The POU (Pit-Oct-Unc) family of transcription factors are defined on the basis of a common POU domain which constitutes the DNA binding domain of these proteins and which can be subdivided into a POU-specific domain and a POU-homeodomain separated by a short linker region (for reviews, see (1) and (2) ). In contrast to the classical homeodomain proteins, the POU proteins bind to extended DNA sequences related to the consensus octamer motif ATGCAAAT and thereby influence transcription(1, 2, 3) . Such modulation of transcription by POU factors plays a critical role in the development of specific cell types. Thus, for example, the Pit-1 factor has been shown to be essential for pituitary gland development in both mice and humans(4, 5) , while the unc-86 mutation in the nematode results in the failure to develop specific neuronal cell types particularly sensory neurons(6, 7) .

Among the mammalian POU proteins, the Brn-3 family of factors are the most closely related to unc-86 within the POU domain and these proteins together with the Drosophila factors I-POU and tI-POU (8, 9) constitute the POU-IV class of POU factors(1, 2) . Following the identification of the founder member of the Brn-3 family (10) , now known as Brn-3a (11, 12, 13) or Brn-3.0(10, 14) , two other members of this family have been identified. Like Brn-3a, each of these factors, Brn-3b (12, 15) (also known as Brn-3.2) (16) and Brn-3c (17) (also known as Brn-3.1) (14) are expressed at high levels in sensory neurons paralleling the important role of Unc-86 in this cell type and are also present in other neuronal cells but not in most non-neuronal cell types(12, 14, 17) . The three different Brn-3 factors are encoded by three distinct genes (13) and show only restricted homology to one another outside the POU domain(10, 11, 12, 13, 14, 15, 16, 17, 18) .

These sequence differences between the different Brn-3 factors are paralleled by differences in their activity. Thus both Brn-3a and Brn-3c can co-operate with the Ha-ras oncogene to transform primary rat embryo fibroblasts(11) . In contrast Brn-3b does not possess this ability and can inhibit the transforming effect of Brn-3a in co-transfection experiments. ()The transforming activity of Brn-3a is dependent on the N-terminal region of the protein(11) which contains a short region known as the POU-IV box that is common to several different POU-IV family members(11, 14, 15) .

In addition to differences in their transforming ability, the Brn-3 proteins can also have radically different effects on promoter activity. Thus, while the POU domains of all three Brn-3 factors can bind to the octamer motif, a thymidine kinase promoter containing an added synthetic octamer motif is trans-activated by co-transfection with Brn-3a and Brn-3c expression vectors and inhibited by Brn-3b(20) . Although, as in the transformation experiments, Brn-3b can inhibit trans-activation by Brn-3a(20) , the ability of Brn-3a to trans-activate the target promoter is not dependent on the N-terminal region of the protein. Rather chimeric molecules containing only the POU domain of Brn-3a linked to the rest of the Brn-3b molecule are able to activate this promoter, whereas a molecule containing the Brn-3b POU domain linked to the remainder of Brn-3a represses it(21) . Hence, the differences in the activity of the Brn-3 factors on this test promoter are determined by the POU domain.

These differences in the region of the Brn-3a protein required for transactivation of an artificial test promoter and transformation suggest the possibility that transformation by Brn-3a might not involve transactivation of target genes. Alternatively, the region of Brn-3a required for transactivation may be different depending on the target promoter with some naturally occurring promoters whose protein products are necessary for transformation requiring the N-terminal domain for transactivation rather than the POU domain.

To investigate this question, we have identified the gene encoding the neuronal intermediate filament protein -internexin (22) as the first neuronally expressed target genes transactivated by Brn-3a and have shown that such transactivation requires the N-terminal region of the protein.

MATERIALS AND METHODS

Plasmid DNAs

()

DNA Transfection

CAT Assay

RESULTS

To identify a natural target gene for the Brn-3 factors we tested the promoters of several genes which like the Brn-3 factors (10, 12, 17) are expressed in sensory neurons and which contain octamer or octamer-related sequences in their promoters that could potentially bind Brn-3. In each case, the gene promoter driving the gene encoding the marker CAT protein was co-transfected with vectors directing the expression of each of the forms of Brn-3(11) . Transfections were carried out both into BHK-21 fibroblast cells (25) which lack endogenous Brn-3 as well as into the ND7 cell line derived by the immortalization of primary sensory neurons (26) which expresses all the different forms of Brn-3(12) .

