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Department of Biological Sciences, Columbia University, New York, New York 10027
Received 8 May 2007/ Returned for modification 30 May 2007/ Accepted 4 October 2007
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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One such homologue is TBP-like protein (TLP; also known as TRF2 or TLF; for a review, see reference 5). For some time it was speculated that TLP regulated transcription by sequestering essential factors (47), preventing their utilization in initiation complexes containing TBP. Indeed, TLP sequences necessary for binding the general transcription factors TFIIA and TFIIB are identical to those found in TBP (5, 11), and TLP, when overexpressed, does repress transcription from the TATA-containing adenovirus major late promoter (39). However, in vitro analysis demonstrated that artificial recruitment of TLP to a promoter by fusion to a Gal-4 DNA-binding domain activated transcription (38), and transcription from the terminal deoxynucleotidyl transferase promoter lacking a TATA box was stimulated by TLP in transient-transfection assays (39). Chicken DT40 cells lacking TLP are viable, although the G2 checkpoint is defective in tlp-null cells. These cells grow faster than wild-type DT40 cells due to a shortened G2 phase, and the cells also appear more tolerant to stress (43). However, RNA interference studies established that TLP is essential for embryogenesis in C. elegans and X. laevis (10, 26, 50). While mice lacking TLP are viable, males are sterile due to defects in spermiogenesis (34, 35, 55). The observation that both TBP and TLP levels increase during spermatogenesis (45) provides further evidence that although structurally similar, TBP and TLP have, at least in part, functionally divergent roles in transcriptional regulation. Taken together, these findings seem to dictate a role for TLP in regulating transcription of a subset of genes required for cell proliferation, perhaps in a species-specific manner.
Another TBP homologue, known as TBP2, TBPL2, or TRF3, was described more recently, in humans, mice, frogs, and zebra fish (3, 24, 41). TBP and TBP2 are ca. 95% identical throughout the conserved C-terminal domain; however, their N-terminal domains are quite divergent, both in the same organisms and between species. TBP2, like TBP, is a component of a multisubunit complex, although the normal complement of TBP-associated factors is not present in the complex associated with TBP2 (41). Like TBP, TBP2 has been shown to bind the TATA box and can mediate RNA polymerase (RNAP) II transcription (3). TBP2 has been shown to be necessary for the embryonic development of both frogs and zebra fish (3, 41). Thus, although TBP2 seems to have specialized functions, it also displays functions that may overlap those of TBP.
TRF-1, a TBP homologue identified only in Drosophila melanogaster, has been found to be capable of both sequence-specific DNA binding and transcriptional activation (16, 21). Some developmental genes in Drosophila require TRF-1 for transcription. In adult flies, however, TRF-1 is largely restricted to neuronal and testicular tissues (16, 21, 46). TRF-1 is associated with a large uncharacterized set of proteins at promoters, termed neuronal TBP-associated factors. TRF-1 also interacts with both TFIIA and TFIIB. The RNAP III specific initiation factor BRF is found together with both TBP and TRF-1 at RNAP III specific promoters (16). Overall, TRF1 seems to function as a general transcription factor for RNAP III, but at different promoters, different times, and in different tissues than TBP.
TBP itself is essential for viability in all eukaryotic cells, and genetic analyses have therefore been limited, especially in metazoans. To analyze the effects of reduced TBP levels, our lab previously generated a line of DT40 cells heterozygous for tbp (TBP-het) (48). While overall transcription was relatively unaffected and TBP-het cells were viable, phenotypic irregularities demonstrated the importance of wild-type levels of TBP during the cell cycle. TBP-het cells were found to be significantly larger than wild-type DT40 cells, and the doubling time for the heterozygotes was about 24 h, more than twice that of wild-type DT40 cells, reflecting a delayed M phase. Intriguingly, the mitotic delay phenotype was attributed to a significant reduction in expression of the M-phase inducer phosphatase cdc25B (48). Providing a possible explanation for this, analysis of the murine cdc25B promoter revealed a cell cycle-regulated repressor (CCRR) element that partly overlaps the TATA box (27). Thus, the reduced levels of TBP were hypothesized to decrease competition with the putative repressor, making the cdc25B promoter especially sensitive to reduced TBP levels.
