Disease relevance of POU2AF1

• Identification of a potential role for POU2AF1 and BTG4 in the deletion of 11q23 in chronic lymphocytic leukemia [1].
• Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans [2].
• In contrast, immunostaining for BOB-1/OCA-B--essentially restricted to B cells in normal lymphoid tissue, with the exception of activated T-lymphocytes--was seen in all of the T-cell lines tested and the majority of the tumor cells in all categories of T-cell lymphoma [3].
• These properties of OCA-B parallel those displayed by the herpes simplex virus Oct-1 coregulator VP16 [4].

High impact information on POU2AF1

• An interaction with OBF-1 is precluded since the same Oct-1 residues that form the MORE dimerization interface are also used for OBF-1/Oct-1 interactions on the PORE [5].
• The OBF-1 mRNA is expressed in a highly cell-specific manner, being most abundant in B cells and essentially absent in most of the other cells or tissues tested [6].
• Using a genetic screen in yeast, we have isolated B cell-derived cDNAs encoding Oct-binding factor 1 (OBF-1), a novel protein that specifically associates with Oct-1 and Oct-2 [6].
• Furthermore, expression of OBF-1 in HeLa cells selectively stimulates the activity of a natural immunoglobulin promoter in an octamer site-dependent manner [6].
• The OCA-B peptide binds in the major groove near the center of the octamer site, and its polypeptide backbone forms a pair of hydrogen bonds with the adenine base at position 5 of the octamer DNA [7].

Biological context of POU2AF1

• POU2AF1 is a B-cell-specific transcriptional coactivator, and BTG4 is a member of the BTG family of negative regulators of the cell cycle, making both of them good candidate genes for the pathogenesis of 11q- CLL [1].
• Here we show that the expression of Osteopontin, which contains a PORE sequence in its enhancer region, depends on the presence of OBF1 in B cells [8].
• Depending on the DNA sequence to which they bind, the dimers are arranged in configurations that are either accessible (PORE sequence) or inaccessible (MORE sequence) to the B-cell-specific cofactor OBF1 (OcaB, Bob1) [8].
• Furthermore, OBF1 stabilizes POU dimer-DNA interactions and overrides Oct1 interface mutations, which abolish PORE-mediated dimerization without OBF1 [8].
• Bob1 transactivation only occurs with select octamer sequences that have an adenosine at position 5 (ATGCAAAT) [9].

Anatomical context of POU2AF1

• POU2AF1 was observed to be differentially expressed in the cells of patients with CLL compared to its expression in normal B cells in the absence of mutations [1].
• The transcriptional coactivator OBF-1, which interacts with Oct-1 and Oct-2 and the octamer site DNA, has been shown to be critical for development of a normal immune response and the formation of germinal centers in secondary lymphoid organs [10].
• Further analysis of general coactivator requirements showed that selective removal of PC4 from the essential USA fraction severely impairs Oct-1 and OCA-B function in a cell-free system reconstituted with partially purified factors [11].
• However, the high frequency of BOB-1 expression in T-cell neoplasms, in contrast to its absence from resting peripheral T cells, suggests that its expression might be a prerequisite for neoplastic transformation, and prompts a search for the transcriptional target(s) of this factor in T cells [3].
• During B cell development OBF-1 expression shows two peaks, one in immature B cells in the bone marrow and the other in germinal center B cells [12].

Associations of POU2AF1 with chemical compounds

• Nucleotidic sequence of a nearly full-length cDNA of the BOB1/OBF1 gene revealed particular features in the 3' untranslated region of the gene, including pyrimidine-rich sequence repeats, an Alu motif, and a polymorphic [CCTT] tetranucleotide microsatellite [13].

Physical interactions of POU2AF1

• Here we have identified the RING finger protein Siah-1 as a protein interacting specifically with OBF-1 [10].
• In pull-down assays, increasing amounts of SMRT could compete the binding of OCA-B to Oct-1 POU domain [14].

Regulatory relationships of POU2AF1

• The RING finger protein Siah-1 regulates the level of the transcriptional coactivator OBF-1 [10].

Other interactions of POU2AF1

• Based on our biochemical data, we propose a mode of OBF1-Oct1 dimer interaction, suggesting a novel arrangement of the subdomain connectivities [8].
• These findings indicate that genomic imbalances or rearrangements are not a cause of PU.1, BOB1, and OCT2 deficiency in cHL and argue for another mechanism underlying this phenomenon [15].
• This interaction is mediated by the C-terminal part of Siah-1 and by residues in the N-terminus of OBF-1, partly distinct from the residues required for formation of a complex with the Oct POU domains and the DNA [10].
• The lymphoid-specific transcriptional coactivator OBF-1 (also known as OCA-B or Bob-1) is recruited to octamer site-containing promoters by interacting with Oct-1 or Oct-2 and thereby enhances the transactivation potential of these two Oct factors [16].
• The activity of Oct-1 could be determined by a regulated balance between SMRT and OCA-B [14].

Analytical, diagnostic and therapeutic context of POU2AF1

• Molecular dissection of the B-cell-specific transcription coactivator OCA-B has revealed distinct regions important, respectively, for recruitment to immunoglobulin promoters through interaction with octamer-bound Oct-1 and for subsequent coactivator function [11].
• By methylation interference analysis we identified bases that react differently in the presence of OBF-1 compared to the POU domain alone, and using phosphothioate backbone-modified probes in electrophoretic mobility shift assays, we identified several positions influencing ternary complex formation [16].
• Assignment of the human gene for Oct-binding factor-1 (OBF1), a B-cell-specific coactivator of octamer-binding transcription factors 1 and 2, to 11q23.1 by somatic cell hybridization and in situ hybridization [17].
• Using microarray analysis, we have identified the Ets transcription factor Spi-B as a direct target gene critically regulated by OBF-1 that can help explain the phenotype of OBF-1-deficient mice [18].
• In addition, the presence of hAd did not significantly modify the AP activity of hBOB (0.163 +/- 0.143 and 0.181 +/- 0.114 nmol/min per microgram of protein in controls and after coculture, respectively) [19].

References