In these experiments, no effect of any of the forms of Brn-3 was observed on the promoters of the genes encoding either calcitonin gene related peptide or tyrosine hydroxylase (data not shown) despite the presence of octamer-related motifs in these promoters(29, 30) . In contrast the promoter of the gene encoding the neuronal intermediate filament protein -internexin showed strong activation by both Brn-3a and Brn-3c expression vectors when co-transfected into the BHK cells, whereas the Brn-3b expression vector repressed the basal activity of the -internexin promoter (Fig. 1). These effects were also observed when the promoter was co-transfected with the various Brn-3 expression vectors into the ND7 cell line which expresses endogenous Brn-3 (Fig. 2).

Figure 1: Assay of CAT activity in BHK-21 cells transfected with a reporter construct containing the -internexin promoter (from -1219 to +73 relative to the transcriptional start site) linked to the CAT gene and expression vectors encoding Brn-3a (A), Brn-3b (B), Brn-3c (C) or the empty expression vector (v).

Figure 2: Assay of CAT activity in ND7 cells transected with the -internexin promoter and expression vectors encoding Brn-3a (track 1), Brn-3b (track 2), Brn-3c (track 3), a mixture of the Brn-3a and Brn-3b vectors (track 4) or the empty expression vector alone (track 5). Values are expressed relative to the level of CAT activity upon co-tranfection of -internexin and the empty expression vector alone and are the average of four determinations whose standard error is shown by the bars.

These results with a natural promoter therefore parallel our previous results with a promoter containing synthetic octamer-related Brn-3 binding sites with activation being observed both with Brn-3a and Brn-3c while Brn-3b has an inhibitory effect on promoter activity(20, 21) . As in our previous experiments(20, 21) , Brn-3b was able to inhibit the stimulatory effect of Brn-3a when the two expression vectors were co-transfected together with the -internexin promoter (Fig. 2). Hence the natural -internexin promoter responds to the different forms of Brn-3 in a similar manner to the tK promoter containing added synthetic octamer-related motifs.

The -internexin promoter contains three octamer-related motifs in the region upstream of the transcriptional start site which might act as targets for Brn-3 binding(22) . Surprisingly, however, a construct containing 254 bases of upstream sequence which lacks all these motifs still responded to the various forms of Brn-3 in a manner identical to the full length construct (Fig. 3A) while a construct containing only 77 bases of upstream sequence was stimulated more strongly by Brn-3a and Brn-3c and was still repressed by Brn-3b (Fig. 3B). Hence the sequences which mediate the response of the -internexin promoter to Brn-3 appear to be located within the 77 bases upstream of the transcriptional start site and/or the 73 bases downstream which are present within the shortest construct. In experiments involving more extensive deletions we have been unable to eliminate the responsiveness of the promoter without also eliminating its basal activity suggesting that this responsiveness is a property of the minimal -internexin promoter. The recent observation that sequences very different from the classical octamer motif can bind Brn-3 very strongly (14, 31) suggests that the minimal -internexin promoter contains such sequences allowing it to respond to Brn-3.

Figure 3: Assay of CAT activity in ND7 cells transfected with reporter constructs containing the -internexin promoter from -254 to -73 (Panel A) or -77 to +73 (Panel B) linked to the CAT gene and expression vectors encoding Brn-3a (track 1), Brn-3b (track 2), Brn-3c (track 3) or the empty expression vector alone (track 4). Values are expressed relative to the value obtained with expression vector alone and are the average of three determinations whose standard error is shown by the bars.

