Department of Biochemistry, Section for Molecular Genetics, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway
Correspondence
Ugo Moens
ugom{at}fagmed.uit.no
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ABSTRACT |
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Present address: The National Hospital, Institute of Microbiology, Section for Gene Therapy, N-0027 Oslo, Norway.
Present address: Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway.
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INTRODUCTION |
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Numerous proteins assemble on the promoter/enhancer region of genes to accomplish transcription of genes. These proteins include the general transcription factors TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH and RNA polymerase II. TFIID comprises the TATA box-binding protein (TBP) and about 12 TBP-associated factors (TAFIIs). Although referred to as general transcription factors, distinct TAFII proteins seem to be recruited selectively by specific promoters and are, therefore, essential for the transcription of a subset of genes (Albright & Tjian, 2000; Tsukihashi et al., 2000
; Li et al., 2002
; and references therein). In addition to these general transcription factors, sequence-specific DNA-binding transcription factors, co-activators and chromatin-remodelling proteins are required to ac2tivate transcription (reviewed by Näär et al., 2001
). St-ag has been shown to influence the expression of several viral and cellular genes (reviewed by Moens et al., 1997
). The exact mechanism by which st-ag exerts its trans-activation function on gene expression remains elusive, but may involve the activation of signalling pathways, probably through association with and inhibition of the serine/threonine protein phosphatase 2A (PP2A). This inhibition of PP2A by st-ag may subsequently regulate the phosphorylation pattern/activity of sequence-specific DNA-binding transcription factors. Indeed, inhibition of PP2A by st-ag led to the activation of several signalling pathways mediated by mitogen-activated protein kinases, calmodulin-dependent protein kinase IV, phosphatidylinositol 3-kinase/PKC
and Akt/PKB (Sontag et al., 1993
, 1997
; Frost et al., 1994
; Watanabe et al., 1996
; Howe et al., 1998
; Westphal et al., 1998
; Garcia et al., 2000
; Yuan et al., 2002
). Wild-type, but not mutant, st-ag proteins deficient in PP2A binding can influence the activity of the transcription factors cyclic AMP response element-binding protein (CREB), AP-1, NF
B, p53, Sp1, STAT3 and HOX11 (reviewed by Janssens & Goris, 2001
; Lacroix et al., 2002
). Moreover, st-ag can regulate both serum- and Sp1-responsive promoters in a PP2A-dependent fashion (Frost et al., 1994
; Garcia et al., 2000
). Whether st-ag can affect the activity of general transcription factors has not been investigated but several studies have demonstrated a TATA-dependent mechanism for transcriptional activation of promoters by other viral proteins. Adenovirus E1A protein exhibits an absolute requirement for a TATA motif, while the varicella-zoster virus immediately-early regulatory protein IE62 trans-activates promoters containing a much broader pattern of TATA sequences. Viral transcriptional activators such as Zta (EpsteinBarr virus) and ICP4 (herpes simplex virus) induce transcription by enhancing or stabilizing TBP binding to the TATA box, again illustrating the importance of the TATA box for virus-induced activation of promoter activity (Perera, 2000
; and references therein). The hepatitis B virus pX regulatory protein can increase levels of TBP, which serves to enhance both RNA polymerase I and III promoter activities, while the effects on RNA polymerase II promoters are different. TATA-lacking promoters are generally unaffected by increased levels of TBP, while overexpression of TBP stimulates TATA-containing promoters (Johnson et al., 2000
).
