Disease relevance of POU4F2

• In this study, we show a strong correlation between elevated levels of the Brn-3b POU transcription factor and high levels of HSP-27 protein in manipulated MCF-7 breast cancer cells as well as in human breast biopsies [1].
• Immunohistochemical experiments show that chicken, mouse, rabbit, monkey, and human retinas contain Brn-3b exclusively within a subpopulation of ganglion cells [2].
• We previously showed that the Brn-3b transcription factor is highly expressed in actively proliferating neuroblastoma cells but is significantly decreased when these cells are induced to differentiate [3].
• We therefore measured expression of Brn-3a and Brn-3b mRNAs in biopsies from 16 women with no detectable cervical abnormality, and in 14 women with cervical intraepithelial neoplasia grade 3 (CIN3) lesions [4].
• Distinct responses of the herpes simplex virus and varicella zoster virus immediate early promoters to the cellular transcription factors Brn-3a and Brn-3b [5].

High impact information on POU4F2

• The cervical cellular transcription factors Brn-3a and Brn-3b have antagonistic effects on transcription of the human papilloma virus types 16 and 18 E6 and E7 oncogenes, with Brn-3a activating expression and Brn-3b repressing it [4].
• Brn-3b: a POU domain gene expressed in a subset of retinal ganglion cells [2].
• During the immediate postnatal period, cells containing Brn-3b are distributed in a number of regions within the brain stem and cerebellum [2].
• A search for POU domain transcription factors in human retina cDNA has led to the identification of Brn-3b, a class IV POU domain protein [2].
• In the adult mouse brain, Brn-3b is found only within cells in the deep layers of the superior colliculus, in the dorsal periaqueductal gray, and in a small cluster of cells in the brain stem near the area postrema [2].

Biological context of POU4F2

• POU transcription factors Brn-3a and Brn-3b interact with the estrogen receptor and differentially regulate transcriptional activity via an estrogen response element [6].
• RNA interference and site-directed mutagenesis support the requirement for the Brn-3b binding site on the HSP-27 promoter, which facilitates maximal transactivation either alone or on interaction with the ER [1].
• These results thus further indicate a role for the Brn-3b transcription factor in regulating mammary cell growth and suggest that its elevation in breast cancer is of functional significance [7].
• Five to ten per cent of the Brn-3b over-expressing cells exhibited a severely altered morphology characterized by reduced adherence to tissue culture plastic, increased cell size, and a vacuolar cell shape [7].
• Here we show that overexpression of Brn-3b can reduce process outgrowth and synaptic vesicle gene expression following exposure to a stimulus which would normally induce differentiation [8].

Anatomical context of POU4F2

• Likewise, the Brn-3b anti-sense cell lines showed reduced cellular growth and proliferation, reached confluence at a lower density, and exhibited a decreased ability to form colonies in soft agar when compared to the vector controls [7].
• The Brn-3b POU domain containing transcription factor is expressed in the developing sensory nervous system as well as in epithelial cells of the breast, cervix, and testes [7].
• The differentiation of the ND7 neuronal cell line to a nondividing phenotype bearing numerous neurite processes is accompanied by a dramatic increase in the levels of the activating POU family transcription factor Brn-3a and a corresponding fall in the levels of the closely related inhibitory factor Brn-3b [8].
• In addition, we observed that overexpression of Brn-3a and Brn-3b in cultured cells enhanced expression of Hsp90 protein and transcription of Hsp90 promoter-reporter constructs [9].
• Hence, as observed in neuronal cells, Brn-3a and Brn-3b may play distinct and important functional roles in the regulation of gene expression during germ cell development [10].

Associations of POU4F2 with chemical compounds

• Cells with high Brn-3b also fail to respond to growth inhibitory retinoic acid, as they continue to proliferate [3].
• The neuronal nicotinic acetylcholine receptor alpha 2 subunit gene promoter is activated by the Brn-3b POU family transcription factor and not by Brn-3a or Brn-3c [11].
• The levels of the transcripts encoding these factors are regulated in opposite directions in neuronal cells by specific cellular signalling pathways with dibutyryl cyclic AMP treatment and serum removal enhancing the level of Brn-3a and reducing the level of Brn-3b expression [12].
• The cellular POU family transcription factors Brn-3a and Brn-3b are expressed in sensory ganglia and bind to the TAATGARAT (R stands for purine) regulatory motifs in the immediate-early gene promoters of these viruses [5].
• Although transcriptional activation by mutant forms of Brn-3a/Brn-3b can occur with a number of different amino acids at position 22 of the POU homeodomain, an isoleucine at this position is of critical importance for transcriptional repression [13].

Physical interactions of POU4F2

• Likely due to POU domain homology, the related factor Brn-3b can also interact with EWS, but to a lesser extent than Brn-3a [14].

Regulatory relationships of POU4F2

• For example, Brn-3b activates the cell cycle regulator CDK4 that provides a mechanism by which Brn-3b controls the growth of breast cancer cells [15].
• We show here that mammary tumours which have reduced levels of BRCA-1 expression show enhanced expression of the Brn-3b POU family transcription factor at both the mRNA and protein levels [16].
• The closely related POU family transcription factors Brn-3a and Brn-3b differ in their effect on a number of different neuronally expressed promoters such as that of the gene encoding the synaptic vesicle component SNAP-25 [17].

Other interactions of POU4F2

• Activation of CDK4 gene expression in human breast cancer cells by the Brn-3b POU family transcription factor [18].
• The Brn-3b POU family transcription factor has previously been shown to be over-expressed in human breast cancer and to enhance the growth rate and anchorage independent growth of human breast cancer cells, acting at least in part by inhibiting the expression of the BRCA-1 anti-oncogene [18].
• The human Brn-3b POU transcription factor shows only limited homology to the Brn-3a/RDC-1 factor outside the conserved POU domain [19].
• Both the Brn-3a and Brn-3c factors can activate the alpha-internexin promoter while Brn-3b represses it and can prevent activation by Brn-3a [20].
• Levels of Brn-3a and Brn-3b messenger RNA (mRNA) in PBMCs were measured by reverse transcription and real-time quantitative polymerase chain reaction [9].

Analytical, diagnostic and therapeutic context of POU4F2

• Chromatin immunoprecipitation provides evidence for association of Brn-3b with the HSP-27 promoter in the intact cell [1].
• Moreover, Brn-3b levels significantly modified tumor growth in vivo with elevated Brn-3b resulting in faster tumor growth in xenograft models whereas decreasing Brn-3b resulted in slower growth compared with controls [3].
• The POU domain transcription factors Brn-3b and Brn-3a, which are expressed in retinal ganglion cells (RGCs) directly after the exit of RGC precursors from the cell cycle, can be employed as RGC-specific differentiation markers to study potential dedifferentiation of RGCs after axotomy [21].
• Serum antibodies to the Brn-3a and Brn-3b transcription factors were measured by enzyme-linked immunosorbent assay [9].
• We determined that 60 min of ischemia caused a 49% and a 32% decrease in Brn-3b positive retinal ganglion cells in Lewis rats after 4 weeks reperfusion, and Sprague-Dawley rats after 2 weeks reperfusion, respectively [22].

References