TRIM28

{{Short description|Protein-coding gene in the species Homo sapiens}}

Tripartite motif-containing 28 (TRIM28), also known as transcriptional intermediary factor 1β (TIF1β) and KRAB-associated protein-1 (KAP1), is a protein that in humans is encoded by the TRIM28 gene.{{cite journal | vauthors = 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 | title = The tripartite motif family identifies cell compartments | journal = The EMBO Journal | volume = 20 | issue = 9 | pages = 2140–51 | date = May 2001 | pmid = 11331580 | pmc = 125245 | doi = 10.1093/emboj/20.9.2140 }}{{cite journal | vauthors = Capili AD, Schultz DC, RauscherIII FJ, Borden KL | title = Solution structure of the PHD domain from the KAP-1 corepressor: structural determinants for PHD, RING and LIM zinc-binding domains | journal = The EMBO Journal | volume = 20 | issue = 1–2 | pages = 165–77 | date = Jan 2001 | pmid = 11226167 | pmc = 140198 | doi = 10.1093/emboj/20.1.165 }}

Function

The protein encoded by this gene mediates transcriptional regulation by interacting with the Krüppel-associated box (KRAB) repression domain found in many transcription factors. The protein localizes to the nucleus and is thought to associate with specific chromatin regions. TRIM28 is a member of the tripartite motif family. This tripartite motif includes three zinc-binding domains, a RING finger domain, a B-box type 1 and a B-box type 2, and a coiled-coil region.{{cite web | title = Entrez Gene: TRIM28 tripartite motif-containing 28| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10155}} TRIM28 additionally possesses a domain that interacts with heterochromatin protein 1 (HP1) and a bromodomain capable of recognizing acetylated lysine residues in other proteins.

TRIM28/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.{{cite journal|last1=Iyengar|first1=Sushma|last2=Farnham|first2=Peggy|title=KAP1 Protein: An Enigmatic Master Regulator of the Genome|journal=The Journal of Biological Chemistry|date=2011-07-29|volume=286|issue=30|doi=10.1074/jbc.r111.252569 |pmc=3143589|pmid=21652716|pages=26267–26276|doi-access=free}}

= Cellular differentiation and proliferation =

Studies have shown that deletion of TRIM28/KAP1 in mice before gastrulation results in death (implicating it as a necessary protein in early development) 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).

= 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-SETDB1-HP1 macromolecular complex.{{cite journal|last1=Sripathy|first1=Smitha|title=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|journal=Molecular and Cellular Biology|date=2006-03-20|volume=26|issue=22|pages=8623–8638|doi=10.1128/mcb.00487-06 |pmid=16954381|pmc=1636786}} KAP1 recruits and interacts directly with the histone methyltransferase SETDB1 and with histone deacetylases via its C-terminal PHD finger and bromodomain. It thus functions as a bridge between sequence-specific DNA-binding KRAB-ZFP transcription factors and various histone-modifying proteins responsible for silencing transcription via nucleosome remodeling, allowing precise epigenetic changes to be made at specific loci across the genome.

= DNA damage repair response =

It has been shown that the kinase 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.

= Apoptosis =

KAP1 forms a complex with MDM2 (a ubiquitin E3 ligase) that binds to p53. This complex marks the bound p53 for degradation by proteasomes. p53 is a known precursor of apoptosis that facilitates the synthesis of proteins necessary for cell death, so its degradation accordingly results in apoptosis inhibition.

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.{{cite journal|last1=Rauwel|first1=Benjamin|title=Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch|journal=eLife|date=2015-04-07|doi=10.7554/eLife.06068|pmc=4384640|pmid=25846574|volume=4 |doi-access=free }} 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 SETDB1. SETDB1 is a histone methyltransferase that recruits HP1, thus inducing heterochromatin formation and preventing 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.

= 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.

