Stimulation of Myc transactivation by the TATA binding protein in promoter-reporter assays
© Barrett et al; licensee BioMed Central Ltd. 2005
Received: 08 February 2005
Accepted: 05 May 2005
Published: 05 May 2005
The c-Myc oncogenic transcription factor heterodimerizes with Max, binds specific DNA sites and regulates transcription. The role of Myc in transcriptional activation involves its binding to TRRAP and histone acetylases; however, Myc's ability to activate transcription in transient transfection assays is remarkably weak (2 to 5 fold) when compared to other transcription factors. Since a deletion Myc mutant D106-143 and a substitution mutant W135E that weakly binds TRRAP are still fully active in transient transfection reporter assays and the TATA binding protein (TBP) has been reported to directly bind Myc, we sought to determine the effect of TBP on Myc transactivation.
We report here a potent stimulation of Myc transactivation by TBP, allowing up to 35-fold transactivation of reporter constructs. Although promoters with an initiator (InR) element briskly responded to Myc transactivation, the presence of an InR significantly diminished the response to increasing amounts of TBP. We surmise from these findings that promoters containing both TATA and InR elements may control Myc responsive genes that require brisk increased expression within a narrow window of Myc levels, independent of TBP. In contrast, promoters driven by the TATA element only, may also respond to modulation of TBP activity or levels.
Our observations not only demonstrate that TBP is limiting for Myc transactivation in transient transfection experiments, but they also suggest that the inclusion of TBP in Myc transactivation assays may further improve the characterization of c-Myc target genes.
The c-myc oncogene is implicated in the genesis of many human cancers and accounts for about 70,000 US cancer deaths annually [1–3]. This oncogene produces the c-Myc transcription factor, which heterodimerizes with Max via the helix-loop-helix-leucine zipper (HLH-Zip) motif to bind specific target DNA sequences and regulate transcription [4–8]. The amino-terminal region of c-Myc, when tethered to the yeast GAL4 DNA binding domain, behaves as a potent transactivation domain (TAD) . On the other hand, the transactivation potential of native c-Myc appears diminished when compared with other transcription factors, such as the HLH-Zip protein USF1 or to the GAL4 chimeric transactivators .
The basis for the diminished transactivation potential of c-Myc has remained elusive despite the discoveries that the Myc activation domain specifically binds to factors such as TRRAP [7, 8, 11–13]. TRRAP is a high molecular weight, multifaceted molecule that is capable of recruiting the histone acetyltransferase GCN5 . The fact that c-Myc is able to transactivate in Saccharomyces cerevisiae and that yeast Tra1 is similar to TRRAP suggest that Myc's ability to transactivate in yeast may involve Tra1 [14, 15]. The c-Myc TAD encompasses two conserved regions, termed Myc Box I and Myc Box II. Although Myc Box I does not appear to affect transactivation, Myc Box II is required for interaction with TRRAP. Although deletion of Myc Box II renders Myc defective in binding TRRAP, it does not affect the ability of Myc to transactivate specific promoter-reporter constructs and in particular it does not affect the ability of GAL4-Myc chimeric protein to transactivate . In addition, deletion of Myc Box II appears to affect the induction of certain endogenous target genes but not others [16, 17]. These observations suggest that transcriptional regulation by Myc is likely to be manifold, involving chromatin modulation as well as direct interaction with components of the basal transcriptional machinery [18–20]. This spectrum of activities allows Myc to regulate subsets of genes that are more tightly controlled and susceptible to chromatin modulation, whereas other genes, such as the so-called "housekeeping" genes, may already exist in open chromatin configuration and hence may be regulated through recruitment of the basal transcriptional machinery.
