TRIM28

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]

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
External IDs	OMIM: 601742 MGI: 109274 HomoloGene: 21175 GeneCards: TRIM28
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 12,999,114 bp[2] End 13,031,035 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein kinase activity • Krueppel-associated box domain binding • chromo shadow domain binding • GO:0001106 transcription corepressor activity • promoter-specific chromatin binding • GO:0001105 transcription coactivator activity • metal ion binding • ubiquitin-protein transferase activity • GO:0001948 protein binding • ubiquitin protein ligase binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 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 • nuclear euchromatin • intracellular • nuclear heterochromatin • chromatin • RNA polymerase II transcription factor complex • cell nucleus • nucleoplasm Biological process • regulation of transcription, DNA-templated • positive regulation of methylation-dependent chromatin silencing • convergent extension involved in axis elongation • embryonic placenta morphogenesis • positive regulation of DNA repair • in utero embryonic development • negative regulation of transcription from RNA polymerase II promoter • transcription, DNA-templated • negative regulation of DNA demethylation • protein phosphorylation • protein oligomerization • 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 from RNA polymerase II promoter • regulation of genetic imprinting • protein sumoylation • epithelial to mesenchymal transition • protein ubiquitination • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • covalent chromatin modification • positive regulation of DNA binding • innate immune system • negative regulation of single stranded viral RNA replication via double stranded DNA intermediate • chromatin organization • GO:0022415 viral process • positive regulation of protein import into nucleus • negative regulation of viral release from host cell 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: 13 – 13.03 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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. Phosphorylation of KAP1 acts as a deactivator of the protein in many of its mechanisms while sumoylation acts as an activator.[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:

• CBX5,[11][12][13][14]
• CEBPB,[15]
• Glucocorticoid receptor,[15]
• SETDB1[16] and
• ZNF10.[17][18]

See also

• Transcription coregulator

References

1. GRCh38: Ensembl release 89: ENSG00000130726 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000005566 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A (May 2001). "The tripartite motif family identifies cell compartments". The EMBO Journal. 20 (9): 2140–51. doi:10.1093/emboj/20.9.2140. PMC 125245. PMID 11331580.
6. Capili AD, Schultz DC, RauscherIII FJ, Borden KL (Jan 2001). "Solution structure of the PHD domain from the KAP-1 corepressor: structural determinants for PHD, RING and LIM zinc-binding domains". The EMBO Journal. 20 (1–2): 165–77. doi:10.1093/emboj/20.1.165. PMC 140198. PMID 11226167.
7. "Entrez Gene: TRIM28 tripartite motif-containing 28".
8. Iyengar, Sushma; Farnham, Peggy (2011-07-29). "KAP1 Protein: An Enigmatic Master Regulator of the Genome". The Journal of Biological Chemistry. 286: 26267–26276. doi:10.1074/jbc.r111.252569. PMC 3143589. PMID 21652716.
9. Rauwel, Benjamin (2015-04-07). "Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch". eLife. 4. doi:10.7554/eLife.06068. PMC 4384640. PMID 25846574.
10. Sripathy, Smitha (2006-03-20). "The KAP1 Corepressor Functions To Coordinate the Assembly of De Novo HP1-Demarcated Microenvironments of Heterochromatin Required for KRAB Zinc Finger Protein-Mediated Transcriptional Repression" (PDF). Molecular and Cellular Biology. doi:10.1128/mcb.00487-06.
11. Nielsen AL, Sanchez C, Ichinose H, Cerviño M, Lerouge T, Chambon P, Losson R (Nov 2002). "Selective interaction between the chromatin-remodeling factor BRG1 and the heterochromatin-associated protein HP1alpha". The EMBO Journal. 21 (21): 5797–806. doi:10.1093/emboj/cdf560. PMC 131057. PMID 12411497.
12. Cammas F, Oulad-Abdelghani M, Vonesch JL, Huss-Garcia Y, Chambon P, Losson R (Sep 2002). "Cell differentiation induces TIF1beta association with centromeric heterochromatin via an HP1 interaction". Journal of Cell Science. 115 (Pt 17): 3439–48. PMID 12154074.
13. Nielsen AL, Oulad-Abdelghani M, Ortiz JA, Remboutsika E, Chambon P, Losson R (Apr 2001). "Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins". Molecular Cell. 7 (4): 729–39. doi:10.1016/S1097-2765(01)00218-0. PMID 11336697.
14. Lechner MS, Begg GE, Speicher DW, Rauscher FJ (Sep 2000). "Molecular determinants for targeting heterochromatin protein 1-mediated gene silencing: direct chromoshadow domain-KAP-1 corepressor interaction is essential". Molecular and Cellular Biology. 20 (17): 6449–65. doi:10.1128/mcb.20.17.6449-6465.2000. PMC 86120. PMID 10938122.
15. Chang CJ, Chen YL, Lee SC (Oct 1998). "Coactivator TIF1beta interacts with transcription factor C/EBPbeta and glucocorticoid receptor to induce alpha1-acid glycoprotein gene expression". Molecular and Cellular Biology. 18 (10): 5880–7. doi:10.1128/mcb.18.10.5880. PMC 109174. PMID 9742105.
16. Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ (Apr 2002). "SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins". Genes & Development. 16 (8): 919–32. doi:10.1101/gad.973302. PMC 152359. PMID 11959841.
17. Moosmann P, Georgiev O, Le Douarin B, Bourquin JP, Schaffner W (Dec 1996). "Transcriptional repression by RING finger protein TIF1 beta that interacts with the KRAB repressor domain of KOX1". Nucleic Acids Research. 24 (24): 4859–67. doi:10.1093/nar/24.24.4859. PMC 146346. PMID 9016654.
18. Peng H, Begg GE, Harper SL, Friedman JR, Speicher DW, Rauscher FJ (Jun 2000). "Biochemical analysis of the Kruppel-associated box (KRAB) transcriptional repression domain". The Journal of Biological Chemistry. 275 (24): 18000–10. doi:10.1074/jbc.M001499200. PMID 10748030.

