Disease relevance of Pax5

• The transcription factor Pax5 activated endogenous mb-1 transcription in a plasmacytoma cell line, but could not when the promoter was methylated [1].
• Several Pax genes are also involved in chromosomal translocations causing malignancies in humans, and Pax5 expression is deregulated in medulloblastomas [2].
• We showed that Pax5(-/-) Lat(-/-) pro-B cell lines can be infected with recombinant retroviruses expressing a LAT cDNA and sorted for the expression of LAT [3].
• All Myc-induced lymphomas invariably maintained expression of Pax5, which is thought to be incompatible with terminal differentiation [4].
• Pax5-deficient mice exhibit early onset osteopenia with increased osteoclast progenitors [5].

Psychiatry related information on Pax5

• The only detectable effect of the Pax5 mutation was a delay in the development of the auditory sensitivity and response latency that correlates with the general growth retardation observed in these mice [6].

High impact information on Pax5

• Independent regulation of the two Pax5 alleles during B-cell development [7].
• Pax5 has an important role in B-cell and midbrain development [7].
• The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene [8].
• The bone marrow of these mice contains a population of cells of Pax5-/- origin with the same phenotype as the donor pro-B cells [9].
• Here we show that cloned Pax5-deficient pro-B cells transferred into RAG2-deficient mice provide long-term reconstitution of the thymus and give rise to mature T cells expressing alpha/beta-T-cell receptors [9].

Chemical compound and disease context of Pax5

• Finally, a tri-peptide motif, KLP, which showed homology with laminin 5 (a ligand for alpha3beta1 integrin), was identified as a binding peptide for peritoneal tumors of gastric cancer [10].

Biological context of Pax5

• Here we present a detailed analysis of the B-cell phenotype of Pax5 mutant mice that revealed a differential dependency of fetal and adult B lymphopoiesis on this transcriptional regulator [11].
• Restoration of BLNK expression in Ig(mu) transgenic Pax5(-/-) pro-B cells resulted in constitutive pre-BCR signaling and increased cell proliferation without inducing progression to the pre-B cell stage [12].
• In exploring the mechanism for Pax5 regulation of V(H)-to-DJ(H) recombination, we have identified multiple Pax5 binding sites in the coding regions of human and mouse V(H) gene segments [13].
• The balance between Pax5 and Id2 activities is the key to AID gene expression [14].
• The kinetics of Pax5, but not E2A, occupancy to AID locus is the same as AID expression in primary B cells [14].

Anatomical context of Pax5

• Long-term in vivo reconstitution of T-cell development by Pax5-deficient B-cell progenitors [9].
• The Pax5 gene coding for the transcription factor BSAP has an essential role in B lymphopoiesis and midbrain development [11].
• However, Pax5-deficient fetal liver cells gave rise to the development of pre-BI cells in bone marrow on transplantation into lethally irradiated mice [11].
• Pax5 thereby interfered with T lineage commitment and early thymocyte development by repressing the transcription of the T cell specification gene Notch1 [15].
• Conditional and constitutive activation of the Ik(Pax5) allele demonstrated that precocious Pax5 expression in hematopoietic stem cells and progenitors failed to interfere with myeloid development and only weakly affected erythroblast formation [15].

Associations of Pax5 with chemical compounds

• Our results suggest that STAT5 phosphorylated by IL-7 can directly up-regulate Pax5 transcription in early B cells [16].
• B cell-specific loss of histone 3 lysine 9 methylation in the V(H) locus depends on Pax5 [17].
• 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the regulation of Pax5 in lipopolysaccharide-activated B cells [18].
• Re-expression of Pax5 was also induced by trichostatin A (TSA), which was a specific inhibitor of histone deacetylase [19].
• Demethylation of FO and Sp-2/0 with 5-aza-2'-deoxycytidine (5-aza-dC) resulted in Pax5 re-expression with the concomitant expression of CD19 and mb-1 genes, which are known to be the target genes of Pax5 [19].
• Significance of these murine studies was established by evidence showing a widespread up-regulation of both MTA1 and Pax5 in DLBCL from humans [20].

Physical interactions of Pax5

• Together these data indicate that Pax2 and homeodomain proteins directly bind to and cooperatively regulate the mhb enhancer of Pax5 [21].
• Blimp-1 binds a site on the Pax-5 promoter in vitro and in vivo and represses the Pax-5 promoter in a binding-site-dependent manner [22].
• When Pax5 binding to the enhancer in B cells was blocked in vivo by transfection with a triple-helix-forming oligonucleotide an alpha P footprint appeared and endogenous immunoglobulin heavy chain transcripts increased [23].
• These studies suggest that different NF-kappaB complexes are able to interact with a sequence overlapping the Pax-5 site on the blk promoter and that the relative levels of "bound" factor influence levels of blk expression [24].
• Gene transfer and gel-shift assays demonstrate that EBB-1 is identical to Pax-5 and binds to promoters of VpreB and lambda5 as well as the KI and KII sites [25].

Regulatory relationships of Pax5

• Pax5 promotes B lymphopoiesis and blocks T cell development by repressing Notch1 [15].
• To investigate whether these contrasting phenotypes are caused by differences in the temporal expression or biochemical activity of these two transcription factors, we have generated a knock-in (ki) mouse, which expresses a Pax5 minigene under the control of the Pax2 locus [26].
• Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene [27].
• Reconstitution of Pax5 expression in Pax5-/- pro-B cells induced large-scale contraction and distal VH-DJH rearrangements of the IgH locus [27].
• To study the effect of Pax5 on the development of other hematopoietic lineages, we generated a heterozygous knockin mouse carrying a Pax5 minigene under the control of the Ikaros locus [15].

Other interactions of Pax5

• These data suggest a molecular basis for the hierarchical dependence of Pax5 function on EBF and E2A in B lymphocyte development [1].
• Therefore, STAT5 functions at a distinct step in regulating distal V(H) recombination in relation to the transcription factor Pax5 and histone methyltransferase Ezh2 [28].
• Phenotypic and expression studies show that Bcl11a functions upstream of the transcription factors Ebf1 and Pax5 in the B cell pathway [29].
• In Pax2 mutant embryos, expression of the endogenous Pax5 gene was, however, delayed and severely reduced in lateral aspects of the neural plate which, on neural tube closure, becomes the dorsal mhb region [21].
• The expression of Pax5 and Pax8 is either not initiated at the midbrain-hindbrain boundary or is later not maintained in other expression domains [30].

Analytical, diagnostic and therapeutic context of Pax5

• As shown by PCR analyses, the pre-BI cells in Pax5-deficient bone marrow have undergone D(H)-to-J(H) rearrangement of the immunoglobulin heavy-chain locus at normal frequency [11].
• To investigate whether signals from the IL-7R regulate Pax5 transcription, we searched the consensus sequence of signal transducers and activators of transcription (STAT) in the Pax5 promoter region, since STAT is one of the components of cytokine signal transduction [16].
• Using an electrophoretic mobility shift assay, it was shown that a B-cell-specific transcription protein, Pax-5, and a T-cell-specific transcription protein, GATA-3, bind to the -80 to -17 nt region in B cells and T cells, respectively [31].
• The targeted mutation of Pax-5 has been reported to have only slight effects in the development of structures derived from the isthmic constriction, whereas the Pax-2 null mutant mice show a background-dependent phenotype with varying penetrance [32].
• By RT-PCR analysis we could also demonstrate expression of the B-cell associated genes Pax-5, Rag-2, and TdT [33].

References