Searches for the interaction of c-Myc with components of the transcriptional machinery have uncovered an interaction with the coactivator CBP . The C-terminal region of Myc has been found to interact with SWI/SNF5 and Miz-1, both implicated in transactivation and transrepression activities of Myc [22–27]. However, these activities could not account for the transactivation potential of the Myc N-terminal region (TAD). The interaction between Myc and the TATA binding protein (TBP) has been observed in diverse systems with evidence from intracellular chemical crosslinking, mammalian two-hybrid assay, yeast two-hybrid assay, and GST fusion protein pull-down assays [28–33]. In fact, two recent studies suggest that the Myc TAD is consisted of a structureless N-terminal (Myc1-88) portion connected by a linker followed by a C-terminal (Myc92-167) partly helical domain, such that the two domains are induced to adopt a specific conformation upon binding TBP [31, 32]. On the basis of these observations, we sought to determine in this study whether TBP is limiting for Myc transactivation in transient transfection experiments.
We sought to characterize the functional interaction of the Myc TAD with TBP using the chimeric GAL4-Myc fusion proteins as well as full-length Myc with four model promoters (adenoviral major late promoter (AdML), lactate dehydrogenase A (LDHA), CDK4 and ornithine decarboxylase (ODC)) [34–37]. We found that addition of a TBP expression vector in the transactivation assays increases the transactivation by c-Myc from several fold to well over 30-fold . By contrast, a GAL4-USF1 transactivator did not respond to increasing input TBP. We also observe different responses by promoters that contain initiator (InR) sequences versus promoters that only contain TATA elements [39–41]. Furthermore, a Myc Box II point mutation W135E does not affect the ability of GAL4-Myc fusions to synergize with TBP , but the deletion mutant D106-143 has a blunted effect with cotransfected TBP. Our findings not only support a functional interaction between c-Myc and TBP, but they also provide a means to improve transient transfection assays to study c-Myc target genes.
TBP is limiting for GAL4-Myc transactivation
Since Myc Box II is necessary for interaction with TRRAP, we sought to determine whether mutations in this region affect the response of the Myc TAD to TBP. While the deletion D106-143, which removes critical residues of Myc BoxII, activates the reporter better than wild-type Myc TAD, this deletion renders Myc TAD non-responsive to increasing input TBP (Fig. 1). A substitution mutation in Myc Box II, W135E, which was previously shown to have diminished interaction with TRRAP and diminished transformation activity [42, 43], has a robust response to increasing TBP. These results suggest that the entire region comprising residues 106–143 is required for synergy with TBP, whereas the transformation defective W135E mutant still responds to increasing input TBP.
GAL4-Myc synergy with TBP is dependent on the TATA element
TBP is not limiting for USF1 TAD
Effects of TBP on full-length wild-type and mutant c-Myc transactivation of the LDHA promoter
We also studied two Myc mutants in the context of additional TBP (Fig. 4). The Myc dHLH mutant lacks the helix-loop-helix domain, and therefore neither dimerizes with Max nor binds DNA. The dHLH mutant minimally affects basal promoter activity and was not affected by increasing input TBP. The W135E mutant contains a substitution in the Myc Box II domain that renders Myc deficient in transformation [42, 43]. Intriguingly, W135E was active and fully responsive to increasing TBP.
The effect of the initiator (InR) element on the synergy between Myc and TBP
We have previously studied the adenoviral major late (AdML) promoter as a model Myc responsive promoter that contains both InR and TATA elements . Others and we have shown that c-Myc regulation of the AdML is biphasic with transactivation followed by transrepression at high levels of input Myc plasmids [37, 45]. The transactivation phase depends on E-boxes, whereas the transrepression phase depends on the InR. Here we chose the AdML promoter to determine the effect of the InR on the synergy between Myc and TBP.
Synergy of Myc and TBP with CDK4 and ODC responsive sequences
Myc's dramatic biological effects, a plethora of well-characterized interactions between Myc and other proteins, an ever-expanding list of putative target genes and a seemingly weak transactivation potential characterize the enigma of c-Myc-mediated gene regulation [4, 46]. Compared with other more potent transactivators, especially in the same family of HLH-Zip proteins, c-Myc stimulates reporter constructs only 2- to 5-fold in an E-box dependent manner. The basis for this apparently weak transactivation is poorly understood. We report in this paper a strong synergy between Myc and TBP resulting in up to 35-fold induction of reporter plasmids. Our observations indicate that TBP is limiting for Myc transactivation and provide a means to enhance the characterization of Myc target genes.
