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Gene Review

TRIM28  -  tripartite motif containing 28

Homo sapiens

Synonyms: E3 SUMO-protein ligase TRIM28, KAP-1, KAP1, KRAB-associated protein 1, KRAB-interacting protein 1, ...
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Disease relevance of TRIM28


High impact information on TRIM28

  • Collectively, these data demonstrate that the interaction between TIF1beta and HP1 proteins is essential for progression through differentiation by regulating the expression of endoderm differentiation master players [2].
  • Here we report that the KAP-1 corepressor for the KRAB-ZFP superfamily of transcriptional silencers binds to SETDB1, a novel SET domain protein with histone H3-K9-specific methyltransferase activity [4].
  • Representational difference analysis (RDA) cloning has identified transcriptional intermediary factor 1 beta (TIF1beta) as a gene inducibly expressed early during myeloid differentiation of the promyelocytic cell lines HL-60 and U937 [5].
  • Although TIF1beta is necessary for macrophage differentiation of U937 cells, it is not sufficient, based on the inability of ectopically expressed TIF1beta to induce or augment phorbol ester-induced macrophage differentiation [5].
  • We conclude that TIF1beta plays an important role in the terminal differentiation program of macrophages, which involves the coactivation of C/EBPbeta and induction of C/EBPbeta-responsive myeloid genes [5].

Chemical compound and disease context of TRIM28


Biological context of TRIM28

  • TIF1alpha is believed to be a euchromatic target for liganded nuclear receptors, while TIF1beta may serve as a co-repressor for the large family of KRAB domain-containing zinc finger proteins [6].
  • This interaction involves a conserved amino acid motif, which is critical for the silencing activity of TIF1beta but not TIF1alpha [6].
  • Depletion of endogenous KAP1 expression by RNAi stimulates p53 transcriptional activity, sensitizes p53 response to DNA damage, and increases apoptosis [7].
  • Here, we report an association of TIF1beta with both heterochromatin and euchromatin in interphase nuclei [6].
  • When tethered to DNA, TIF1 beta can repress transcription in transiently transfected mammalian cells both from promoter-proximal and remote (enhancer) positions, similarly to the KRAB domain itself [8].

Anatomical context of TRIM28

  • TIF1beta functions as a coactivator for C/EBPbeta and is required for induced differentiation in the myelomonocytic cell line U937 [5].
  • Furthermore, we demonstrate that KAP-1 but not TIF1alpha interacts with the KRAB multifinger ZNF74 in the nuclear matrix [9].
  • In addition, by means of a pan-hKAP1 antibody, we confirm the previous hKAP1 family mRNA localization data in the middle to upper cortex of the human anagen hair follicle [10].

Associations of TRIM28 with chemical compounds

  • Like TIF1 alpha, TIF1 beta also contains an additional Cys/His cluster (PHD finger) and a bromo-related domain [8].
  • KAP1 may serve as a therapeutic target against cancer in combination with actinomycin D [11].
  • Here, we examined TIF1beta distribution in the nucleus of mouse embryonic carcinoma F9 cells during retinoic-acid-induced primitive endodermal differentiation [12].
  • Elicitation of bean cell suspensions with glutathione does not affect the total cellular activities of KAP-1 or KAP-2, but causes a rapid increase in the specific activities of both factors in the nuclear fraction, consistent with a role for these factors in the signal pathway for elicitor induction of chs15 and related defense genes [13].
  • Co-expression of Fes with full-length KAP-1 in human 293T cells stimulated Fes autophosphorylation and led to KAP-1 tyrosine phosphorylation [14].

Physical interactions of TRIM28

  • Here, we present evidence that MDM2 interacts with the nuclear corepressor KAP1 [7].
  • Transcriptional repression by RING finger protein TIF1 beta that interacts with the KRAB repressor domain of KOX1 [8].
  • Furthermore, the TIF1beta/KRAB complex was devoid of mSin3A and HDAC1 [15].
  • Additional biochemical assays demonstrate that the KS1 KRAB domain interacts with the KAP-1 corepressor, and mutations that abolish this interaction alleviate KS1-mediated transcriptional repression [16].
  • MM-1 was found to bind to the central portion of TIF1 beta in vitro and in vivo, and these proteins were found to be colocalized in the nucleus [17].

Enzymatic interactions of TRIM28

  • In response to DSB induction, KAP-1 is phosphorylated in an ATM-dependent manner on Ser 824 [18].

