TRIM28
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTRIM28, KAP1, PPP1R157, RNF96, TF1B, TIF1B, tripartite motif containing 28, TIF1beta
External IDsOMIM: 601742 MGI: 109274 HomoloGene: 21175 GeneCards: TRIM28
Orthologs
SpeciesHumanMouse
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 MbChr 7: 12.73 – 12.76 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000130726 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 4 5 6 Iyengar, Sushma; Farnham, Peggy (2011-07-29). "KAP1 Protein: An Enigmatic Master Regulator of the Genome". The Journal of Biological Chemistry. 286 (30): 26267–26276. doi:10.1074/jbc.r111.252569. PMC 3143589. PMID 21652716.
  9. 1 2 3 4 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". Molecular and Cellular Biology. 26 (22): 8623–8638. doi:10.1128/mcb.00487-06. PMC 1636786. PMID 16954381.
  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. doi:10.1242/jcs.115.17.3439. 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. hdl:10261/308369. 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. 1 2 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

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