Activation of the α-Internexin Promoter by the Brn-3a Transcription Factor Is Dependent on the N-terminal Region of the Protein

Budhram-Mahadeo, Vishwanie; Morris, Peter J.; Lakin, Nick D.; Theil, Thomas; Ching, Gee Y.; Lillycrop, Karen A.; Möröy, Tarik; Liem, Ronald K.H.; Latchman, David S.

doi:10.1074/jbc.270.6.2853

Cited by 63 publications

(89 citation statements)

References 38 publications

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“…Thus, Brn-3a can directly activate the promoters of genes that are associated with protection against apoptosis (Bcl-2 and Bcl-X L ) and differentiation (e.g. in structural genes such as ␣-internexin (13), neurofilament (9), receptors such as neurotrophin receptor TrkA (14), and synaptic genes such as SNAP-25 (15) and synaptophysin (16)). In addition to direct effects, Brn-3a can also modify gene transcription indirectly by interaction with cellular proteins such as p53, thus effectively increasing the range of target genes regulated by this transcription factor.…”

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confidence: 99%

Brn-3a Transcription Factor Blocks p53-mediated Activation of Proapoptotic Target Genes Noxa and Bax in Vitro and in Vivo to Determine Cell Fate

Hudson¹,

Morris²,

Latchman

et al. 2005

Journal of Biological Chemistry

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The Brn-3a POU transcription factor is associated with survival and the differentiation of sensory neuronal cells during development. Brn-3a mediates its effects either by the direct regulation of target genes or indirectly upon interaction with proteins such as p53. Brn-3a differentially regulates p53-mediated gene expression and modifies its effect on cell fate. Here we show that, like Bax, Brn-3a antagonizes p53-mediated transcription of another proapoptotic target, Noxa, significantly reducing transactivation of the Noxa promoter by p53. This effect requires the p53 binding site, and electrophoretic mobility shift assay studies suggest that Brn-3a is associated with p53 when it is bound to its site in the Noxa promoter. The wild type but not the mutant promoter can be immunoprecipitated with Brn-3a in chromatin immunoprecipitation assays. Thus, Brn-3a may act by preventing the recruitment of cofactors required for p53 to transactivate this promoter. The co-expression of Brn-3a and p53 results in decreased endogenous Noxa protein in the neuronal cell line, ND7, suggesting a direct functional effect of this interaction. Moreover, there is a significant elevation of both proapoptotic Bax and Noxa proteins in sensory neuronal tissue taken from Brn-3a؊/؊ embryos during development, compared with wild type controls. Striking changes occurred at embryonic day 14.5, a time that precedes a significant loss of specific neurons in the mutant embryos, but not at embryonic day 16.5 when Brn-3a-expressing cells are already lost by apoptosis. Therefore, the lack of antagonism by Brn-3a on activation of proapoptotic p53 target genes may contribute to the increased apoptosis seen in the Brn-3a؊/؊ embryos. These results support a crucial role for Brn-3a in determining the pathway taken by p53 when co-expressed during development and thus in controlling the fate of these cells.During neuronal development, transcription factors, which are expressed in a temporal/spatial manner or in response to specific signals, play a critical role in determining the fate of specific progenitor cells in terms of proliferation, survival and differentiation, or apoptosis of excess cells. This role is necessary to achieve the correct balance of specific neurons required for the normal innervation and function. The pit-1, oct-1/2, and unc-86 (POU) transcription factor Brn-3a protein (also referred to as POU4f1 and Brn-3.0) is essential for the survival and differentiation of specific populations of sensory neuronal cells (1, 2), but the mechanism by which this is achieved has yet to be elucidated fully.Brn-3a is expressed in regions of the developing and adult central nervous system and peripheral nervous system (3, 4). During development, Brn-3a expression is initiated just before neurons exit the cell cycle in the peripheral nervous system and just after exiting the cell cycle in the central nervous system (5). This transcription factor is expressed in and acts as a marker of the earliest postmitotic sensory neurons to appear in primary cultures...