In previous experiments we have shown that treatment of ND7 cells with dibutyryl cyclic AMP results in an increase in the level of the Brn-3a mRNA and a decrease in the level of the Brn-3b mRNA(12) . This results in a corresponding increase in the activity of a transfected tK promoter linked to a synthetic octamer motif which is not observed for the unmodified tK promoter lacking this added binding site for Brn-3 (20) . Interestingly, the level of the -internexin mRNA has been shown to be increased following cyclic AMP treatment(22) , although the gene promoter does not contain any cyclic AMP response elements (CRE) which normally mediate the transcriptional response to this compound (32) .

We therefore transfected ND7 cells with the constructs containing different amounts of the internexin promoter 5` upstream sequence and measured their response to treatment with 1 mM dibutyryl cyclic AMP. In these experiments (Fig. 4) all three constructs were stimulated by cyclic AMP with the strongest response being observed for the shortest construct paralleling its strong activation by Brn-3a. These findings together with the absence of a CRE in either the shortest construct or further upstream (22) suggest that the Brn-3 factors may play a role in the activation of the -internexin promoter by cyclic AMP paralleling their role in the cyclic AMP inducibility of the tK promoter carrying a synthetic octamer motif(20) . Consistent with this possibility, the -internexin promoter constructs did not respond to cyclic AMP in BHK-21 fibroblast cells which do not express Brn-3a (data not shown).

Figure 4: Assay of CAT activity in ND7 cells transfected with the indicated -internexin constructs and either left untreated(-) or treated with 1 mM dibutyryl cyclic AMP (+). Values are expressed relative to the level observed with each construct in the absence of cyclic AMP.

As discussed above, the effects of cyclic AMP and the different forms of Brn-3 on the -internexin promoter parallel our findings using an artificial promoter containing a Brn-3 binding site and extend them to a natural promoter. In our previous experiments using this artificial promoter(21) , we used chimeric constructs containing different regions of Brn-3a or Brn-3b (Fig. 5) to show that the ability of Brn-3a to activate this promoter was dependent on its POU domain so that for example construct 1 (AAAB) was not able to activate the promoter, whereas construct 4 (-BBA) was able to do so (21) (Fig. 5). We therefore tested the effect of these chimeric constructs in co-transfections with the full internexin promoter (-1219 to +73).

Figure 5: Summary of gene trans-activation data obtained using either the tK promoter carrying a synthetic octamer motif (tK-Oct) (data from Morris et al.(21) ) or the -internexin promoter (see Fig. 6) together with Brn-3a or -b or with constructs encoding chimeric proteins with different regions derived from Brn-3a or Brn-3b. The division of Brn-3a and -3b subdomains I, II, III, and IV is as follows. For Brn-3a: domain I, amino acids 1-40; domain II, amino acids 41-108; domain III, amino acids 109-267; domain IV (POU domain), amino acids 268-end. For Brn-3b: subdomain II, amino acids 1-92; subdomain III, amino acids 93-169; subdomain IV (POU domain), amino acids 170-end. The domains I and II contain the region with similarity to the POU factors I-POU and UNC 86 (11, 14) while region IV contains the POU domain.

Figure 6: CAT assay using the full -internexin promoter and either Brn-3a (A) or b (B) expression vectors, constructs encoding the chimeric proteins 1-4 as illustrated in Fig. 5, or the empty expression vector alone (V). Panel A shows a typical result of the assay while Panel B shows the data from four experiments whose standard error is shown by the bars.

As illustrated in Fig. 6, the effect of these chimeric constructs was completely different to that which we had previously observed. Thus for example construct 1 (AAAB) was now able to activate this promoter as was construct 3 (AABB). In contrast construct 4 (-BBA) did not activate the promoter, although unlike intact Brn-3b it did not repress it. These findings indicate, therefore, that in the case of the -internexin promoter, the N-terminal region of Brn-3a rather than the POU domain is of critical importance for transactivation. Similar results were also obtained with the shorter -internexin promoter constructs containing respectively 254 and 77 bases of upstream promoter (data not shown). All the chimeric constructs have previously been shown to produce similar levels of protein in the transfected cells(21) .

