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Protein Phosphatase 2A and Phosphatidylinositol 3-Kinase Regulate the Activity of Sp1-responsive Promoters*

  • Alphonse Garcia
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  • Silvia Cereghini
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  • Estelle Sontag
    Correspondence
    To whom correspondence should be addressed: Dept. of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9073; Tel.: 214-648-2327; Fax: 214-648-2077
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  • Author Footnotes
    * This work was supported by National Institutes of Health Grant AG12300 (to E. S), “Biotec Contrat B102CT-920319,” “La ligue de la Recherche sur le Cancer” (to S. C.), and ARC Grants 9449 and 9294 (to A. G.) and 1704 (to S. C.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Open AccessPublished:March 31, 2000DOI:https://doi.org/10.1074/jbc.275.13.9385
      The transcription factor Sp1 regulates the activity of a large number of eukaryotic gene promoters, including early SV40 and human immunodeficiency virus type 1 (HIV-1). Here, we report that expression of SV40 small tumor antigen (small t) in quiescent CV-1 cells transactivates two Sp1-responsive promoters, including a deletion mutant of HIV-1 LTR, through specific inhibition of endogenous AC and ABαC forms of protein phosphatase 2A (PP2A). Expression of a small t mutant, lacking the PP2A-binding domain, failed to transactivate Sp1. Overexpression of the B56α, B56β, and B56γ1 regulatory PP2A subunits strongly inhibited the ability of small t, but not the phosphatase inhibitor, okadaic acid, to enhance Sp1-driven gene expression. Using inhibitors and co-expression of kinase-deficient mutants, we also show that functional phosphatidylinositol 3-kinase (PI 3-kinase) and atypical protein kinase C ζ are required for small t-induced Sp1-dependent promoter transcriptional activation. Moreover, two inhibitors of PI 3-kinase, wortmannin and LY294002, inhibit the initiation of SV40 DNA replication in quiescent CV-1 cells. Taken together, these results suggest that PP2A and PI 3-kinase contribute to the ability of small t to regulate Sp1 activity, stimulate early SV40 DNA replication, and enhance the transformation of resting cells during SV40 infection.
      small t
      small tumor antigen
      large T
      large tumor antigen
      PP2A
      protein phosphatase 2A
      HIV-1
      human immunodeficiency virus type 1
      LTR
      long terminal repeat
      PKC ζ
      protein kinase C ζ isoform
      PI 3-kinase
      phosphatidylinositol 3-kinase
      CAT
      chloramphenicol acetyltransferase
      ERK
      extracellular signal-regulated kinase
      The nuclear transcription factor Sp1 is expressed in most mammalian cells and binds to GC-rich elements in the promoters of a wide variety of cellular and viral genes (
      • Dynan W.S.
      • Tjian R.
      ,
      • Kadonaga J.T.
      • Carner K.R.
      • Masiarz F.R.
      • Tjian R.
      ,
      • Kingsley C.
      • Winoto A.
      ). Sp1 can undergo two major post-translational modifications, including glycosylation (
      • Jackson S.P.
      • Tjian R.
      ) and phosphorylation (
      • Armstrong S.A.
      • Barry D.A.
      • Leggett R.W.
      • Mueller C.R.
      ,
      • Jackson S.P.
      • MacDonald J.J.
      • Lees-Miller S.
      • Tjian R.
      ,
      • Leggett R.W.
      • Armstrong S.A.
      • Barry D.
      • Mueller C.R.
      ), that are believed to modulate its DNA-binding and -transactivating activities. Sp1 was first isolated as a transcription factor that binds to the SV40 early promoter (
      • Dynan W.S.
      • Tjian R.
      ). Sp1 accumulates and becomes phosphorylated during the early phase of SV40 infection and is critically required for transcription of viral early genes (
      • Armstrong S.A.
      • Barry D.A.
      • Leggett R.W.
      • Mueller C.R.
      ,
      • Jackson S.P.
      • MacDonald J.J.
      • Lees-Miller S.
      • Tjian R.
      ,
      • Saffer J.D.
      • Jackson S.P.
      • Thurston S.J.
      ). The SV40 early gene encodes two proteins: the small tumor (small t)1 and large tumor (large T) antigens (
      • Tooze J.
      ). Large T plays an essential role in the initiation of viral DNA synthesis and in cell transformation (
      • Tooze J.
      ,
      • Virshup D.M.
      • Russo A.A.R.
      • Kelly T.J.
      ,
      • Bikel I.
      • Montano X.
      • Agha M.E.
      • McMormack M.