In the present study we have investigated further the consequences of tbp heterozygosity. We first examined in more detail the effect of lowered TBP levels on cdc25B expression. We inserted the human cdc25B promoter into a reporter vector and performed luciferase assays after stable transfection of both wild-type DT40 and TBP-het cells. The results demonstrated a significant downregulation of cdc25B promoter activity in the TBP-het cells. Significantly, mutations introduced into the portion of the CCRR that did not overlap the TATA box restored expression in TBP-het cells but had only minimal effects in wild-type cells, supporting the idea that the cdc25B promoter is indeed regulated by competitive binding of the CCRR repressor and TBP. We also investigated the expression of the two TBP homologues in TBP-het cells. We found that TLP expression was upregulated in TBP-het cells and that this reflects increased activity of the core TLP promoter. This was confirmed by transient-transfection assays in HeLa cells, which indicated that TBP and TLP overexpression affected the TLP promoter in opposite ways. Significantly, chromatin immunoprecipitation (ChIP) assays revealed the presence of both TBP and TLP on the TLP promoter, indicating that TLP interacts physically with its own promoter. We identified the tbp2 gene in chickens and found that as in other organisms, TBP2 is closely related to the conserved core domain of TBP. We also found that transcription of the tbp2 gene was upregulated significantly in TBP-het cells. These results provide a plausible explanation for the lack of global effects on transcription caused by lower levels of TBP and point to a significant cross-regulation among the different TBP isoforms.
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MATERIALS AND METHODS |
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Plasmids and constructs.
All cloning was done using standard subcloning methods. Luciferase reporter vectors were derived from the PGL3 Promoter Vector (Promega). The simian virus 40 promoter was replaced with the promoters under study by digesting the vector with KpnI and HindIII and inserting the appropriate promoter. The promoterless construct was made by blunt ending the KpnI and HindIII sites and ligating the vector to itself. An antibiotic-resistant cassette derived from loxP vectors (1) was inserted into the BamHI site of the PGL3 vector. Expression vectors were made by subcloning full-length cDNA with a sequence encoding the hemagglutinin epitope fused to the 5' end into pExpress (1). The cDNA expression cassette from pExpress was then subcloned into suitable loxP vectors. Mutagenesis of the cdc25B promoter was done by DpnI-mediated site-directed mutagenesis (14). Briefly, mutant DNA was amplified by using complementary primers designed to change the first four nucleotides of the CCRR. Parental DNA was digested with DpnI. Mutant plasmids were amplified in DH5
. All plasmids were sequenced by GeneWiz.
Cell culture and transfections. DT40 cells were maintained as previously described (52) in RPMI 1640 (Sigma) supplemented with chicken serum and fetal bovine serum (HyClone). HeLa cells were maintained in Dulbecco modified Eagle medium (Gibco) supplemented with fetal bovine serum (HyClone). Lipofectamine 2000 (Invitrogen) was used to transfect approximately 4 x 105 DT40 cells with 800 ng of linearized or supercoiled DNA. Selection of stably transfected cells took place 48 h after transfection in either 0.5 µg of puromycin/ml, 30 µg of Blasticidin/ml, or 1.5 mg of G418 (Gibco)/ml. Transient transfections of HeLa cells were done by using Lipofectamine 2000 to transfect 5 x 105 cells using 300 ng of reporter vector and 400 ng of the appropriate protein expression vector. An empty protein expression vector was used to bring DNA totals for transient transfections up to 800 ng. Nocodazole was used at a concentration of 40 ng/ml for 16 h. A Becton Dickinson fluorescence-activated cell sorter was used to confirm cell cycle arrest. Cells were harvested and fixed with methanol. Propidium iodide (Sigma) was used to stain cellular DNA after cells were washed.