Interactions

TRIM28/KAP1 has been shown to interact with:

CBX5{{cite journal | vauthors = Nielsen AL, Sanchez C, Ichinose H, Cerviño M, Lerouge T, Chambon P, Losson R | title = Selective interaction between the chromatin-remodeling factor BRG1 and the heterochromatin-associated protein HP1alpha | journal = The EMBO Journal | volume = 21 | issue = 21 | pages = 5797–806 | date = Nov 2002 | pmid = 12411497 | pmc = 131057 | doi = 10.1093/emboj/cdf560}}{{cite journal | vauthors = Cammas F, Oulad-Abdelghani M, Vonesch JL, Huss-Garcia Y, Chambon P, Losson R | title = Cell differentiation induces TIF1beta association with centromeric heterochromatin via an HP1 interaction | journal = Journal of Cell Science | volume = 115 | issue = Pt 17 | pages = 3439–48 | date = Sep 2002 | doi = 10.1242/jcs.115.17.3439 | pmid = 12154074 | doi-access = free }}{{cite journal | vauthors = Nielsen AL, Oulad-Abdelghani M, Ortiz JA, Remboutsika E, Chambon P, Losson R | title = Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins | journal = Molecular Cell | volume = 7 | issue = 4 | pages = 729–39 | date = Apr 2001 | pmid = 11336697 | doi = 10.1016/S1097-2765(01)00218-0| doi-access = free | hdl = 10261/308369 | hdl-access = free }}{{cite journal | vauthors = Lechner MS, Begg GE, Speicher DW, Rauscher FJ | title = Molecular determinants for targeting heterochromatin protein 1-mediated gene silencing: direct chromoshadow domain-KAP-1 corepressor interaction is essential | journal = Molecular and Cellular Biology | volume = 20 | issue = 17 | pages = 6449–65 | date = Sep 2000 | pmid = 10938122 | pmc = 86120 | doi = 10.1128/mcb.20.17.6449-6465.2000}}
CEBPB{{cite journal | vauthors = Chang CJ, Chen YL, Lee SC | title = Coactivator TIF1beta interacts with transcription factor C/EBPbeta and glucocorticoid receptor to induce alpha1-acid glycoprotein gene expression | journal = Molecular and Cellular Biology | volume = 18 | issue = 10 | pages = 5880–7 | date = Oct 1998 | pmid = 9742105 | pmc = 109174 | doi = 10.1128/mcb.18.10.5880}}
Glucocorticoid receptor
SETDB1{{cite journal | vauthors = Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ | title = 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 | journal = Genes & Development | volume = 16 | issue = 8 | pages = 919–32 | date = Apr 2002 | pmid = 11959841 | pmc = 152359 | doi = 10.1101/gad.973302 }}
ZNF10{{cite journal | vauthors = Moosmann P, Georgiev O, Le Douarin B, Bourquin JP, Schaffner W | title = Transcriptional repression by RING finger protein TIF1 beta that interacts with the KRAB repressor domain of KOX1 | journal = Nucleic Acids Research | volume = 24 | issue = 24 | pages = 4859–67 | date = Dec 1996 | pmid = 9016654 | pmc = 146346 | doi = 10.1093/nar/24.24.4859}}{{cite journal | vauthors = Peng H, Begg GE, Harper SL, Friedman JR, Speicher DW, Rauscher FJ | title = Biochemical analysis of the Kruppel-associated box (KRAB) transcriptional repression domain | journal = The Journal of Biological Chemistry | volume = 275 | issue = 24 | pages = 18000–10 | date = Jun 2000 | pmid = 10748030 | doi = 10.1074/jbc.M001499200 | doi-access = free }}

References

External links

{{MeshName|TRIM28+protein,+human|3=TRIM28 protein, human}}
{{NURSA|C153}}
{{FactorBook|KAP1}}
{{UCSC genome browser|TRIM28}}
{{UCSC gene details|TRIM28}}

Category:Gene expression

Category:Transcription coregulators