Having established that within chimeric constructs, the Brn-3a POU domain was necessary for the activation of the octamer-tK promoter but not the -internexin promoter we wished to investigate whether either of these promoters would be affected by the isolated POU domain alone. The isolated POU domains of Brn-3a and Brn-3b with an added ATG codon to allow translational initiation were therefore cloned under the control of the strong CMV immediate-early promoter in the pJ7 vector (33) . These constructs were then co-transfected with the two promoters. Interestingly, the octamer-tK promoter was clearly transactivated by the isolated Brn-3a POU domain and inhibited by the Brn-3b POU domain (Fig. 7A). In contrast, neither of the constructs was able to activate the -internexin promoter (Fig. 7B). Indeed both constructs were able to repress this promoter presumably by binding to the promoter and preventing the binding of endogenous Brn-3 proteins. Hence the isolated DNA binding domain of Brn-3a is able to act as a transactivation domain for the octamer-tK promoter explaining the dependence of this promoter on the source of the POU domain when it is co-transfected with different natural and chimeric forms of Brn-3. In contrast this domain is inactive on the -internexin promoter in agreement with the data indicating that the N-terminal domain of Brn-3a is required for transactivation of this promoter.

Figure 7: Assay of CAT activity in cells transfected with either the tK promoter carrying a synthetic octamer motif (Panel A) or the -internexin promoter (Panel B) together with expression vectors encoding the isolated POU domain of Brn-3a (1) or Brn-3b (2) or the empty expression vector alone (3).

DISCUSSION

The Brn-3a transcription factor has been shown to be able to transactivate both artificial promoters containing an appropriate binding site cloned upstream of a test promoter (14, 21) or the natural promoters for the genes encoding proopiomelanocortin (14) and -internexin (this report). Here we show, however, that at least two distinct regions of the protein can independently mediate such transactivation depending on the promoter concerned. Thus in the case of the tK promoter with a cloned upstream binding site we have extended our previous findings using chimeric constructs to show that the isolated POU domain of Brn-3a can act both as a DNA binding domain and as a transactivation domain for this promoter. In contrast in the case of the -internexin promoter, the Brn-3a POU domain is inactive either in isolation or in chimeric constructs and an N-terminal region is required for transactivation. Further studies will be required to determine whether these differences are determined by the sequence of the Brn-3 binding site in each promoter, its context relative to other transcription factor binding sites or its position relative to the transcriptional start site.

The presence of two distinct activation domains in Brn-3a is paralleled in the Oct-2 POU transcription factor which contains two distinct activation domains at the N and C termini of the protein(35, 36) . Interestingly only the N-terminal activation domain is present in the related Oct-1 factor(37) , resulting in Oct-1 and Oct-2 having differing abilities in the activation of different octamer-containing genes such as those encoding the immunoglobulins and snRNA molecules (37, 38) .

In the case of the Brn-3 factors, Brn-3b unlike Brn-3a is not able to activate either the tK-octamer or the -internexin promoters due to differences between the two POU factors in respectively the POU domain and the N-terminal region. Interestingly, however, while intact Brn-3b represses the -internexin promoter, the chimeric -BBA construct did not activate or repress the promoter (Fig. 6). This suggests that whilst the N-terminal region is required for activation by Brn-3a, the POU domain of Brn-3b may be involved in its ability to repress the -internexin promoter below its basal level. This is likely to involve the recently described ability of Brn-3b to interact with Brn-3a and prevent its binding to DNA since such interactions between different POU proteins normally involve heterodimerization via the POU domain(34) . In agreement with this idea, unlike Brn-3b, the -BBA construct was not able to interfere with activation of the internexin promoter when co-transfected with Brn-3a (data not shown).

The N-terminal region of Brn-3a which activates transcription contains the POU-IV box, a region of 40 amino acids which is also present in Brn-3c, and the other members of the POU-IV family, I-POU, tI-POU, and Unc-86(11, 14) . Interestingly only a fragment of this POU-IV box is present in the form of Brn-3b we have used here which is derived from the major transcript in the spinal cord(11) . Hence the POU-IV box may be of direct relevance to the ability of Brn-3a to activate transcription. Interestingly however, a transcript encoding a longer form of Brn-3b with additional N-terminal sequences including a complete POU-IV box has been detected in the retina (15) and the CNS (16) , although it was absent in the spinal cord(11) . This longer form of Brn-3b (also known as Brn-3.2:-) (16) has been shown to activate a promoter containing a synthetic Brn-3 binding site upstream of the prolactin promoter(16) . Hence two distinct forms of Brn-3b may exist which differ in their ability to activate promoters which require the N-terminal region for transactivation. However, neither form would be likely to activate promoters which rely on transactivation by the Brn-3a POU domain since the POU domain common to both forms of Brn-3b is inactive in this assay.