Luciferase assays. Cells were lysed in reporter lysis buffer and assayed by using the luciferase assay system (Promega). Fluorescence was detected using a luminometer (Berthold). Each luciferase assay was done in triplicate with three to five pools of cells, each independently transfected with the appropriate promoter construct, and the results were averaged. Equal numbers of HeLa cells were lysed using passive lysis buffer (Promega), and the extracts were used to assay luciferase activity. Protein concentrations of cell extracts were used for normalization when assaying luciferase in DT40 cells, rather than cell number, because of differences in cell sizes. Each luciferase assay was also normalized by using values from the same cells transfected with the promoterless construct.
ChIP assays.
The ChIP protocol was adapted from the fast protocol described by Nelson et al. (37). HeLa cells were cross-linked with 1.4% formaldehyde, typically for 20 min at room temperature. Cross-linking was stopped with 125 mM glycine for 5 min at room temperature, and cells were harvested and washed twice with cold phosphate-buffered saline. Cells were lysed with immunoprecipitation buffer (150 mM NaCl, 50 mM Tris-HCl [pH 7.5], 5 mM EDTA, 0.5% [vol/vol] NP-40, 1% [vol/vol] Triton X-100), and chromatin was sheared by sonication with a Branson Sonifier 250 (output: 2.5, 10 s at constant duty cycle, six times with 20-s intervals on ice). Lysates were cleared by centrifugation at 12,000 x g for 10 min at 4°C. Antibodies (anti-RNA polymerase II [N-20; catalog no. sc-899, 4 µg], anti-TBP [N-12; catalog no. sc-204, 4 µg], and anti-TLP [C-16; catalog no. sc-10105, 8 µg]; all from Santa Cruz Biotechnology) were added to samples (equivalent to 4 million cells each), followed by incubation in an ultrasonic water bath for 1 h at 4°C. Chromatin was cleared by centrifugation at 12,000 x g for 10 min at 4°C, and protein G-Sepharose (20 µl per sample) was added. Tubes were rotated overnight at 4°C, beads were collected by centrifugation and washed five times with immunoprecipitation buffer, and antibody-protein-DNA complexes were eluted by adding elution buffer (1% [vol/vol] sodium dodecyl sulfate, 100 mM NaHCO3). Reversal of cross-linking was performed overnight at 65°C with an NaCl and RNase A solution, followed by proteinase K treatment for 90 min at 45°C. DNA was phenol-chloroform extracted and ethanol precipitated and eventually used as a template for PCR. PCR were performed for 30 cycles using [32P]dCTP and primers corresponding to the NF1, β-actin, and TLP promoters and to an intergenic region used as a control [
4 kb downstream the β-actin poly(A) site]. PCR products were resolved on an 8% native polyacrylamide gel, exposed by using a phosphorimager (Storm 860), and quantified by ImageQuant 5.2. Signals were normalized to the control (intergenic amplification) after subtraction of the protein G-Sepharose background signal. Experiments were repeated four independent times with similar results.
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RESULTS |
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We next wanted to determine whether the changes in cdc25B mRNA levels were due to alterations in cdc25B promoter activity. Several attempts to isolate the cdc25B promoter from chicken genomic DNA were unsuccessful, and its sequence is not present in the available chicken genomic databases. We therefore isolated the human cdc25B promoter (–330 to +20), confirmed that the CCRR was conserved and correlated in position with the murine promoter (data not shown), and cloned it into a luciferase reporter vector. Pools of transfected cells stably expressing luciferase driven by this promoter, or by a promoterless control, were derived from wild-type and TBP-het cells. Luciferase expression from the cdc25B promoter was relatively high in wild-type cells, and treatment of the cells with nocodazole increased expression, with levels 3.0 times higher than in untreated cells (Fig. 2A, columns 1 and 2). Strikingly, TBP-het cells expressed luciferase barely above the background levels observed with the promoterless control (Fig. 2B, columns 1 and 2), reflecting a nearly 10,000-fold decrease in enzyme activity from levels in wild-type cells. In addition, nocodazole treatment of the TBP-het transformed cells did not cause a significant increase in luciferase levels (column 3). The remarkable magnitude of the decrease in luciferase expression in the TBP-het cells likely reflects in part some property of the enzyme reporter system. Indeed, analysis of luciferase mRNA levels by RT-PCR revealed a smaller decrease, of three- to fourfold (Fig. 2C, lanes 1 and 2), which is comparable to the decrease in cdc25B mRNA levels (Fig. 1A, lanes 1 and 3). Nonetheless, these results, which were observed reproducibly with multiple independent pools of transformed cells, indicate that the reduced levels of cdc25B mRNA in TBP-het cells reflect a reduction in core promoter activity.
