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Overview

ARID3A is a member of the A+T rich interactive domain (ARID) family of DNA-binding proteins. There are 15 human ARID family members. ARID3A is classified in the ARID3 subfamily which contains an extended area of conserved 40 amino acids outside the core DNA-binding domain that facilitates sequence-specific DNA binding. This complete DNA-binding domain is referred to as the extended ARID domain (eARID)[1]. ARID3a is one of the few ARID family members for which a discrete DNA-binding recognition sequence has been identified [2].

ARID3a was first cloned through homology with the Drosophila orthologue (Dril1) [3], and later re-identified as a protein associated with E2F (E2FBP) [4]. ARID3A, like its Drosophila and Xenopus orthologues, is developmentally regulated during embryogenesis, but becomes tissue-restricted in the adult. In man, ARID3A expression in the adult occurs in B lymphocytes where its expression is tightly regulated in accordance with B cell differentiation.

The mouse homologue of ARID3a, Bright, was first characterized as a transcription factor that upregulates immunoglobulin heavy chain (IgH) transcription as part of a larger protein complex, containing the enzyme Bruton's tyrosine kinase (Btk) and the ubiquitously expressed transcription factor II-I (TFII-I)(Figure 1). Likewise, ARID3a expression in mature B cells acts to enhance transcription of the immunoglobulin heavy chain locus[5]. Human ARID3A also associates with Btk and TFII-I to upregulate IgH transcription [6], but has additional functions in hematopoietic cells and embryonic tissue which may include chromatin remodeling. Several other ARID family members act directly as DNA demethylases or recruit histone modifying enzymes to DNA resulting in epigenetic regulation of multiple genes.

Inappropriate ARID3A expression in fibroblasts alters growth potential. Because over-expression over-comes RAS-induced senescence, it has been associated with oncogenic functions [7]. However, in other systems it has been proposed to function as a tumor suppressor, through its effects on the cell cycle and promyelocytic leukemia bodies [8]. More recently, ARID3A was shown to heterodimerize with the protein inhibitor of DNA-binding (ID) 1 to regulate TGF-Beta mediated fibroblast to myofibroblast transformation [9]. Although these data suggest that ARID3a plays important functions in many pathways through its association with other proteins, discrete functions for ARID3a itself, other than interactions with DNA, have not been identified.

References
  1. Wilsker D et al. ARID proteins: a diverse family of DNA binding proteins implicated in the control of cell growth, differentiation, and development. Cell Growth Differ., 13(3):95-106. (PMID 11959810)
  2. Herrscher RF et al. The immunoglobulin heavy-chain matrix-associating regions are bound by Bright: a B cell-specific trans-activator that describes a new DNA-binding protein family. Genes Dev., 9(24):3067-82. (PMID 8543152)
  3. Kortschak RD et al. The human dead ringer/bright homolog, DRIL1: cDNA cloning, gene structure, and mapping to D19S886, a marker on 19p13.3 that is strictly linked to the Peutz-Jeghers syndrome. Genomics, 51(2):288-92. (PMID 9722953)
  4. Suzuki M et al. A novel E2F binding protein with Myc-type HLH motif stimulates E2F-dependent transcription by forming a heterodimer. Oncogene, 17(7):853-65. (PMID 9780002)
  5. Nixon JC et al. The transcription factor, Bright, is not expressed in all human B lymphocyte subpopulations. Cell. Immunol., 228(1):42-53. (PMID 15203319)
  1. Rajaiya J et al. Induction of immunoglobulin heavy-chain transcription through the transcription factor Bright requires TFII-I. Mol. Cell. Biol., 26(12):4758-68. (PMID 16738337)
  2. Peeper DS et al. A functional screen identifies hDRIL1 as an oncogene that rescues RAS-induced senescence. Nat. Cell Biol., 4(2):148-53. (PMID 11812999)
  3. Fukuyo Y et al. E2FBP1/hDril1 modulates cell growth through downregulation of promyelocytic leukemia bodies. Cell Death Differ., 11(7):747-59. (PMID 15017387)
  4. Lin L et al. Cross talk between Id1 and its interactive protein Dril1 mediate fibroblast responses to transforming growth factor-beta in pulmonary fibrosis. Am. J. Pathol., 173(2):337-46. (PMID 18583319)
Figures
FIGURE 1 Bright DNA Binding Complex
Bright binds to the immunoglobulin heavy chain (IgH) locus in activated B cells as a larger protein complex that upregulates transcription. (A) The IgH locus is transcribed at basal levels without the association of the Bright DNA binding protein complex. (B) Homodimers of ARID3A interact with Bruton's tyrosine kinase and transcription factor II-I (TFII-I) forming a complex that binds to the IgH locus and upregulates its transcription 5-6 fold. The phosphorylation (P) of TFII-I by Btk is essential for upregulation of IgH transcription.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.