Previous studies in NIH 3T3 and CV-1 cells have shown that st-ag can stimulate NFB- and Sp1-dependent transcription and that this induction of transcription was mediated by PKC
and its upstream regulator phosphatidylinositol 3-kinase (Sontag et al., 1997
; Garcia et al., 2000
). Because NF
B and Sp1 interact physically with PP2A and st-ag inhibits PP2A, it is generally assumed that a major mechanism by which st-ag induces NF
B- and Sp1-dependent transcription relies on prevention of PP2A-mediated dephosphorylation of these transcription factors (Yamashita et al., 1999
; Yang et al., 2001
; Lacroix et al., 2002
). Here, we report that trans-activation of NF
B- and Sp1-responsive promoters by st-ag depends on a consensus TATAAAAG TATA motif. Such st-ag responder promoters were also stimulated by the general transcription factor hTAFII130/135. Wild-type st-ag, but not a mutant unable to bind PP2A, or a mutant in the conserved hexapeptide HPDKGG, increased the intrinsic transcriptional activity of hTAFII130/135. These data suggest that hTAFII130/135 is a promoter-specific transcription factor whose activity may be regulated by PP2A-dependent and -independent mechanisms. Transcriptional activation of specific cellular genes by st-ag through preventing PP2A-mediated dephosphorylation of hTAFII130/135 may, therefore, facilitate virus replication or transformation.
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METHODS |
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Materials.
Recombinant murine TNF was purchased from Alexis Biochemicals. Sonicated salmon sperm and calf thymus DNA were from Amersham Pharmacia. Newborn calf serum was from BioWhittaker. Oligonucleotides were purchased from Eurogentec or Invitrogen.
Plasmids.
The NFB-responsive luciferase reporter plasmids and their corresponding control plasmids
BconA-LUC and conA-LUC, TI-3x
B-LUC and TI-LUC, 2x
B-LUC and 2x
B-m1LUC, ENH-TK-LUC and mENH-TK-LUC were kindly provided by E. Sontag (Sontag et al., 1997
), X.-F. Wang (Li et al., 1998
), C. Scheidereit (Hirano et al., 1998
) and F. Bachelerie (Bachelerie et al., 1991
), respectively. The plasmids pTAL-LUC and pNF
B-LUC(C) were purchased from Clontech, while the plasmid pNF
B-LUC(S) was obtained from Stratagene. Expression plasmid for the dominantnegative mutant of I
B (pCMV-I
B
S32/36A) has been described previously and was kindly made available by M. Körner (Ferreira et al., 1998
). The GAL4 fusion plasmids pGAL4-p65 and pGAL4-p65(416-550) were kindly provided by B. R. Cullen (Blair et al., 1994
). The RelA/p65 expression plasmid was obtained from J. A. Didonato (Zhang et al., 1994
), while the plasmid pG5E1bLuc was a kind gift from R. Davis (Seth et al., 1991
). The plasmid pCMV5 and the st-ag expression plasmid pCMV5st (wild-type st-ag) were a generous gift from E. Sontag (Sontag et al., 1993
). The pMIEP-LUC plasmid, containing the major immediate-early promoter of human cytomegalovirus, and the double mutant pMIEPdm-LUC with non-functional NF
B motifs have been described previously (Moens et al., 2001
). Plasmid pNF
B-fosTATA-LUC was constructed by annealing the double-stranded oligonucleotide 5'-AGCTCGGGAATTTCCGGGATTTCCGGGAATTTCTCATTCATAAAACGCTTGTTATAAAAGCAGTGGCTGCGGCGCCTCGTACTCCAAC-3' (only one strand is given) into the BamHI/HindIII sites of pO-LUC. The resulting plasmid contains three copies of the consensus NF
B-binding site linked to the TATA box region of the c-fos promoter. The plasmid was sequenced to verify the insertion. Plasmid pCMVhTAFII130/135 was kindly provided by N. Tanese (Saluja et al., 1998
). An expression plasmid for GAL4hTAFII130/135 fusion protein was prepared by amplifying the hTAFII130/135 cDNA sequences using the pCMVhTAFII130/135 plasmid as template and the primers 5'-CAACAGCGAGGTCGACGAGAAAGTGGG-3' and 5'-GAGCAGCAGTGAAAAGCTTGTCTCACG-3'. The PCR product was digested with SalI/BamHI (restriction sites are underlined) and cloned in the corresponding sites of the GAL4 DNA-binding domain expression plasmid pM (Clontech) to generate pGAL4-hTAFII130/135. The plasmid was sequenced to ensure ligation of the hTAFII130/135 cDNA sequences in the correct reading frame. Expression vectors for hTAFII28 and hTAFII80 were a generous gift from R. G. Roeder (Guermah et al., 2001
).