The weak transactivation potential of c-Myc may well be biologically significant when the degree of gene induction by c-Myc is considered . The emergence of an increasing number of Myc target genes reveals several characteristics among the genes. With only a few exceptions, Myc induces endogenous genes by only a few fold above background. In multiple instances, it appears that the broad-based effect of inducing multiple genes in the same pathway by c-Myc may be more important than the marked induction of a few genes [7, 47]. Perhaps c-Myc globally affects gene expression through multiple mechanisms. The connection between c-Myc and histone acetylation has become more firmly established, suggesting a role for Myc to modulate chromatin [47–51]. Beyond chromatin modulation, the role of Myc in transcriptional initiation or elongation is less well understood. Searches for an interaction between Myc and members of the general transcription factors have revealed an interaction between the Myc transactivation domain and TBP . In the work reported here, we provide evidence for a functional interaction between Myc and TBP in transient transfection reporter assays. Although the addition of TBP dramatically enhances these assays, the biological significance of this synergism is not delineated in our study. In particular, since many Myc target genes are induced only several fold in vivo, the role of TBP in modulating these target genes in vivo is not at all clear.
In response to TBP and Myc, promoters with an initiator element respond differently compared with those with a TATA element only [39–41]. With both the GAL4 chimeric proteins and full length Myc, InR driven promoters respond to the Myc TAD briskly. However, the increase in TBP did not further augment the activities of InR driven promoters. These observations are consistent with previous findings that TBP is limiting for TATA driven, but not InR driven promoters in Drosophila . It is intriguing to note the initial brisk response of InR containing promoters to Myc, which at high levels can inhibit the same InR driven promoters. We surmise from these findings that promoters comprising both TATA and InR elements may control Myc responsive genes that require brisk increased expression within a narrow window of Myc levels independent of TBP. Such genes would be sharply induced by Myc, which in excess can inhibit the same genes through the InR [37, 45].
In contrast to InR containing promoters, promoters with TATA element only, such as CDK4 and LDHA, increase in activity with increasing TBP levels in the presence of a constant amount of Myc. These promoters may be regulated by the activity of TBP in vivo, although evidence for this is lacking. The observation that oncogenic Ras can augment TBP activity suggests that a subset of Myc target genes may also be further responsive to increased TBP through activated oncogenic Ras . In fact, Myc and Ras can cooperate to regulated cdc2 . Hence, it will be instructive to determine the set of Myc responsive genes versus the set of genes that are responsive to both Myc and Ras. Comparison of promoters or regulatory regions of these genes are likely to uncover a level of transcriptional complexity previously unappreciated.
The fact that the synergy between TBP and Myc was observed with the GAL4 chimeric activator system and full length Myc suggests that the synergy is mediated through the Myc transactivation domain. Furthermore, the Myc Box II deletion mutant D106-143 was unresponsive to increasing TBP, indicating that this region of Myc is required for synergy with TBP. This observation is consistent with the previous finding that in vitro interaction between Myc and TBP requires Myc Box II . Although we observed a significant synergy between Myc and TBP, none of the TBP mutants retained any synergistic activity. It is not surprising that both TATA box binding mutant and Pol II interaction defective TBP mutants were dysfunctional. Although it may seem surprising that Pol III interaction defective TBP mutants were also inactive, recent studies suggest a significant overlap between Pol II and Pol III interactions with TBP . Although beyond the scope of the current study, it will be of significant interest to map the regions of TBP required for the interaction with Myc and correlate this with the ability for TBP mutants to synergize with Myc.
