Regulation of Neurite Outgrowth and SNAP-25 Gene Expression by the Brn-3a Transcription Factor

Lakin, Nick D.; Morris, Peter J.; Theil, Thomas; Sato, Tom N.; Möröy, Tarik; Wilson, Michael C.; Latchman, David S.

doi:10.1074/jbc.270.26.15858

Cited by 66 publications

(55 citation statements)

References 35 publications

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“…In contrast, the only other known target for activation by Brn-3b, the nicotinic acetylcholine receptor α2 subunit gene is not activated by the isolated POU domain of Brn-3b. 26 This is similar to observations with the related Brn-3a factor, where some genes are activated by the isolated POU domain alone [23][24][25] whereas others require additional N-terminal sequences. 35,36 Whatever the case, the data presented here identify CDK4 as a target for transcriptional activation by Brn-3b.…”

Section: Discussionsupporting

confidence: 71%

“…Thus, although Brn-3b can activate the promoter of the nicotinic acetylcholine receptor α2 subunit gene. 26 Brn-3b represses the expression of a variety of genes involved in neuronal differentiation including SNAP-25 24 and the neurofilaments 25 and thereby represses neuronal differentiation itself. 27 Our initial studies in breast cancer cells, identified the BRCA-1 gene as a target for transcriptional repression by Brn-3b.…”

Section: Discussionmentioning

confidence: 99%

“…21,22 A construct containing the isolated POU domain of Brn-3b was also able to activate the CDK4 promoter, indicating that, as in the related Brn-3a factor, [23][24][25] the POU domain can act as a transcriptional activation domain, as well as a DNA binding domain.…”

Section: Identification Of Genes Regulated By Brn-3b Using Microarraymentioning

confidence: 99%

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Activation of CDK4 Gene Expression in Human Breast Cancer Cells by the Brn-3b POU Family Transcription Factor

Samady

Dennis²,

Budhram-Mahadeo³

et al. 2004

Cancer Biology & Therapy

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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Activation of CDK4 Gene Expression in Human Breast Cancer Cells by the Brn-3b POU Family Transcription Factor

Samady

Dennis²,

Budhram-Mahadeo³

et al. 2004

Cancer Biology & Therapy

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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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“…In agreement with this idea the three members of the Brn-3 family are expressed in distinct but overlapping populations of neuronal cells during development and in the adult organism (1)(2)(3)(4)(5)11) with Brn-3a for example being expressed in the first differentiated neurons to appear in the midbrain, hindbrain, and spinal cord during development (12). Interestingly Brn-3a has been shown in co-transfection experiments to activate several promoters including those of the neuronally expressed genes encoding pro-opiomelancortin (1), ␣-internexin (13), and the presynaptic vesicle protein SNAP-25 (14) as well as a thymidine kinase (tk) 1 promoter containing an added synthetic binding site for the various forms of Brn-3 (tk-Oct) (15,18). In contrast Brn-3b represses these promoters (13,15,18) and also inhibits their activation by Brn-3a.…”

mentioning

confidence: 99%

Inhibition of Neuronal Process Outgrowth and Neuronal Specific Gene Activation by the Brn-3b Transcription Factor

Dawson

Latchman

1997

Journal of Biological Chemistry

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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. We have previously shown that the artificial overexpression of Brn-3a in these cells can induce neurite outgrowth and the activation of genes encoding synaptic vesicle proteins in the absence of a differentiation-inducing stimulus. 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. These inhibitory effects are abolished by altering a single amino acid in the POU homeodomain of Brn-3b to its equivalent in Brn-3a. The converse mutation in Brn-3a allows it to inhibit process outgrowth in response to a differentiation-inducing stimulus. Hence a single amino acid difference results in these closely related factors having opposite effects and allows the balance between them to regulate differentiation.The Brn-3a, Brn-3b, and Brn-3c transcription factors (also known as Brn-3.0, 3.2, and 3.1, respectively) (1, 2) are closely related members of the POU family of transcription factors which are encoded by three distinct genes (3-6) (for review of POU factors see Refs. 7 and 8). Among the mammalian POU factors, the Brn-3 proteins are the most closely related to the nematode POU factor Unc-86, which plays a critical role in neuronal development in the nematode (9, 10) suggesting that the Brn-3 factors may play a similar role in mammals. In agreement with this idea the three members of the Brn-3 family are expressed in distinct but overlapping populations of neuronal cells during development and in the adult organism (1-5, 11) with Brn-3a for example being expressed in the first differentiated neurons to appear in the midbrain, hindbrain, and spinal cord during development (12). Interestingly Brn-3a has been shown in co-transfection experiments to activate several promoters including those of the neuronally expressed genes encoding pro-opiomelancortin (1), ␣-internexin (13), and the presynaptic vesicle protein SNAP-25 (14) as well as a thymidine kinase (tk) 1 promoter containing an added synthetic binding site for the various forms of Brn-3 (tk-Oct) (15, 18). In contrast Brn-3b represses these promoters (13,15,18) and also inhibits their activation by Brn-3a. Similarly Brn-3c has only a weak activating effect on these promoters (13,15,18).When the proliferating ND7 cell line (obtained by fusing primary dorsal root ganglion neurons with C1300 neuroblastoma cells) (17) is induced to cease dividing and differentiate to a mature neuronal-like phenotype by treatment with cyclic AMP or removal of serum from the medium (18), the levels of Brn-3a rise dramatically, and those of Brn-3b fall (3, 15), while Brn-3c levels remain unchanged.2 This differentiation process is likely to require the induct...

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Regulation of Neurite Outgrowth and SNAP-25 Gene Expression by the Brn-3a Transcription Factor

Cited by 66 publications

References 35 publications

Activation of CDK4 Gene Expression in Human Breast Cancer Cells by the Brn-3b POU Family Transcription Factor

Activation of CDK4 Gene Expression in Human Breast Cancer Cells by the Brn-3b POU Family Transcription Factor

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

Inhibition of Neuronal Process Outgrowth and Neuronal Specific Gene Activation by the Brn-3b Transcription Factor

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