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confidence: 99%

Brn-3a Transcription Factor Blocks p53-mediated Activation of Proapoptotic Target Genes Noxa and Bax in Vitro and in Vivo to Determine Cell Fate

Hudson¹,

Morris²,

Latchman

et al. 2005

Journal of Biological Chemistry

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“…19 Additonally, only Brn-3a[l], possessing both the POU homeodomain and an N-terminal activation domain, was found to regulate the promoters of BRCA1, a-internexin and Bcl-2 in neuroblastoma and breast cancer cells. [22][23][24] In the present study, we determined that overexpression of only Brn-3a[s] (and not Brn-3a[l]) had marked effects on growth. This isoform specificity would suggest that Brn-3a[s] might regulate important growth-related target genes in CaP cells, such as Bcl-2, Bcl-x, Bax, Hsp27.…”

Section: Upregulation Of Brn-3a[s] In Cap and Role In Growthmentioning

confidence: 96%

“…Functional differences between alternative Brn-3 transcription factor isoforms have been noted before, but typically involve significant effects of the long isoform which are not reproduced by the shorter isoform. [22][23][24] For example, overexpression of Brn-3a[l] but not Brn-3a[s] was found to be oncogenic in primary rat embryonic fibroblasts, conferring upon them the capability for anchorage-independent cell growth. 19 Additonally, only Brn-3a[l], possessing both the POU homeodomain and an N-terminal activation domain, was found to regulate the promoters of BRCA1, a-internexin and Bcl-2 in neuroblastoma and breast cancer cells.…”

Section: Upregulation Of Brn-3a[s] In Cap and Role In Growthmentioning

confidence: 99%

“…[19][20][21] The longer 43 kDa isoforms of Brn-3a and Brn-3b (Brn-3a [l] and Brn-3b [l]) contain an additional domain at the amino terminus absent in the shorter 33 kDa Brn-3a [s] and Brn-3b[s], which is required for the cell-specific regulation of target genes including a-internexin, BRCA1 and Bcl-2. [22][23][24] Thus, long and short isoforms can be functionally distinct.…”

Section: Introductionmentioning

confidence: 99%

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Brn-3a neuronal transcription factor functional expression in human prostate cancer

Diss

Faulkes

Walker

et al. 2005

Prostate Cancer Prostatic Dis

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Neuroendocrine differentiation has been associated with prostate cancer (CaP). Brn-3a (short isoform) and Brn-3c, transcriptional controllers of neuronal differentiation, were readily detectable in human CaP both in vitro and in vivo. Brn-3a expression, but not Brn-3c, was significantly upregulated in 450% of tumours. Furthermore, overexpression of this transcription factor in vitro (i) potentiated CaP cell growth and (ii) regulated the expression of a neuronal gene, the Nav1.7 sodium channel, concomitantly upregulated in human CaP, in an isoform-specific manner. It is concluded that targeting Brn-3a could be a useful strategy for controlling the expression of multiple genes that promote CaP.

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“…In a variety of transfected cells in culture, Brn3a enhances the transcription of reporters linked to both synthetic and naturally occurring binding sites. Several downstream targets of the Brn3 genes have been suggested (Budhram-Mahadeo et al, 1995;Erkman et al, 2000;Smith et al, 1997), but a direct role in the regulation of these genes in vivo has not been established. In previous work, we have shown that Brn3a can interact with specific recognition sequences within its own sensory enhancer region, suggesting that Brn3a may regulate its own expression (Trieu et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Direct autoregulation and gene dosage compensation by POU-domain transcription factor Brn3a

Trieu

Eng

et al. 2003

Development

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Brn3a is a POU-domain transcription factor expressed in peripheral sensory neurons and in specific interneurons of the caudal CNS. Sensory expression of Brn3a is regulated by a specific upstream enhancer, the activity of which is greatly increased in Brn3a knockout mice, implying that Brn3a negatively regulates its own expression. Brn3a binds to highly conserved sites within this enhancer, and alteration of these sites abolishes Brn3a regulation of reporter transgenes. Furthermore, endogenous Brn3a expression levels in the sensory ganglia of Brn3a +/+ and Brn3a +/-mice are similar, demonstrating that autoregulation can compensate for the loss of one allele by increasing transcription of the remaining gene copy. Conversely, transgenic overexpression of Brn3a in the trigeminal ganglion suppresses the expression of the endogenous gene. These findings demonstrate that the Brn3a locus functions as a self-regulating unit to maintain a constant expression level of this key regulator of neural development.

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Activation of the α-Internexin Promoter by the Brn-3a Transcription Factor Is Dependent on the N-terminal Region of the Protein

Cited by 63 publications

References 38 publications

Brn-3a Transcription Factor Blocks p53-mediated Activation of Proapoptotic Target Genes Noxa and Bax in Vitro and in Vivo to Determine Cell Fate

Brn-3a Transcription Factor Blocks p53-mediated Activation of Proapoptotic Target Genes Noxa and Bax in Vitro and in Vivo to Determine Cell Fate

Brn-3a neuronal transcription factor functional expression in human prostate cancer

Direct autoregulation and gene dosage compensation by POU-domain transcription factor Brn3a

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