In summary, we describe in this report a significant stimulation of Myc transactivation by TBP. However, the presence of an InR diminishes the promoter response to TBP. We surmise that these differences may be exploited in vivo to increase the complexity and range of gene regulation by Myc.
GAL4 constructs were as described . GAL4-MycW135E (GMW135E) is GAL4(1-262) in which the Pst1-Pst1 fragment was exchanged with a fragment containing the substitution W135E from full length c-myc in MLVMycW135E . GAL4-USF1 was constructed by inserting a PCR-amplified, sequence-verified 560-bp USF1 fragment (corresponding to residues 1–180) into the NdeI-BstEII sites of pGALm. The USF1 cDNA template for PCR was a gift from M. Sawadogo and R. Roeder . The Gal4 TATA-driven reporter G5TATALuc was constructed from G5TATA-CAT(gift from M. Green) by replacing CAT with luciferase (Luc) . The Gal4 InR-driven G5INRLuc reporter (gift from J. Gralla) was as described .
Murine sarcoma virus long terminal repeat (MSV-LTR) promoter driven wild-type and mutant TBP expression vectors were gifts from A. Berk and are as described . Expression vectors for wild-type and mutant c-myc are as described .
The reporter ornithine decarboxylase ODC-Luc is a gift from J. Cleveland . The wild-type and mutant lactate dehydrogenase promoter LDH-Luc reporters were previously described . Wild-type and mutant adenoviral major late promoter AdML-Luc constructs were previously reported . Wild-type and mutant cyclin dependent kinase CDK4-Luc was described .
Cell culture and transfection
Chinese Hamster Ovary (CHO) cells were grown in 5% CO2 at 37°C in αMEM
(LTI) supplemented with 10% fetal bovine serum (LTI) and antibiotics as described . Cells were transiently transfected using DEAE-dextran (0.275 mg/ml). Two μg of GAL4 reporter luciferase plasmid, two μg of GAL4 chimeric activator plasmid and increasing amounts of pLTRTBP (0.5 to 4 μg) were cotransfected into 100 mm plates of 60% confluent CHO cells. DNA concentration was maintained at 8 μg by the addition of pLTR empty vector. Cells were incubated with the DNA in serum-free DEAE-dextran/MEM media overnight. Cells were harvested 48 hours after DMSO/ chloroquine shock and assayed for luciferase activity as described.
NIH3T3 cells (gift from R. Eisenman) were grown in 5% CO2 at 37°C in DMEM (low glucose) (LTI) supplemented with 10% fetal bovine serum and antibiotics. Cells were transfected with Lipofectin (LTI). Lipofectin was added at 5 X the total concentration of DNA to serum-free Opti-MEM media (LTI) and incubated at room temperature for 45 min. Two μg of various promoter-reporter luciferase plasmid and one μg of full-length wild-type or mutant c-myc activator plasmid were added with increasing amounts of pLTRTBP (0.5 to 4 μg) to the Opti-MEM/Lipofectin mixture. DNA concentrations were maintained at 7 μg by adding pLTR empty vector. The Opti-MEM/ Lipofectin/ DNA mixture was incubated at room temperature for 10 min. then added to 100 mm plates of 30% confluent NIH3T3 cells. Cells were incubated for 5 hours, aspirated and fed fresh media and harvested after 48 hours for luciferase activity.
Luciferase activity was measured using the luciferase assay system according to manufacturer's instructions (Promega). Cells were washed in phosphate buffered saline (PBS), scraped using Cell Lysis Solution (Promega) and centrifuged for 2 min at 1000 rpm. Luciferin cocktail (80 μl) was added to 20 μl lysate and luciferase activity was measured in a luminometer. Samples were run in duplicate.
We thank J. Cleveland, A. Berk, R. Eisenman, J. Gralla, M. Green, and G. Kato for reagents or comments. This work was supported in part by NIH grant CA 51497 and CA09159. C.V.D. is The Johns Hopkins Family Professor in Oncology Research.
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