Further reading

• Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Friedman JR, Fredericks WJ, Jensen DE, Speicher DW, Huang XP, Neilson EG, Rauscher FJ (Aug 1996). "KAP-1, a novel corepressor for the highly conserved KRAB repression domain". Genes & Development. 10 (16): 2067–78. doi:10.1101/gad.10.16.2067. PMID 8769649.
• Kim SS, Chen YM, O'Leary E, Witzgall R, Vidal M, Bonventre JV (Dec 1996). "A novel member of the RING finger family, KRIP-1, associates with the KRAB-A transcriptional repressor domain of zinc finger proteins". Proceedings of the National Academy of Sciences of the United States of America. 93 (26): 15299–304. doi:10.1073/pnas.93.26.15299. PMC 26399. PMID 8986806.
• Moosmann P, Georgiev O, Le Douarin B, Bourquin JP, Schaffner W (Dec 1996). "Transcriptional repression by RING finger protein TIF1 beta that interacts with the KRAB repressor domain of KOX1". Nucleic Acids Research. 24 (24): 4859–67. doi:10.1093/nar/24.24.4859. PMC 146346. PMID 9016654.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Chang CJ, Chen YL, Lee SC (Oct 1998). "Coactivator TIF1beta interacts with transcription factor C/EBPbeta and glucocorticoid receptor to induce alpha1-acid glycoprotein gene expression". Molecular and Cellular Biology. 18 (10): 5880–7. doi:10.1128/mcb.18.10.5880. PMC 109174. PMID 9742105.
• Eng FC, Barsalou A, Akutsu N, Mercier I, Zechel C, Mader S, White JH (Oct 1998). "Different classes of coactivators recognize distinct but overlapping binding sites on the estrogen receptor ligand binding domain". The Journal of Biological Chemistry. 273 (43): 28371–7. doi:10.1074/jbc.273.43.28371. PMID 9774463.
• Ryan RF, Schultz DC, Ayyanathan K, Singh PB, Friedman JR, Fredericks WJ, Rauscher FJ (Jun 1999). "KAP-1 corepressor protein interacts and colocalizes with heterochromatic and euchromatic HP1 proteins: a potential role for Krüppel-associated box-zinc finger proteins in heterochromatin-mediated gene silencing". Molecular and Cellular Biology. 19 (6): 4366–78. doi:10.1128/mcb.19.6.4366. PMC 104396. PMID 10330177.
• Agata Y, Matsuda E, Shimizu A (Jun 1999). "Two novel Krüppel-associated box-containing zinc-finger proteins, KRAZ1 and KRAZ2, repress transcription through functional interaction with the corepressor KAP-1 (TIF1beta/KRIP-1)". The Journal of Biological Chemistry. 274 (23): 16412–22. doi:10.1074/jbc.274.23.16412. PMID 10347202.
• Nielsen AL, Ortiz JA, You J, Oulad-Abdelghani M, Khechumian R, Gansmuller A, Chambon P, Losson R (Nov 1999). "Interaction with members of the heterochromatin protein 1 (HP1) family and histone deacetylation are differentially involved in transcriptional silencing by members of the TIF1 family". The EMBO Journal. 18 (22): 6385–95. doi:10.1093/emboj/18.22.6385. PMC 1171701. PMID 10562550.