Site-directed mutagenesis.
Site-directed mutagenesis was performed with the QuickChange Site-Directed Mutagenesis kit from Stratagene, according to the instructions of the manufacturer. The TATA box motif in BconA-LUC (see Fig. 3A
) was replaced by the TATA element of pNF
B-LUC(C) (Fig. 3A
) using complementary oligonucleotides (5'-GGGCTGCTCCTCTATATTTTGGGAAGAAAG-3', only one primer is shown; the TATA box is shown in bold). The TATA elements of pTAL-LUC and pNF
B-LUC were converted into the TATA element of the
BconA promoter using a complementary primer set (5'-GACATGCAAATATAAAAGTTCCGGGGACAC-3', only one primer is given; the converted TATA motif is shown in bold). The st-ag mutants P43L/K45N and P101A were obtained by site-directed mutagenesis applying the primers of the complementary set (5'-GAGTTTCATCTAGATAACGGAGGAGATG-3' and 5'-GCAAACAATGCGCAGAGTGTGCAAAGATGTCTGC-3', respectively, only one primer of the complementary set is shown). All mutations were verified by cycle sequencing using the Big Dye Sequencing kit (Perkin Elmer). Sequencing reactions were analysed on an ABI377 Prism Sequencer (Perkin Elmer).
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Western blotting.
Western blotting was performed as described previously (Seternes et al., 1999). GAL4 antibodies were from Santa Cruz Biotechnology (cat #sc-577). Densitometry quantification of the hybridization signals was performed with a LumiImager F1 using LumiAnalyst software (Boehringer Mannheim).
Statistics.
Statistical significance of results was determined by Student's t-test with P<0·01.
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RESULTS |
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A Sp-1-responsive promoter with the consensus TATA motif but not with a non-consensus TATA box is also trans-activated by st-ag
The minimal chicken conalbumin (conA) promoter lacking the NFB-binding motifs was not stimulated by st-ag (Fig. 1d
). This suggested to us that the TATA box per se is not sufficient to induce activation by st-ag but, in addition to an appropriate TATA motif, an upstream binding motif (e.g. NF
B) is required to mediate promoter trans-activation by st-ag. A recent report demonstrated that st-ag could activate Sp1-responsive promoters (Garcia et al., 2000
). The authors used promoter constructs containing either the adenovirus major late promoter or the human immunodeficiency virus LTR promoter/enhancer. Both promoters possess a consensus TATA motif (Fig. 3a
). This observation indicates that Sp1 motifs in concert with a consensus TATA box sequence may also mediate st-ag-induced trans-activation. This assumption was investigated by testing whether st-ag could activate promoter activity of the plasmid pTAL-LUC. This plasmid contains a single Sp1 motif linked to the same non-consensus TATA box present in pNF
B-LUC(C) (Fig. 3a
). We also converted the TATA motif in pTAL-LUC into the conA TATA box to generate the reporter plasmid pTALmTATA-LUC. St-ag did not induce transcription from the pTAL-LUC plasmid but changing the TATA box into a consensus TATA motif stimulated luciferase activity about 2-fold in the presence of st-ag (Fig. 4
). These results prove that the consensus TATA box combined to specific upstream binding elements can mediate st-ag induction.
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DISCUSSION |
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The fact that st-ag also affects the activities of the TATA-less cyclin A, cyclin D1 and PCNA promoters (Travali et al., 1989; Herber et al., 1994
; reviewed by Moens et al., 1997
) may suggest that the flanking regions are important. This observation supports further a plausible importance of the flanking sequences. Converting the consensus TATAAAAGGG motif of the
BconA promoter into a non-consensus TATATTTTGG sequence of the NF
B-LUC plasmid did not completely abrogate trans-activation by st-ag or hTAFII130/135, as this mutated promoter was still induced 2·5-fold compared to 4- to 5-fold for the unmutated promoter. On the other hand, the promoter of the NF
B-LUC plasmid was not responsive to st-ag or hTAFII130/135. This discrepancy may be explained by assuming that sequences flanking the TATA box could be involved in recruiting hTAFII130/135. Indeed, recent studies have demonstrated that TAFIIs are not only recruited through proteinprotein interaction with TBP and each other but also that they can bind DNA directly in a sequence-specific mode, thereby contributing to promoter selectivity (Albright & Tjian, 2000
; Green, 2001
). Moreover, binding of hTAFII130/135 to the flanking sequences may affect the binding of TBP to the TATA box, as was shown recently (Furukawa & Tanese, 2000
). Point mutations of the flanking sequences and in the consensus TATA motif may enable the identification of crucial nucleotides required to mediate trans-activation by st-ag.
