation detected in a Canadian patient is predicted to generate a truncated 249 aa protein.

    7. c.965G>T : This mutation detected in a Canadian patient is predicted to generate a missense amino acid at the 322th position (Gly322Val).

    8. c.1037_1040dupAGAT : This mutation detected in a Canadian patient is a four base-pair duplication in exon 13. It is predicted to generate a frame-shift at amino acid position 347, and truncation of the protein product after seven code-shifted amino acids.

    9. c.1411C>T : This mutation detected in Tunusian-German and Canadian patients is predicted to generate a truncated 471 aa protein.

    10. c.1314+507_1668-207del : This mutation detected in a Sicilian patient is predicted to generate a genomic deletion of 8603 bp with break points in introns 14 and 16 (c.1314+507_1668-207del), thus deleting exons 15 and 16. At the protein level this mutation leads to a frame-shift at 439th aa and truncation of the protein product after four code-shifted amino acids.

    11. c.2056C>T : This mutation detected in a Saudi-Arabian patient is predicted to generate a truncated 686 aa protein.

    Implicated in

    Entity name
    Mulibrey nanism(MUL)
    Disease
    Mutations of TRIM37 have been linked to Mulibrey nanism (MUL): muscle-liver-brain-eye nanism. MUL is a rare autosomal recessively inherited disorder that is characterized by severe growth failure with prenatal onset, constrictive pericardium, hepatomegaly and characteristic dysmorphic features. Four percent of MUL patients develop Wilms tumors.
    Oncogenesis
    The role(s) of TRIM37 has not been established for oncogenesis. Evidence suggests amplification and overexpression of TRIM37 in breast cancer cells as part of the 17q23 amplicon. The fact that 4% of the MUL patients develop Wilms tumor also suggests that this gene is involved in oncogeneisis

    Bibliography

    Pubmed IDLast YearTitleAuthors
    108888772000Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism.Avela K et al
    117740342001Overexpressed genes/ESTs and characterization of distinct amplicons on 17q23 in breast cancer cells.Erson AE et al
    163109762006Characterisation of the mulibrey nanism-associated TRIM37 gene: transcription initiation, promoter region and alternative splicing.Hämäläinen RH et al
    127547102003A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity.Jagiello P et al
    117048502001PML protein isoforms and the RBCC/TRIM motif.Jensen K et al
    165145492006Tissue expression of the mulibrey nanism-associated Trim37 protein in embryonic and adult mouse tissues.Kallijärvi J et al
    163063792005Insulin resistance syndrome in subjects with mutated RING finger protein TRIM37.Karlberg N et al
    115788802001Expression of MUL, a gene encoding a novel RBCC family ring-finger protein, in human and mouse embryogenesis.Lehesjoki AE et al
    113317602001Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer.Monni O et al
    103398151999BLAST 2 Sequences, a new tool for comparing protein and nucleotide sequences.Tatusova TA et al
    112790552001A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains.Zapata JM et al

    Other Information

    Locus ID:

    NCBI: 4591
    MIM: 605073
    HGNC: 7523
    Ensembl: ENSG00000108395

    Variants:

    dbSNP: 4591
    ClinVar: 4591
    TCGA: ENSG00000108395
    COSMIC: TRIM37

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000108395ENST00000262294O94972
    ENSG00000108395ENST00000393065O94972
    ENSG00000108395ENST00000393066O94972
    ENSG00000108395ENST00000577554J3KS72
    ENSG00000108395ENST00000580122J3QSH5
    ENSG00000108395ENST00000580973J3QSA0
    ENSG00000108395ENST00000581468J3KT90
    ENSG00000108395ENST00000583945J3KT32
    ENSG00000108395ENST00000584889J3QRK3
    ENSG00000108395ENST00000585287J3QSF6
    ENSG00000108395ENST00000625984J3KS72

    Expression (GTEx)

    0
    10
    20
    30
    40
    50
    60
    70
    80
    90
    100

    Pathways

    PathwaySourceExternal ID
    Ubiquitin mediated proteolysisKEGGko04120
    Ubiquitin mediated proteolysisKEGGhsa04120
    Immune SystemREACTOMER-HSA-168256
    Adaptive Immune SystemREACTOMER-HSA-1280218
    Class I MHC mediated antigen processing & presentationREACTOMER-HSA-983169
    Antigen processing: Ubiquitination & Proteasome degradationREACTOMER-HSA-983168

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    254700422014TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein.39
    158856862005TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase.19
    262084562015Over-expression of TRIM37 promotes cell migration and metastasis in hepatocellular carcinoma by activating Wnt/β-catenin signaling.13
    243177242014Anti-HIV-1 activity of Trim 37.11
    293243132018Knockdown of TRIM37 suppresses the proliferation, migration and invasion of glioma cells through the inactivation of PI3K/Akt signaling pathway.9
    263952612016TRIM37 promoted the growth and migration of the pancreatic cancer cells.7
    280988732017TRIM37 promotes epithelial‑mesenchymal transition in colorectal cancer.7
    119384942002The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder.6
    171009912006Wilms' tumor and novel TRIM37 mutations in an Australian patient with mulibrey nanism.6
    287245252017TRIM37, a novel E3 ligase for PEX5-mediated peroxisomal matrix protein import.6

    Citation

    Elif Ayse Erson ; .M Elizabeth Petty

    TRIM37 (tripartite motif-containing 37)

    Atlas Genet Cytogenet Oncol Haematol. 2006-06-01

    Online version: http://atlasgeneticsoncology.org/gene/42703/trim37