Alternative titles; symbols
HGNC Approved Gene Symbol: ARID4A
Cytogenetic location: 14q23.1 Genomic coordinates (GRCh38): 14:58,298,555-58,373,876 (from NCBI)
Starting with the information that the E7 transforming protein of human papillomavirus-16 binds to the RB1 gene (614041) through a 9-amino acid segment of E7 that is homologous to the RB-binding domains of the simian virus-40 large T and adenovirus E1A transforming proteins, and that all of these viral transforming proteins bind to the same region of the RB1 protein, Defeo-Jones et al. (1991) isolated cellular proteins that interact with this viral protein-binding domain of the RB protein. Two partial cDNAs were isolated that encode RB-binding proteins, ARID4A and JARID1A (180202), which Defeo-Jones et al. (1991) designated RBP1 and RBP2, respectively. Both proteins contain the RB protein-binding motif conserved in the 3 viral transforming proteins mentioned.
Using the partial cDNA clone isolated by Defeo-Jones et al. (1991) to screen pre-B-cell leukemia cell line and fetal brain cDNA libraries, Fattaey et al. (1993) obtained a full-length cDNA encoding RBP1. The deduced 1,257-amino acid protein has a calculated molecular mass of 142.6 kD. The N-terminal region of RBP1 contains a cluster of charged amino acids, and the C-terminal region contains the LxCxE RB-binding motif. Northern blot analysis detected RBP1 expression at variable levels in all tissues examined, and Western blot analysis detected RBP1 expression in all human cell lines examined. Endogenous RBP1 migrated at an apparent molecular mass of 200 kD. Immunoprecipitation of fractionated glioblastoma cells indicated that RBP1 is a nuclear protein.
By screening an MCF7 breast cancer cell line cDNA expression library with IgG purified from serum of a patient with breast cancer, Cao et al. (1999) cloned RBP1. Northern blot analysis detected a 4.8-kb transcript in MCF7 cells and peripheral blood leukocytes. Western blot analysis revealed an immunoreactive protein of about 46 kD in MCF7 cell lysates. Immunohistochemical analysis detected ARID4B in the cytoplasm of MCF7 cells and in 12 of 15 primary breast cancer tissues, but not in adjacent normal tissue.
Defeo-Jones et al. (1991) determined that a sequence within RBP1 containing an LxCxE motif was required for interaction of RBP1 with RB.
By immunoprecipitation of RBP1 from a myeloid leukemia cell line, Fattaey et al. (1993) confirmed that RBP1 interacts with RB in vivo. Mutation of the LxCxE motif of RBP1 disrupted the RBP1-RB interaction. The interaction was also disrupted in the presence of E7 viral oncoprotein.
By mutation analysis, Lai et al. (1999) determined that RBP1 contains 2 repression domains. Repression domain-1 (RD1), located in the N-terminal half of RBP1, bound HDAC1 (601241), HDAC2 (605164), and HDAC3 (605166) and repressed transcription in an HDAC-dependent manner. RD2, located at the C terminus of RBP1, repressed transcription independently of HDACs. Lai et al. (1999) found that RBP1 interacted with the pocket domain of RB family members. The RB pocket domain is required to mask the transcriptional activation domain of E2F (see E2F1; 189971) and repress E2F-dependent promoters. RBP1 preferentially interacted with hypophosphorylated forms of RB and p107 (RBL1; 116957), and the interaction required the LxCxE pocket-binding motif of RBP1. Lai et al. (1999) concluded that RB family members repress transcription by recruiting RBP1 to the RB pocket domain. RBP1, in turn, serves as an adaptor to recruit HDACs and provides a second HDAC-independent repression function.
Lai et al. (2001) found that human RBP1 recruited SIN3 (see SIN3A; 607776)-HDAC complexes to RB family members. Antibodies against SIN3A and SIN3B (607777) coimmunoprecipitated RBP1 from a lung carcinoma cell line and from HeLa cells. RBP1 did not coimmunoprecipitate with NURD-HDAC complex components (see MTA1; 603526). Protein pull-down experiments with RBP1 deletion mutants indicated that the C-terminal R2 region of RBP1 was responsible for SIN3-HDAC binding. The R2 region of RBP1 also interacted with the SIN3-HDAC subunit SAP30 (603378), and SAP30 was required to recruit HDAC activity to RB proteins. RBP1 and RB colocalized with SIN3-HDAC complexes in quiescent human fibroblasts at perinucleolar sites associated with DNA replication following growth stimulation. Lai et al. (2001) concluded that RB-mediated recruitment of the SIN3-HDAC complex via RBP1 may repress transcription from E2F-dependent promoters and drive exit from the cell cycle.
