TRIM28

TRIM28
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1FP0, 2RO1, 2YVR
Identifiers
Aliases	TRIM28, KAP1, PPP1R157, RNF96, TF1B, TIF1B, tripartite motif containing 28, TIF1beta
External IDs	OMIM: 601742; MGI: 109274; HomoloGene: 21175; GeneCards: TRIM28; OMA:TRIM28 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.43 Start 58,544,064 bp[1] End 58,550,722 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 A1 Start 12,733,041 bp[2] End 12,764,962 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ganglionic eminence stromal cell of endometrium right uterine tube right lobe of thyroid gland left uterine tube fundus body of pancreas left lobe of thyroid gland prostate body of stomach Top expressed in spermatocyte spermatid internal carotid artery somite morula hand abdominal wall external carotid artery ganglionic eminence maxillary prominence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein kinase activity Krueppel-associated box domain binding chromo shadow domain binding transcription corepressor activity promoter-specific chromatin binding transcription coactivator activity metal ion binding ubiquitin-protein transferase activity protein binding ubiquitin protein ligase binding DNA-binding transcription factor activity sequence-specific DNA binding DNA binding chromatin binding zinc ion binding RNA binding transferase activity SUMO transferase activity Cellular component intracellular anatomical structure chromatin RNA polymerase II transcription regulator complex nucleus nucleoplasm Biological process regulation of transcription, DNA-templated positive regulation of DNA methylation-dependent heterochromatin assembly convergent extension involved in axis elongation embryonic placenta morphogenesis positive regulation of DNA repair in utero embryonic development negative regulation of transcription by RNA polymerase II transcription, DNA-templated negative regulation of DNA demethylation protein phosphorylation protein complex oligomerization protein autophosphorylation DNA methylation involved in embryo development Ras protein signal transduction transcription initiation from RNA polymerase II promoter DNA repair embryo implantation positive regulation of transcription by RNA polymerase II regulation of genetic imprinting protein sumoylation epithelial to mesenchymal transition protein ubiquitination negative regulation of transcription, DNA-templated positive regulation of transcription, DNA-templated positive regulation of DNA binding innate immune response negative regulation of single stranded viral RNA replication via double stranded DNA intermediate chromatin organization viral process positive regulation of protein import into nucleus Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10155 21849 Ensembl ENSG00000130726 ENSMUSG00000005566 UniProt Q13263 Q62318 RefSeq (mRNA) NM_005762 NM_011588 RefSeq (protein) NP_005753 NP_035718 Location (UCSC) Chr 19: 58.54 – 58.55 Mb Chr 7: 12.73 – 12.76 Mb PubMed search [3] [4]
Wikidata
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Tripartite motif-containing 28 (TRIM28), also known as transcriptional intermediary factor 1β (TIF1β) and KAP1 (KRAB-associated protein-1), is a protein that in humans is encoded by the TRIM28 gene.^[5][6]

Function

The protein encoded by this gene mediates transcriptional control by interaction with the Krüppel-associated box repression domain found in many transcription factors. The protein localizes to the nucleus and is thought to associate with specific chromatin regions. The protein is a member of the tripartite motif family. This tripartite motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region.^[7]

KAP1 is a ubiquitously expressed protein involved in many critical functions including: transcriptional regulation, cellular differentiation and proliferation, DNA damage repair, viral suppression, and apoptosis. Its functionality is dependent upon post-translational modifications. Sumoylated TRIM28 can assemble epigenetic machinery for gene silencing, while phosphorylated TRIM28 is involved in DNA repair.^[8]

Cellular differentiation and proliferation

Studies have shown that deletion of KAP1 in mice before gastrulation results in death (implicating it as a necessary protein for proliferation) while deletion in adult mice results in increased anxiety and stress-induced alterations in learning and memory. KAP1 has been shown to participate in the maintenance of pluripotency of embryonic stem cells and to promote and inhibit cellular differentiation of adult cell lines. Increased levels of KAP1 have been found in liver, gastric, breast, lung, and prostate cancers as well, indicating that it may play an important role in tumor cell proliferation (possibly by inhibiting apoptosis).^[8]

Transcriptional regulation

KAP1 can regulate genomic transcription through a variety of mechanisms, many of which remain somewhat unclear. Studies have shown that KAP1 can repress transcription by binding directly to the genome (which can be sufficient in and of itself) or through the induction of heterochromatin formation via the Mi2α-SETB1-HP1 macromolecular complex.^[9][10] KAP1 can also interact with histone methyltransferases and deacetylases via the C-terminal PHD and Bromodomain to control transcription epigenetically.^[8]

DNA damage repair response

It has been shown that ATM phosphorylates KAP1 upon the discovery of damaged or broken DNA. Phosphorylated KAP1, along with many other DNA damage proteins, rapidly migrate to the site of the DNA damage. Its exact involvement in this pathway is somewhat unclear, but it has been implicated in triggering cell arrest, allowing for the damaged DNA to be repaired.^[8]

Apoptosis

KAP1 forms a complex with MDM2 (a ubiquitin E3 ligase) that binds to p53. The complex marks the bound p53 for degradation. p53 is a known precursor of apoptosis that facilitates the synthesis of proteins necessary for cell death so its degradation results in apoptosis inhibition.^[8]

Clinical significance

Role in the establishment of viral latency

KAP1 facilitates the establishment of viral latency in certain cell types for Human Cytomegalovirus (HCMV) and other endogenous retroviruses^[8][9] . KAP1 acts as a transcriptional corepressor of the viral genome. The protein binds to the histones of the viral chromatin and then recruits Mi2α and SETB1. SETB1 is a histone methyltransferase that recruits HP1, thus inducing heterochromatin formation. This heterochromatin formation prevents the transcription of the viral genome. mTOR has been implicated in the phosphorylation of KAP1 resulting in a switch from latency to the lytic cycle.^[9]

Manipulations and potential for future treatment

Ataxia telangiectasia mutated (ATM) is a kinase that (similar to mTOR) can phosphorylate KAP1 resulting in the switch from viral latency to the lytic cycle. Chloroquine (an ATM) activator has been shown to result in increases in transcription of the HCMV genome. This effect is augmented by the use of tumor necrosis factor It has been proposed that this treatment (accompanied by antiretroviral treatment) has the potential to purge the virus from infected individuals.^[9]

Interactions

TRIM28 has been shown to interact with:

See also

• Transcription coregulator

References

Further reading

External links

• TRIM28 protein, human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• NURSA C153
• FactorBook KAP1
• TRIM28 human gene location in the UCSC Genome Browser.
• TRIM28 human gene details in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.