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TIF1 family

Transcriptional activation of nuclear receptors (NRs) is thought to involve transcriptional intermediate factors (TIF) that work by remodeling of chromatin templates and altering the activity of the underlying transcriptional mechanism. TIF1α is a putative nuclear receptor mediator, a protein kinase with multiple conserved domains. The N-terminal RING finger / B-box / coil (RBCC) pattern and C-terminal region, including the "plant homology domain" (PHD) finger and a bromine domain. TIF1α is the only member of the TIF1 family, including TIF1β / KAP-1 / KRIP-1. TIF1γ and TIF1γ are known to interact directly with the ligand NR. TIF1α is a rich nuclear protein that is closely related to autochromatin in undifferentiated pluripotent cells. During the differentiation of retinoic acid (RA) -induced P19 cells, the level of TIF1α decreased sharply, indicating that it is involved in maintaining the undifferentiated state of totipotent cells during development. TIF1 protein is encoded by an extended family of developmental and physiological control genes and is conserved from flies to humans. These proteins are characterized by an N-terminal RING-B box spiral coil (RBCC) motif and a C-terminal PHD finger/bromo domain unit and have been shown to be involved in transcriptional repression involving histone modifiers and heterochromatin-binding proteins epigenetic mechanisms.

Introductions

In response to developmental or environmental signals, transcriptional regulation of gene expression in eukaryotes is a complex, multi-step process that requires the concerted action of many cytokines. The core role in this complex process is sequence-specific transcription factors, which actively and / or negatively control transcription through interaction with transcription intermediate factors (TIFs1; also known as co-activators and co-expression factors), which ultimately reshape the function is to the chromatin structure. To stimulate or inhibit the formation of (pre) starting complexes, or to associate target genes with specialized nuclear compartments. TIF1s are a growing member of the chromatin-related/associated TIFs family. TIF1s are a subset that emerge as key regulators of developmental and physiological processes. Three members of the family (TIF1α, -β, and -γ) are in mammals, and one member (Bonus) in Drosophila consists of two conserved amino acid regions: an N-terminal RING has potential self-assembly properties -B box-coil (RBCC) domain; and a C-terminal region containing a PHD finger and a bromine domain, two highly conserved signature motifs that are widely distributed at nuclear proteins that function at the chromatin level between

TIF1α

TIF1α is a founding member of this family. A protein that regulates the reactivation potential of the retinoid X receptor (RXR) was initially identified in yeast genetic screening, and was subsequently found to interact with AF-2 transcription via a single LXXLL motif Nuclear receptor activation domains include retinoic acid (RAR), thyroid (TR), vitamin D3 (VDR), and estrogen (ER) receptors. TIF1α is a chromosomal protein rich in autochromatin, and is widely expressed in early development and in many adult tissues. It has been reported that in mouse NIH 3T3 cells, TIF1α plays a role in the growth inhibitory activity of RXR / RAR and exhibits transforming activity when fused with truncated B-Raf. The biological function of TIF1α is achieved by regulating the state of chromatin, which supports the view of TIF1α. TIF1α has been shown to have inherent transcriptional silencing activity and requires histone deacetylation. In addition, TIF1α has the ability to directly interact with members of the heterochromatin protein 1 (HP1) family, which is a class of non-histone chromosomal proteins that can be used as a dose-dependent regulator of higher-order chromatin structure to promote autosomal Gene silencing. The location of the HPIF interaction domain in TIF1α led to the identification of a conserved PXVXL motif located in its central region, which directly binds to the C-terminal chromosomal shaded domain of the HP1 protein and exists in other potential transcriptional regulatory targets.

TIF1β

The identification of TIF1β establishes the TIF1 family of transcription cofactors. TIF1β (also known as KAP-1 or KRIP-1) is isolated for its ability to interact with mouse HP1α and the human Krüppel-like proteins KOX1 and KRAB domains of Kid-1. The KRAB transcriptional repression domain is a widely distributed motif, often found at the N-terminus of Krüppel Cys2-His2 type zinc finger proteins. This domain contains a conservative KRAB A box, usually followed by a KRAB B box. So far, all variants of the KRAB domain studied have functioned by recruiting TIF1β. Consistent with its role in chromatin tissue, TIF1β silences transcription by mechanisms involving histone deacetylation, histone H3 Lys-9 methylation, and recruitment of HP1 protein through the PXVXL motif. Most importantly, this motif is also required during cell differentiation to trigger the relocation of TIF1β to the centromeric heterochromatin region. In mice, TIF1β is universally expressed throughout development and is expressed in many adult tissues. Our recent research indicates that the destruction of TIF1β in mice can lead to developmental arrest at the egg flask stage before germ formation, leading to an embryonic lethal phenotype, thus demonstrating that TIF1β plays an important and non-redundant role in early subsequent secondary processes. Features. Implant development. Subsequently, the use of conditional germ cell line-specific TIF1β disruption in adult testes revealed the subsequent function of TIF1β in the homeostatic epithelial homeostasis.

TIF1γ

The third mammalian member of the TIF1 family, TIF1γ, was discovered by low stringency hybridization screening using TIF1α as a probe. Amino acid comparisons showed that TIF1γ is closer to TIF1α than TIF1β in the three mammalian members of the family (the overall identity between TIF1α and TIF1γ is 50%, and the identity between other TIF1s is ~ 30%). In vitro, TIF1α and TIF1γ are heteropolymeric with the same efficiency as homopolymerization, while TIF1β is indeed homopolymeric but not heteropolymerized with TIF1α or TIF1γ. In addition, it has been shown that overexpression of TIF1γ in transiently transfected cells interferes with the expression inhibitory activity of TIF1α. Further evidence supporting the mutual interference between TIF1α and TIF1γ is that two new types of RET rearrangements in children with papillary thyroid cancer, PTC6 and PTC7, have recently been identified, which share a common RET receptor tyrosine kinase domain Fusion with TIF1α RBCC domain (PTC6) and TIF1γ (PTC7) In humans and mice, TIF1γ transcripts are widely expressed at different levels in adult and fetal tissues. Like other TIF1 family members, TIF1γ contains an intrinsic transcriptional silencing function. However, downstream targets that mediate gene silencing have not been identified.

Reference

  1. Khetchoumian K; et al. IF1δ, a Novel HP1-interacting Member of the Transcriptional Intermediary Factor 1 (TIF1) Family Expressed by Elongating Spermatids. Journal of Biological Chemistry, 2004, 279.