St-ag-responsive promoters were also activated when hTAFII130/135 was overexpressed and vice versa: st-ag non-responsive promoters were not induced by hTAFII130/135. The exact molecular mechanism(s) underlying the activator effect of st-ag on promoters containing a consensus TATA box combined with a NFB- or Sp1-binding motif remains unknown. St-ag may prevent PP2A-mediated dephosphorylation of hTAFII130/135, as the non-PP2A binding P101A st-ag mutant was unable to stimulate the intrinsic transcriptional activity of hTAFII130/135 and also failed to activate the
BconA promoter (result not shown). However, a PP2A-independent mechanism is suggested by the studies with the P43L/K45N double mutant. This mutant st-ag is still able to bind PP2A but failed to stimulate GAL4hTAFII130/135-mediated transcription and could not activate the
BconA promoter (result not shown). Previous studies have demonstrated that this mutant failed to trans-activate the adenovirus E2 and the cyclin A promoters (Mungre et al., 1994
; Porrás et al., 1996
) but induced the activity of the cyclin D1 promoter with comparable levels as wild-type st-ag (Watanabe et al., 1996
). The cyclin A and D1 promoters both lack a TATA box, while a non-consensus TATA motif is present in the adenovirus E2 promoter (Herber et al., 1994
). These findings, combined with our observations, add to the diversity of transcriptional regulation by st-ag and require future research to solve the exact mechanisms by which st-ag can trans-activate promoters.
It remains to be established whether the novel mechanism by which st-ag can activate gene expression contributes to a successful SV40 infection or transformation. Prevalence for this mechanism derives from the following observations: SV40 infection induced quiescent cells to re-enter the S phase and re-entering the cell cycle coincided with increased c-fos transcription. St-ag was important for enhanced expression of c-fos (Morike et al., 1988; Glenn & Eckhart, 1990
; Ogris et al., 1992
). Another study showed that granulocyte macrophage colony-stimulating factor promoter was induced upon polyomavirus replication in haematopoietic cells. The effect of st-ag was, however, not examined (Watanabe et al., 1995
). Both the c-fos and the granulocyte macrophage-colony stimulating factor promoter contain a consensus TATA motif and Sp1 (c-fos) or NF
B (granulocyte macrophage-colony stimulating factor) binding sites. Finally, this mechanism may also contribute to virus immune evasion. EpsteinBarr virus encodes a protein homologous to cellular IL-10. IL-10 is a negative regulator of IL-12, itself a cytokine that both promotes IFN-
production and influences the development of Th1- and Th2-like cytokine-producing cells, and of TAP, a protein involved in transport and presentation of processed peptide antigens (Ploegh, 1998
). The promoter of IL-10 contains a consensus TATAAAAG TATA box and a crucial Sp1 site (Tone et al., 2000
; Ma et al., 2001
). This makes this gene a putative target for trans-activation by st-ag and a strategy for SV40 to subvert the immune system.
In conclusion, trans-activation of specific promoters by st-ag may rely upon at least two different mechanisms. First, st-ag may prevent PP2A-mediated dephosphorylation of specific transcription factors like CREB, Sp1, NFB, STAT and AP-1 and thereby stimulate the activity of promoters regulated by these transcription factors (reviewed by Janssens & Goris, 2001
). In addition, st-ag may stimulate the promoter activity of promoters utilizing the general transcription factor hTAFII130/135. The exact molecular mechanism by which st-ag induces hTAFII130/135-responsive promoters needs to be elucidated.
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ACKNOWLEDGEMENTS |
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Received 20 December 2002;
accepted 21 February 2003.