Interestingly the N-terminal region of the POU-IV box is similar to a domain found in the N terminus of all c-myc family members (14) which has been shown to modulate their transforming ability(39) . It has therefore been suggested (11) that the POU-IV box may be involved in the ability of Brn-3a to co-operate with the Ha-ras protein in transforming primary cells in the same manner as the c-myc proteins. Whatever the precise role of this box, it is clear that the N-terminal region of Brn-3a is involved both in transactivation of some promoters (this report) and transformation(11) . Hence the transforming ability of Brn-3a is likely to be dependent on the ability of its N-terminal region to activate specific target genes whose protein products are required for transformation.

Although the activation of the gene encoding the neuronal intermediate filament protein -internexin is unlikely to be relevant to transformation of fibroblasts by Brn-3a, this gene may well represent a physiologically relevant target for Brn-3a within the nervous system. Thus the only previously described natural promoter to be activated by Brn-3a is derived from the gene encoding proopiomelanocortin which is expressed in the pituitary gland where levels of Brn-3a are so low as to be undetectable by in situ hybridization(14) . In contrast -internexin is widely expressed in the developing and adult nervous system (19, 40) with high levels being found in sensory neurons within dorsal root ganglia (40) which also express high levels of Brn-3a (10, 14) Brn-3b (12, 16) and Brn-3c(14, 17) . As the -internexin gene is expressed in only a subset of cells within the DRG(40) , it will clearly be of interest to determine the relationship between these cells and those which express Brn-3a or Brn-3c, both of which have also been detected in some but not all DRG neurons (10, 14, 17) as well as those which express Brn-3b whose distrubution within the DRG has not been reported.

In summary, therefore, we have identified the -internexin promoter as a target for transactivation by Brn-3a and have shown that this effect requires an N-terminal transactivation domain unlike other promoters which are dependent upon the POU domain for transactivation by Brn-3a. Further studies will be required to characterize the physiological role of the Brn-3 factors in the regulation of -internexin expression as well as to characterize the promoters whose activation via the N-terminal domain is involved in transformation by Brn-3a.

FOOTNOTES

*

This work was supported by Action Research, the Medical Research Council and Wellbeing (to D. S. L.), by the Deutsche Forschungsgemeinschaft (SFB215, D10) and the Mildred Scheel Stiftung Fur Krebsforschung (to T. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence should be addressed.

()

T. Theil and T. Möröy, submitted for publication.

()

The abbreviations used are: CAT, chloramphenicol acetyltransferase; CRE, cyclic AMP response element.

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				C. Perez-Sanchez, V. S. Budhram-Mahadeo, and D. S. Latchman Distinct promoter elements mediate the co-operative effect of Brn-3a and p53 on the p21 promoter and their antagonism on the Bax promoter Nucleic Acids Res., November 15, 2002; 30(22): 4872 - 4880. [Abstract] [Full Text] [PDF]

				K. L. Sugars, V. Budhram-Mahadeo, G. Packham, and D. S. Latchman A minimal Bcl-x promoter is activated by Brn-3a and repressed by p53 Nucleic Acids Res., November 15, 2001; 29(22): 4530 - 4540. [Abstract] [Full Text] [PDF]

				I. Röckelein, S. Röhrig, R. Donhauser, S. Eimer, and R. Baumeister Identification of Amino Acid Residues in the Caenorhabditis elegans POU Protein UNC-86 That Mediate UNC-86-MEC-3-DNA Ternary Complex Formation Mol. Cell. Biol., July 1, 2000; 20(13): 4806 - 4813. [Abstract] [Full Text]

