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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
Homo sapiens
 Ppara
Mus musculus
 Thrb
Mus musculus
 SNAI2
Homo sapiens
 Tbr1
Mus musculus
Transcription Factor Encyclopedia  BETA
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Overview

The Krüppel-box associated protein 1 (KAP1/TRIM28/TIF1B/KRIP-1) was discovered through its interaction with the KRAB (Krüppel-associated box) domain found in many transcription factors.[1] C2H2 zinc finger proteins (ZFPs) constitute the largest family of transcription factors in the human genome. In humans about one third of ZFPs contain the KRAB domain, a potent and highly conserved repression domain. These findings have led to the current model of KAP1 as a universal obligate corepressor for KRAB zinc finger proteins. The model suggests that KAP1 is recruited to DNA via KRAB ZFPs and then acts as a molecular scaffold that coordinates various activities necessary for gene-specific silencing such as assembly and maintenance of transcriptionally inactive, higher order chromatin structures.

ChIP-chip (chromatin immunoprecipitation followed by DNA microarray)technology has identified ~7000 KAP1 binding sites throughout the human genome and revealed that genes encoding zinc finger proteins are themselves targeted by the KAP1 repression complex. While some KAP1 binding sites are located in promoter regions, the majority of KAP1 binding was observed within the coding region of genes, preferentially at their 3’ end.[2]

Although the specific mechanism of KAP1 function remains unknown, biochemical studies have identified a network of KAP1 interacting proteins.[3][4] KAP1 acts as a scaffold protein for recruiting SETDB1 (Histone H3 Lysine 9 specific methylase)and Mi2α (a member of the NuRD/HDAC histone deacetylases complex).[5][6] The recruitment of both, histone deacetylases and histone methylases, results in loss of acetylation and increase in methylation at lysine 9 of histone H3. KAP1 also interacts with HP1 (Heterochromatin protein 1) which dynamically regulates changes in histone modification and formation of facultative heterochromatin. HP1 protein directly recognizes histone H3 that is methylated at lysine 9 and is needed for gene silencing. Histone H3K9 trimethylation associated with the KAP1 repression complex is lost when the interaction between KAP1 and HP1 is disrupted.

KAP1 is a member of the tripartite motif family. The overall architecture of TIF1 familiy members consisting of TIF1A, TIF1B (KAP1), TIF1C and TIF1D is similar. Like KAP1, TIF1A contains an NH2-terminal RBCC motif and carboxy-terminal PHD and bromodomains (see Figure 1). However, there is little functional similarity between these two proteins. TIF1A acts as a co-activator for nuclear hormone receptors. KAP1 does not bind to nuclear hormone receptors and TIF1A binds very weakly to the KRAB domain.

KAP1 exerts cellular functions essential in early embryonic development and cell differentiation. In fact, KAP1 knock-out mice are embryonic lethal and are impaired in their ability to undergo gastrulation.[7] Analysis of the embryos has revealed reduced cell number in the ectoderm, morphological alterations of the endoderm and absence of mesoderm formation. Differentiation of a mouse embryonic carcinoma cell line by retinoic acid has shown that the KAP1-HP1 interaction is essential during a window of time for differentiation.[8] [6]

References
  1. Abrink M et al. Conserved interaction between distinct Krüppel-associated box domains and the transcriptional intermediary factor 1 beta. Proc. Natl. Acad. Sci. U.S.A., 98(4):1422-6. (PMID 11171966)
  2. O'Geen H et al. Genome-wide analysis of KAP1 binding suggests autoregulation of KRAB-ZNFs. PLoS Genet., 3(6):e89. (PMID 17542650)
  3. Sripathy SP et al. 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. Mol. Cell. Biol., 26(22):8623-38. (PMID 16954381)
  4. Ryan RF et al. 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. Mol. Cell. Biol., 19(6):4366-78. (PMID 10330177)
  1. Schultz DC et al. 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 Dev., 15(4):428-43. (PMID 11230151)
  2. Schultz DC et al. 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 Dev., 16(8):919-32. (PMID 11959841)
  3. Cammas F et al. Mice lacking the transcriptional corepressor TIF1beta are defective in early postimplantation development. Development, 127(13):2955-63. (PMID 10851139)
  4. Cammas F et al. Association of the transcriptional corepressor TIF1beta with heterochromatin protein 1 (HP1): an essential role for progression through differentiation. Genes Dev., 18(17):2147-60. (PMID 15342492)
Figures
FIGURE 1 Schematic diagram illustrating the architecture of the KAP1/TIF1 family of transcriptional regulatory proteins
Conserved motifs include the RING finger, B boxes (B1 and B2), coiled-coil, plant homeo domain (PHD), and bromodomain (Bromo). Note the overall similar architectures among this family of proteins defined by the layout of the various domains. The putative HP1BD (black boxes) is conserved in each protein; the nuclear receptor interaction domain (NRID) is conserved only in TIF1 . Regions of significantly enriched amino acids, serine-glycine-proline (SGP) and serine-threonine-alanine-glycine-proline (STAGP), are also spatially conserved in this family. The minimal KRAB binding domain comprises the N terminal RBCC domain, while the Mi2a and SETDB1 interaction domains are at the C terminus.
This figure is from a publication. Please click here to view the publication's entry in Pubmed (PMID 10330177).