Prader-Willi syndrome (PWS; 176270) and Angelman syndrome (AS; 105830) are caused by deficiency of imprinted gene expression from paternal and maternal chromosome 15, respectively. Genomic imprinting of the PWS/AS domain is regulated through a bipartite cis-acting imprinting center (IC) within and upstream of the SNRPN (182279) promoter. Using gene trap mutagenesis selecting for altered expression of an SNRPN-EGFP fusion gene in mouse embryonic stem cells, Wu et al. (2006) identified Arid4a and Arid4b (609696). Coimmunoprecipitation experiments and chromatin immunoprecipitation assays showed that human ARID4A interacted with mouse Arid4b and with the SNRPN promoter. To further elucidate the roles of ARID4A and ARID4B in the regulation of imprinting, Wu et al. (2006) deleted the Arid4a and Arid4b genes in mice. Combined homozygous deficiency for Arid4a and heterozygous deficiency for Arid4b altered epigenetic modifications at the PWS-IC with reduced trimethylation of histone H4 (see 602822) lys20 and H3 (see 602810) lys9 and reduced DNA methylation, changing the maternal allele toward a more paternal epigenotype. Mutations in Arid4a, Arid4b, or Rb suppressed an AS imprinting defect caused by a mutation in the AS-IC. Wu et al. (2006) concluded that ARID4A and ARID4B are members of epigenetic complexes that regulate genomic imprinting at the PWS/AS domain.
Hurst et al. (2008) stated that BRMS1 (606259) interacts with ARID4A as part of SIN3-histone deacetylase chromatin remodeling complexes. Yeast 2-hybrid analysis showed that the second coiled-coil domain of BRMS1 interacted directly with ARID4A, and the L174D point mutation in the second coiled-coil domain abolished the interaction. Coimmunoprecipitation analysis of human breast cancer cell lines expressing these BRMS1 mutations suggested an indirect association between mutant BRMS1 and ARID4A remained intact. Deletion of the first coiled-coil domain of BRMS1 abolished the indirect interaction. The BRMS1 L174D point mutation also impaired the suppression of basal transcription by BRMS1/ARID4A, but it did not alter BRMS1-mediated suppression of metastasis.
Stumpf (2024) mapped the ARID4A gene to chromosome 14q23.1 based on an alignment of the ARID4A sequence (GenBank BC026230) with the genomic sequence (GRCh38).
Wu et al. (2006) found that Arid4a -/- mice were viable and fertile, whereas Arid4b -/- embryos died before embryonic day 7.5.
Cao, J., Gao, T., Giuliano, A. E., Irie, R. F. Recognition of an epitope of a breast cancer antigen by human antibody. Breast Cancer Res. Treat. 53: 279-290, 1999. [PubMed: 10369074] [Full Text: https://doi.org/10.1023/a:1006115922401]
Defeo-Jones, D., Huang, P. S., Jones, R. E., Haskell, K. M., Vuocolo, G. A., Hanobik, M. G., Huber, H. E., Oliff, A. Cloning of cDNAs for cellular proteins that bind to the retinoblastoma gene product. Nature 352: 251-254, 1991. [PubMed: 1857421] [Full Text: https://doi.org/10.1038/352251a0]
Fattaey, A. R., Helin, K., Dembski, M. S., Dyson, N., Harlow, E., Vuocolo, G. A., Hanobik, M. G., Haskell, K. M., Oliff, A., Defeo-Jones, D., Jones, R. E. Characterization of the retinoblastoma binding proteins RBP1 and RBP2. Oncogene 8: 3149-3156, 1993. [PubMed: 8414517]
Hurst, D. R., Xie, Y., Vaidya, K. S., Mehta, A., Moore, B. P., Accavitti-Loper, M. A., Samant, R. S., Saxena, R., Silveira, A. C., Welch, D. R. Alterations of BRMS1-ARID4A interaction modify gene expression but still suppress metastasis in human breast cancer cells. J. Biol. Chem. 283: 7438-7444, 2008. [PubMed: 18211900] [Full Text: https://doi.org/10.1074/jbc.M709446200]
Lai, A., Kennedy, B. K., Barbie, D. A., Bertos, N. R., Yang, X. J., Theberge, M.-C., Tsai, S.-C., Seto, E., Zhang, Y., Kuzmichev, A., Lane, W. S., Reinberg, D., Harlow, E., Branton, P. E. RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest. Molec. Cell. Biol. 21: 2918-2932, 2001. [PubMed: 11283269] [Full Text: https://doi.org/10.1128/MCB.21.8.2918-2932.2001]
Lai, A., Lee, J. M., Yang, W.-M., DeCaprio, J. A., Kaelin, W. G., Jr., Seto, E., Branton, P. E. RBP1 recruits both histone deacetylase-dependent and -independent repression activities to retinoblastoma family proteins. Molec. Cell. Biol. 19: 6632-6641, 1999. [PubMed: 10490602] [Full Text: https://doi.org/10.1128/MCB.19.10.6632]
Stumpf, A. M. Personal Communication. Baltimore, Md. 04/04/2024.
Wu, M.-Y., Tsai, T.-F., Beaudet, A. L. Deficiency of Rbbp1/Arid4a and Rbbp1l1/Arid4b alters epigenetic modifications and suppresses an imprinting defect in the PWS/AS domain. Genes Dev. 20: 2859-2870, 2006. [PubMed: 17043311] [Full Text: https://doi.org/10.1101/gad.1452206]