• Peng H, Begg GE, Harper SL, Friedman JR, Speicher DW, Rauscher FJ (Jun 2000). "Biochemical analysis of the Kruppel-associated box (KRAB) transcriptional repression domain". The Journal of Biological Chemistry. 275 (24): 18000–10. doi:10.1074/jbc.M001499200. PMID 10748030.
• Lechner MS, Begg GE, Speicher DW, Rauscher FJ (Sep 2000). "Molecular determinants for targeting heterochromatin protein 1-mediated gene silencing: direct chromoshadow domain-KAP-1 corepressor interaction is essential". Molecular and Cellular Biology. 20 (17): 6449–65. doi:10.1128/MCB.20.17.6449-6465.2000. PMC 86120. PMID 10938122.
• Underhill C, Qutob MS, Yee SP, Torchia J (Dec 2000). "A novel nuclear receptor corepressor complex, N-CoR, contains components of the mammalian SWI/SNF complex and the corepressor KAP-1". The Journal of Biological Chemistry. 275 (51): 40463–70. doi:10.1074/jbc.M007864200. PMID 11013263.
• Gebelein B, Urrutia R (Feb 2001). "Sequence-specific transcriptional repression by KS1, a multiple-zinc-finger-Krüppel-associated box protein". Molecular and Cellular Biology. 21 (3): 928–39. doi:10.1128/MCB.21.3.928-939.2001. PMC 86683. PMID 11154279.
• Capili AD, Schultz DC, RauscherIII FJ, Borden KL (Jan 2001). "Solution structure of the PHD domain from the KAP-1 corepressor: structural determinants for PHD, RING and LIM zinc-binding domains". The EMBO Journal. 20 (1–2): 165–77. doi:10.1093/emboj/20.1.165. PMC 140198. PMID 11226167.
• Schultz DC, Friedman JR, Rauscher FJ (Feb 2001). "Targeting histone deacetylase complexes via KRAB-zinc finger proteins: the PHD and bromodomains of KAP-1 form a cooperative unit that recruits a novel isoform of the Mi-2alpha subunit of NuRD". Genes & Development. 15 (4): 428–43. doi:10.1101/gad.869501. PMC 312636. PMID 11230151.
• Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A (May 2001). "The tripartite motif family identifies cell compartments". The EMBO Journal. 20 (9): 2140–51. doi:10.1093/emboj/20.9.2140. PMC 125245. PMID 11331580.
• Hsu SI, Yang CM, Sim KG, Hentschel DM, O'Leary E, Bonventre JV (May 2001). "TRIP-Br: a novel family of PHD zinc finger- and bromodomain-interacting proteins that regulate the transcriptional activity of E2F-1/DP-1". The EMBO Journal. 20 (9): 2273–85. doi:10.1093/emboj/20.9.2273. PMC 125435. PMID 11331592.
• Nielsen AL, Oulad-Abdelghani M, Ortiz JA, Remboutsika E, Chambon P, Losson R (Apr 2001). "Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins". Molecular Cell. 7 (4): 729–39. doi:10.1016/S1097-2765(01)00218-0. PMID 11336697.

External links

• TRIM28 protein, human at the US 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.