				S. Certel, P. Clyne, J. Carlson, and W. Johnson Regulation of central neuron synaptic targeting by the Drosophila POU protein, Acj6 Development, January 6, 2000; 127(11): 2395 - 2405. [Abstract] [PDF]

				M. Trieu, J. M. Rhee, N. Fedtsova, and E. E. Turner Autoregulatory Sequences are Revealed by Complex Stability Screening of the Mouse brn-3.0 Locus J. Neurosci., August 1, 1999; 19(15): 6549 - 6558. [Abstract] [Full Text] [PDF]

				V. Budhram-Mahadeo, P. J. Morris, M. D. Smith, C. A. Midgley, L. M. Boxer, and D. S. Latchman p53 Suppresses the Activation of the Bcl-2 Promoter by the Brn-3a POU Family Transcription Factor J. Biol. Chem., May 21, 1999; 274(21): 15237 - 15244. [Abstract] [Full Text] [PDF]

				M. D. Smith, E. A. Ensor, R. S. Coffin, L. M. Boxer, and D. S. Latchman Bcl-2 Transcription from the Proximal P2 Promoter Is Activated in Neuronal Cells by the Brn-3a POU Family Transcription Factor J. Biol. Chem., July 3, 1998; 273(27): 16715 - 16722. [Abstract] [Full Text] [PDF]

				V. Budhram-Mahadeo, M. Parker, and D. S. Latchman POU Transcription Factors Brn-3a and Brn-3b Interact with the Estrogen Receptor and Differentially Regulate Transcriptional Activity via an Estrogen Response Element Mol. Cell. Biol., February 1, 1998; 18(2): 1029 - 1041. [Abstract] [Full Text]

				M. D. Smith, P. J. Morris, S. J. Dawson, M. L. Schwartz, W. W. Schlaepfer, and D. S. Latchman Coordinate Induction of the Three Neurofilament Genes by the Brn-3a Transcription Factor J. Biol. Chem., August 22, 1997; 272(34): 21325 - 21333. [Abstract] [Full Text] [PDF]

				M. D. Smith, S. J. Dawson, and D. S. Latchman Inhibition of Neuronal Process Outgrowth and Neuronal Specific Gene Activation by the Brn-3b Transcription Factor J. Biol. Chem., January 10, 1997; 272(2): 1382 - 1388. [Abstract] [Full Text] [PDF]

				S. J. Dawson, P. J. Morris, and D. S. Latchman A Single Amino Acid Change Converts an Inhibitory Transcription Factor into an Activator J. Biol. Chem., May 17, 1996; 271(20): 11631 - 11633. [Abstract] [Full Text] [PDF]

				V. Budhram-Mahadeo, P. J. Morris, N. D. Lakin, S. J. Dawson, and D. S. Latchman The Different Activities of the Two Activation Domains of the Brn-3a Transcription Factor Are Dependent on the Context of the Binding Site J. Biol. Chem., April 12, 1996; 271(15): 9108 - 9113. [Abstract] [Full Text] [PDF]

				N. D. Lakin, P. J. Morris, T. Theil, T. N. Sato, T. Möröy, M. C. Wilson, and D. S. Latchman Regulation of Neurite Outgrowth and SNAP-25 Gene Expression by the Brn-3a Transcription Factor J. Biol. Chem., June 30, 1995; 270(26): 15858 - 15863. [Abstract] [Full Text] [PDF]

				N. G. N. Milton, A. Bessis, J.-P. Changeux, and D. S. Latchman The Neuronal Nicotinic Acetylcholine Receptor [IMAGE]2 Subunit Gene Promoter Is Activated by the Brn-3b POU Family Transcription Factor and Not by Brn-3a or Brn-3c J. Biol. Chem., June 23, 1995; 270(25): 15143 - 15147. [Abstract] [Full Text] [PDF]

				E. Ensor, M. D. Smith, and D. S. Latchman The BRN-3A Transcription Factor Protects Sensory but Not Sympathetic Neurons from Programmed Cell Death/Apoptosis J. Biol. Chem., February 9, 2001; 276(7): 5204 - 5212. [Abstract] [Full Text] [PDF]

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