Regulatory relationships of TRIM28


Other interactions of TRIM28

  • Therefore, MDM2 interaction with KAP1 contributes to p53 functional regulation [7].
  • The binding is mediated by the N-terminal coiled-coil domain of KAP1 and the central acidic domain of MDM2 [7].
  • Indirect immunofluorescence has revealed that both KAP-1 and N-CoR colocalize throughout the nucleus [20].
  • Here we show that KAP-1, CAF-1 p150, and NIPBL carry a canonical amino acid motif, PxVxL, which binds directly to the CSD with high affinity [21].
  • The interaction of ZNF74 with KAP-1 did not prevent KAP-1 homomerization indicating that the oligomers most likely represent the transcriptionally active species [9].
  • In keeping with the role of NGFI-B as mediator of CRH signaling, we found that TIF1beta is recruited to the POMC promoter following CRH stimulation and that TIF1beta potentiates CRH and protein kinase A signaling through the NurRE; it acts synergistically with the SRC2 coactivator [22].

Analytical, diagnostic and therapeutic context of TRIM28

  • Co-immunoprecipitation of nuclear extracts shows that endogenous TIF1beta, but not TIF1alpha, is associated with members of the heterochromatin protein 1 (HP1) family [6].
  • The region of KAP-1 harboring the HP1BD binds as a monomer to a dimer of the CSD, as revealed by gel filtration, analytical ultracentrifugation, and optical biosensor analyses [23].
  • Through a combination of proteomic screening and site-directed mutagenesis approaches, we have identified lysines 554, 779, and 804 as the major sumoylation sites in KAP1 [24].
  • The analyses of electrophoretic mobility shift assays, GST association assays, and plasmon resonance interaction data have indicated that the KRAB binding to KAP-1 is direct, highly specific, and high affinity [25].
  • Moreover, DNA affinity chromatography and Western blot studies indicate that a Kruppel-related zinc finger protein and the transcriptional intermediary factor 1beta (TIF1beta) are involved in an MRE-binding complex, thereby regulating the S100A9 gene expression [26].