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TLP is upregulated during G2 phase and in TBP-het cells. The data presented above provide strong support for the idea that transcription of a specific gene, cdc25B, is indeed very sensitive to levels of TBP. Previous results, however, indicated that overall transcription was largely unaffected in TBP-het cells (42). While this difference undoubtedly reflects, at least in part, the unusual structure of the cdc25B promoter, we wondered whether additional factors might ensure that cells are resistant to fluctuations in TBP levels. Specifically, might expression of TLP or TBP2 be enhanced when TBP levels are decreased? To address this, we first assessed the levels of TLP mRNA in DT40 and TBP-het cells. Indeed, RT-PCR revealed that TBP-het cells expressed TLP mRNA at about three times the level found in wild-type cells (Fig. 4A, lanes 1 and 2; real-time PCR in Fig. 4B, columns 1 and 3). Western blots confirmed that the upregulation of TLP mRNA in TBP-het cells was reflected in increased levels of TLP protein (Fig. 4C). To investigate whether the TBP-het phenotype (i.e., mitotic delay) might contribute to the elevated TLP levels, we treated both wild-type and TBP-het cell lines with nocodazole. Although expression of TLP mRNA was more than doubled in nocodazole-treated wild-type cells (Fig. 4A, lanes 1 and 3, and Fig. 4B, columns 1 and 2), TBP-het cells exhibited no further increase in TLP levels (Fig. 4A, lanes 2 and 4, and Fig. 4B, columns 3 and 4). These results suggest that TLP mRNA is expressed at maximal levels in TBP-het cells and that the upregulation reflects at least in part the cell cycle phenotype. TBP-het cells have an extended G2 phase, and TLP has previously been implicated in the G2 checkpoint (43).
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TBP levels control TLP promoter activity. The data described above indicate that TBP levels can influence the expression of TLP mRNA and protein in DT40 cells. We next wanted to determine whether this change in expression levels results from a direct effect on the activity of the TLP promoter and also whether such regulation extends to human cells. Comparison of the human and chicken TLP promoters indicates that while both promoters have multiple binding sites for heat shock factors, they otherwise share little homology (data not shown). To investigate whether the activity of the two TLP promoters is sensitive to TBP levels in DT40 cells, we first cloned the human (–280 to +90) and chicken (–320 to +72) TLP promoters into luciferase reporter vectors and stably transfected the vectors into wild-type DT40 cells, TBP-het cells, and (in the case of the human promoter) TBP-het cells expressing full-length TBP or TBP-dN. Luciferase activity was then measured in pools of stably transformed cells. Strikingly, the TBP-het cells expressed luciferase at very high levels, nearly nine times greater than in wild-type cells from vectors containing the human TLP promoter (Fig. 5A, columns 1 and 2). Luciferase expression from the chicken TLP promoter was 10 times higher in TBP-het cells than in the wild type (Fig. 5B, columns 1 and 3). TBP-het cells expressing full-length exogenous TBP actually expressed 30% less luciferase from the human promoter than did the wild-type cells (Fig. 5A, column 3). TBP-het cells expressing TBP-dN (column 4) expressed roughly twice as much luciferase as wild-type cells (column 1), but still four times less than TBP-het cells not supplied with exogenous TBP (column 2). As observed with endogenous TLP expression, nocodazole increased luciferase expression from the chicken TLP promoter 2.5-fold in wild-type cells but did not further increase luciferase activity in TBP-het cells (Fig. 5B, columns 2 and 4). The human TLP promoter also expressed elevated levels of luciferase in wild-type cells treated with nocodazole (data not shown). Together, these results indicate that the TLP core promoter itself is sensitive both to TBP levels and to the cell cycle and suggest that, despite limited sequence similarity, this response is conserved among vertebrates.
