TRIM28
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| Location (UCSC) | Chr 19: 58.54 – 58.55 Mb | Chr 7: 12.73 – 12.76 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/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
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000130726 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005566 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 11331580.
- PMID 11226167.
- ^ "Entrez Gene: TRIM28 tripartite motif-containing 28".
- ^ PMID 21652716.
- ^ PMID 25846574.
- PMID 16954381.
- PMID 12411497.
- PMID 12154074.
- PMID 11336697.
- PMID 10938122.
- ^ PMID 9742105.
- PMID 11959841.
- PMID 9016654.
- 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. 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. 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. 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. 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. 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. 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" (PDF). The Journal of Biological Chemistry. 273 (43): 28371–7. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. PMID 11336697.
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.