  1. The Epstein-Barr virus replication protein BBLF2/3 provides an origin-tethering function through interaction with the zinc finger DNA binding protein ZBRK1 and the KAP-1 corepressor. Liao, G., Huang, J., Fixman, E.D., Hayward, S.D. J. Virol. (2005) [Pubmed]
  2. Association of the transcriptional corepressor TIF1beta with heterochromatin protein 1 (HP1): an essential role for progression through differentiation. Cammas, F., Herzog, M., Lerouge, T., Chambon, P., Losson, R. Genes Dev. (2004) [Pubmed]
  3. Differential effects of retinoic acid isomers on the expression of nuclear receptor co-regulators in neuroblastoma. Lovat, P.E., Annicchiarico-Petruzzelli, M., Corazzari, M., Dobson, M.G., Malcolm, A.J., Pearson, A.D., Melino, G., Redfern, C.P. FEBS Lett. (1999) [Pubmed]
  4. 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. Schultz, D.C., Ayyanathan, K., Negorev, D., Maul, G.G., Rauscher, F.J. Genes Dev. (2002) [Pubmed]
  5. TIF1beta functions as a coactivator for C/EBPbeta and is required for induced differentiation in the myelomonocytic cell line U937. Rooney, J.W., Calame, K.L. Genes Dev. (2001) [Pubmed]
  6. 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. Nielsen, A.L., Ortiz, J.A., You, J., Oulad-Abdelghani, M., Khechumian, R., Gansmuller, A., Chambon, P., Losson, R. EMBO J. (1999) [Pubmed]
  7. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. Wang, C., Ivanov, A., Chen, L., Fredericks, W.J., Seto, E., Rauscher, F.J., Chen, J. EMBO J. (2005) [Pubmed]
  8. Transcriptional repression by RING finger protein TIF1 beta that interacts with the KRAB repressor domain of KOX1. Moosmann, P., Georgiev, O., Le Douarin, B., Bourquin, J.P., Schaffner, W. Nucleic Acids Res. (1996) [Pubmed]
  9. Oligomerization of transcriptional intermediary factor 1 regulators and interaction with ZNF74 nuclear matrix protein revealed by bioluminescence resonance energy transfer in living cells. Germain-Desprez, D., Bazinet, M., Bouvier, M., Aubry, M. J. Biol. Chem. (2003) [Pubmed]
  10. Polymorphisms in the human high sulfur hair keratin-associated protein 1, KAP1, gene family. Shimomura, Y., Aoki, N., Schweizer, J., Langbein, L., Rogers, M.A., Winter, H., Ito, M. J. Biol. Chem. (2002) [Pubmed]
  11. KAP1 dictates p53 response induced by chemotherapeutic agents via Mdm2 interaction. Okamoto, K., Kitabayashi, I., Taya, Y. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  12. Cell differentiation induces TIF1beta association with centromeric heterochromatin via an HP1 interaction. Cammas, F., Oulad-Abdelghani, M., Vonesch, J.L., Huss-Garcia, Y., Chambon, P., Losson, R. J. Cell. Sci. (2002) [Pubmed]
  13. Purification and biochemical characterization of proteins which bind to the H-box cis-element implicated in transcriptional activation of plant defense genes. Yu, L.M., Lamb, C.J., Dixon, R.A. Plant J. (1993) [Pubmed]
  14. The KRAB-associated co-repressor KAP-1 is a coiled-coil binding partner, substrate and activator of the c-Fes protein tyrosine kinase. Delfino, F.J., Shaffer, J.M., Smithgall, T.E. Biochem. J. (2006) [Pubmed]
  15. Transcriptional repression mediated by the KRAB domain of the human C2H2 zinc finger protein Kox1/ZNF10 does not require histone deacetylation. Lorenz, P., Koczan, D., Thiesen, H.J. Biol. Chem. (2001) [Pubmed]
  16. Sequence-specific transcriptional repression by KS1, a multiple-zinc-finger-Krüppel-associated box protein. Gebelein, B., Urrutia, R. Mol. Cell. Biol. (2001) [Pubmed]
  17. A novel transrepression pathway of c-Myc. Recruitment of a transcriptional corepressor complex to c-Myc by MM-1, a c-Myc-binding protein. Satou, A., Taira, T., Iguchi-Ariga, S.M., Ariga, H. J. Biol. Chem. (2001) [Pubmed]
  18. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Ziv, Y., Bielopolski, D., Galanty, Y., Lukas, C., Taya, Y., Schultz, D.C., Lukas, J., Bekker-Jensen, S., Bartek, J., Shiloh, Y. Nat. Cell Biol. (2006) [Pubmed]
  19. Role for KAP1 serine 824 phosphorylation and sumoylation/desumoylation switch in regulating KAP1-mediated transcriptional repression. Li, X., Lee, Y.K., Jeng, J.C., Yen, Y., Schultz, D.C., Shih, H.M., Ann, D.K. J. Biol. Chem. (2007) [Pubmed]
  20. A novel nuclear receptor corepressor complex, N-CoR, contains components of the mammalian SWI/SNF complex and the corepressor KAP-1. Underhill, C., Qutob, M.S., Yee, S.P., Torchia, J. J. Biol. Chem. (2000) [Pubmed]
  21. The mammalian heterochromatin protein 1 binds diverse nuclear proteins through a common motif that targets the chromoshadow domain. Lechner, M.S., Schultz, D.C., Negorev, D., Maul, G.G., Rauscher, F.J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  22. TIF1beta/KAP-1 is a coactivator of the orphan nuclear receptor NGFI-B/Nur77. Rambaud, J., Desroches, J., Balsalobre, A., Drouin, J. J. Biol. Chem. (2009) [Pubmed]
  23. Molecular determinants for targeting heterochromatin protein 1-mediated gene silencing: direct chromoshadow domain-KAP-1 corepressor interaction is essential. Lechner, M.S., Begg, G.E., Speicher, D.W., Rauscher, F.J. Mol. Cell. Biol. (2000) [Pubmed]
  24. Doxorubicin down-regulates Kruppel-associated box domain-associated protein 1 sumoylation that relieves its transcription repression on p21WAF1/CIP1 in breast cancer MCF-7 cells. Lee, Y.K., Thomas, S.N., Yang, A.J., Ann, D.K. J. Biol. Chem. (2007) [Pubmed]
  25. Biochemical analysis of the Kruppel-associated box (KRAB) transcriptional repression domain. Peng, H., Begg, G.E., Harper, S.L., Friedman, J.R., Speicher, D.W., Rauscher, F.J. J. Biol. Chem. (2000) [Pubmed]
  26. Binding of two nuclear complexes to a novel regulatory element within the human S100A9 promoter drives the S100A9 gene expression. Kerkhoff, C., Hofmann, H.A., Vormoor, J., Melkonyan, H., Roth, J., Sorg, C., Klempt, M. J. Biol. Chem. (2002) [Pubmed]
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