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DISCUSSION |
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Our data indicate a strong correlation between the CCRR described by Korner et al. (27), cdc25B expression, and levels of TBP. Cdc25B is directly implicated in several types of cancer (18, 19, 22, 23, 54), and in fact cdc25B protein levels are often used as indicators of a patient prognosis (22, 42). Patients with cdc25B-positive tumors exhibit a significantly lower disease-free survival rate (22). Furthermore, immunostains of brains from patients with Alzheimer's disease show increased levels of cdc25B expression (51). Given that TBP is overexpressed in certain tumors (25), it will be of interest to determine whether cdc25B levels are correspondingly elevated in such tumors. Another possibility is that mutations in the cdc25B promoter region (i.e., in the CCRR element) cause upregulation of cdc25B. Identification of the protein and/or protein complex that binds to the CCRR element and represses cdc25B expression is an important goal and may be a key to possible gene therapy techniques for cancers that overexpress this important mitotic regulator.
The CCRR site of the cdc25B promoter directly overlaps the TATA box. There are precedents for repressor binding sites that overlap the TATA box, inhibiting assembly of the initiation complex by directly competing with TBP. The basal transcription apparatus of Archaea contains proteins that correspond to the eukaryotic RNA polymerase II and TBP. A protein, Lrs 14, represses transcription from its own promoter by binding to a site that overlaps the TATA box (4). In Drosophila, the homeodomain protein Engrailed binds not only to a specific consensus sequence but also to the TATA box, repressing transcription from promoters that are activated by other homeotic proteins (40). Another example of a repressor exhibiting steric hindrance of TBP-DNA binding is the proline-rich homeodomain protein PRH, which binds directly to the TATA box of an engineered simian virus 40 promoter, as well as to TBP itself (15). The promoter of the osteocalcin gene contains glucocorticoid receptor (GR) response elements that when occupied by the GR directly prevents binding of TBP to the TATA box (44). The TATA box in the osteocalcin promoter is a "weak" TATA box, and replacement with a canonical TATA box (TATAAAA) increases transcription from this promoter (36). It will be of interest to learn how altered levels of TBP affect expression from these types of promoters.
Our results indicate that disrupting the binding site for the putative Cdc25B repressor by mutation of the four nucleotides of the CCRR that are not part of the TATA box can increase transcription from the cdc25B promoter when TBP levels are limiting. The fact that the same mutations had much smaller effects in wild-type cells, where TBP levels are higher, strongly supports our idea that a competition between TBP and the CCRR modulates cdc25B transcription. Whether the relatively small differences in expression from the various mutant promoters we observed reflect differential binding of the repressor to the mutated CCRR sequences and/or whether the sequences flanking the TATA box also have the potential to affect TBP (31, 53) or TFIIB (7, 8, 13, 29) binding cannot be determined until the CCRR protein is identified and characterized.
The first TBP homologue we investigated, TLP, also seems to be a significant component in cell cycle regulation and apoptosis in DT40 cells (43). No role for TLP has yet been discovered in human disease. However, the function of TLP appears to vary between species (10, 26, 34, 43), which may limit the use of model systems in elucidating potential role(s) that TLP plays in mammals. Nevertheless, the study of this transcription factor is important because TLP directly regulates transcription of a subset of genes. For example, TLP upregulates the NF1 gene and represses transcription of c-fos (9). In addition to our findings that TLP interacts with its own promoter, we have recently identified a high-affinity recognition motif for TLP, which has suggested a number of additional target genes (S. D. Bush, P. Richard, and J. L. Manley, unpublished data). The results reported here support the idea that TLP and TBP may reciprocally regulate the transcription of a larger subset of genes than currently described.
