TRIM28
Description
The TRIM28 (tripartite motif containing 28) is a protein-coding gene located on chromosome 19.
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.
== 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. 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.
=== 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.
TRIM28, also known as KAP1, is a nuclear corepressor for KRAB domain-containing zinc finger proteins (KRAB-ZFPs). It mediates gene silencing by recruiting CHD3, a subunit of the NuRD complex, and SETDB1 (which methylates histone H3 at Lys-9) to the promoter regions of KRAB target genes. TRIM28 enhances transcriptional repression by increasing H3K9me, decreasing histone H3 Lys-9 and Lys-14 acetylation, and promoting the disposition of HP1 proteins to silence gene expression. Recruitment of SETDB1 induces heterochromatinization. TRIM28 can also act as a coactivator for CEBPB and NR3C1 in the transcriptional activation of ORM1 and is a corepressor for ERBB4. It inhibits E2F1 activity by stimulating E2F1-HDAC1 complex formation and inhibiting E2F1 acetylation. TRIM28 may serve as a partial backup to prevent E2F1-mediated apoptosis in the absence of RB1 and is an important regulator of CDKN1A/p21(CIP1). TRIM28 has E3 SUMO-protein ligase activity towards itself via its PHD-type zinc finger and specifically sumoylates IRF7, thereby inhibiting its transactivation activity. It ubiquitinates p53/TP53, leading to its proteasomal degradation, a function enhanced by MAGEC2 and MAGEA2, and possibly MAGEA3 and MAGEA6. TRIM28 mediates the nuclear localization of KOX1, ZNF268, and ZNF300 transcription factors. In association with isoform 2 of ZFP90, TRIM28 is required for the transcriptional repressor activity of FOXP3 and the suppressive function of regulatory T-cells (Treg). It probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells. TRIM28 is required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs). In ESCs, in collaboration with SETDB1, TRIM28 is also required for H3K9me3 and silencing of endogenous and introduced retroviruses in a DNA-methylation independent-pathway. It associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing. The SETDB1-TRIM28-ZNF274 complex may play a role in recruiting ATRX to the 3'-exons of zinc-finger coding genes with atypical chromatin signatures to establish or maintain/protect H3K9me3 at these transcriptionally active regions.
TRIM28 is also known as KAP1, PPP1R157, RNF96, TF1B, TIF1B, TIF1beta.