The more recent identification of TBP2 has introduced another layer of complexity to core promoter function. One interesting fact is that while the core domains of TBP and TBP2 are nearly identical, their N termini are quite distinct. The upregulation of TBP2 in TBP-het cells may allow resolution of the role of the N-terminal domain of TBP. Given that the upregulation of TBP2 that occurs in TBP-het cells is not sufficient to prevent the tbp (+/–) phenotype, it seems likely that the N-terminal domain of TBP is uniquely necessary for at least some regulatory functions. It will be interesting to determine whether expression of exogenous TBP2, to even higher levels than occur from the upregulation of the endogenous gene, can result in a partial rescue of the phenotype as seen with TBP-het cells expressing TBP-dN (42), or if overexpression of TBP2 can fully rescue TBP-het cells. The N-terminal domain of TBP has been implicated in transcription from TATA-less promoters (30) and has been shown to reduce the binding of TBP to promoters containing a TATA box (28, 32). It is doubtful that TBP2 can fully replace TBP, since no successful knockout of TBP has been documented and, in fact, mice lacking most of the N-terminal of TBP exhibit a lethal defect midway through gestation (20). The upregulation of TBP2 that occurs in TBP-het cells is not sufficient to compensate for the effect of lower TBP levels on transcription of cdc25B. However, the possibility that TBP2 has functions that overlap those of TBP is not unreasonable. For example, overall transcription is not severely affected in TBP-het cells (48), perhaps indicating a compensatory role for TBP2 and explaining why TBP2 levels increase when TBP levels decrease.
Comparison of the human TBP2 and TLP promoters shows no similarity in sequence or in putative transcription factor binding sites. Neither promoter has a TATA box in the –30 position, although TLP does have two upstream sequences that correspond to canonical TBP binding sites. Indeed, an intriguing possibility is that TBP binding to these or to related sequences contributes to the downregulation of the two promoters that is alleviated by tbp heterozygosity. However, the levels of upregulation (TLP mRNA is expressed to a significantly higher level than TBP2 mRNA) lends credence to the idea that the mechanism(s) regulating the expression of these two TBP homologues likely differ. This concept is reinforced by the upregulation of TLP that occurs in cells arrested in mitosis, while TBP2 expression is unaffected in such cells. TLP has also been implicated in regulation of the G2 cell cycle checkpoint, as well as in the response to cellular stress, such as UV and heat shock (43), while a role for TBP2 in the cell cycle or the stress response has not been established. Experiments to examine the regulation of TBP2 during all phases of the cell cycle will help to clarify the role of this TBP homologue and could be especially informative using TBP-het cells.
In summary, our data have provided additional insights into the functions of the three TBP-related proteins that are conserved throughout metazoa. Two of the three, TBP and TLP, have previously been implicated in the G2 cell cycle checkpoint (33, 43). As we have shown here, cdc25B transcription is directly affected by TBP levels, likely reflecting competitive binding with the CCRR. The TLP upregulation we documented is likely at least in part a result of the cell cycle phenotype exhibited by TBP-het cells. While the elevated levels of TBP2 suggest it may be involved in a transcriptional backup mechanism that compensates for irregular TBP expression, it has yet to be determined whether this expression ameliorates the effect of lower levels of TBP on transcription of specific genes. Indeed, it is intriguing that its upregulation is insufficient to compensate for reduced TBP levels in cdc25B transcription. Whether this reflects insufficient levels of TBP2 to compete effectively with the CCRR even after upregulation, or a sequence difference, which would likely be in the N-terminal domain, remains to be determined. It will be of interest, for example, to determine whether downregulation of TBP2 in TBP-het cells further reduces cdc25b transcription and/or exasperates the tbp (+/–) phenotype. In any event, our data have shown that reduced TBP levels affect transcription of several specific genes and do so by distinct mechanisms.
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FOOTNOTES |
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Published ahead of print on 22 October 2007.
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REFERENCES |
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