      • Boltax J.
      • Livingston D.M.
      ). Small t is required for efficient transformation of growth-arrested cells by SV40 (
      • Martin R.G.
      • Setlow V.P.
      • Edwards C.A.F.
      • Vembu D.
      ) and enhances the transforming activity of limiting concentrations of large T (
      • Bikel I.
      • Montano X.
      • Agha M.E.
      • McMormack M.
      • Boltax J.
      • Livingston D.M.
      ). During infection of the permissive monkey kidney CV-1 cells, nearly all of the host's protein phosphatase 2A (PP2A) becomes complexed with SV40 small t (
      • Rundell K.
      ). PP2A, a predominant protein serine/threonine phosphatase in most mammalian cells, participates in the regulation of many cellular processes, including metabolism and division (
      • Cohen P.T.W.
      ). The core enzyme is a dimeric complex consisting of a catalytic subunit (C) bound to a subunit (A), that can associate with a third polypeptide termed “B” or the phosphatase regulatory (PR) subunit.
      The PP2A regulatory subunits are categorized into several distinct families that generate a diversity of holoenzymes (
      • Cohen P.T.W.
      ,
      • Kamibayashi C.
      • Mumby M.C.
      ). Besides regulating phosphatase activity, the B subunits are thought to be responsible for the substrate specificity and targeting of PP2A (
      • Cohen P.T.W.
      ,
      • Kamibayashi C.
      • Mumby M.C.
      ,
      • McCright B.
      • Rivers A.M.
      • Audin S.
      • Virshup D.M.
      ). We have reported that SV40 small t is able to associate with endogenous PP2A and inhibit phosphatase activity in transfected monkey kidney CV-1 cells (
      • Sontag E.
      • Fedorov S.
      • Kamibayashi C.
      • Robbins D.
      • Cobb M.
      • Mumby M.
      ). Interaction of small t with PP2A promotes the growth of quiescent cells through stimulation of a signaling cascade involving phosphatidylinositol 3-kinase (PI 3-kinase), atypical protein kinase C ζ (PKC ζ), and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase kinase (
      • Sontag E.
      • Fedorov S.
      • Kamibayashi C.
      • Robbins D.
      • Cobb M.
      • Mumby M.
      ,
      • Sontag E.
      • Sontag J.M.
      • Garcia A.
      ). Moreover, SV40 small t forces quiescent cells to re-enter the S phase of the cell cycle and stimulates SV40 DNA replication in CV-1 cells (
      • Cicala C.
      • Avantaggiati M.L.
      • Graessmann A.
      • Rundell K.
      • Levine A.S.
      • Carbone M.
      ). Small t also regulates the cyclic AMP-response element-binding protein (
      • Wheat W.H.
      • Roesler W.J.
      • Klemm D.J.
      ), AP-1- (
      • Frost J.A.
      • Alberts A.S.
      • Sontag E.
      • Guan K.
      • Mumby M.C.
      • Feramisco J.R.
      ), NF-κB- (
      • Sontag E.
      • Sontag J.M.
      • Garcia A.
      ), and serum response element-regulated promoters (
      • Frost J.A.
      • Alberts A.S.
      • Sontag E.
      • Guan K.
      • Mumby M.C.
      • Feramisco J.R.
      ) in a PP2A-dependent fashion. All of these cellular effects of small t may explain its “helper” function during SV40 infection.
      Besides SV40, human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) is one of the numerous viral promoters tightly regulated by Sp1 (
      • Gaynor R.
      ,
      • Sune C.
      • Garcia-Blanco M.A.
      ). Incubation of T lymphocytes with okadaic acid, an inhibitor of type 1 and 2A protein phosphatases (
      • Cohen P.
      ), induces the phosphorylation of Sp1 and activation of Sp1-dependent HIV-1 gene transcription (
      • Vlach J.
      • Garcia A.
      • Jacqué J.-M.
      • Rodriguez M.S.
      • Michelson S.
      • Virelizier J.-L.
      ). Taken together, these findings prompted us to investigate whether interaction of small t with PP2A leads to up-regulation of Sp1 activity. We show here that expression of SV40 small t in quiescent CV-1 cells induces transactivation of two Sp1-dependent promoters through specific inhibition of endogenous PP2A activity. We also demonstrate that PI 3-kinase and PKC ζ are required for the transactivating effects of small t. Last, we show that inhibition of PI 3-kinase significantly delays the initiation of SV40 DNA replication during infection of CV-1 cells. Thus, in addition to providing evidence for a novel role for PI 3-kinase during SV40 infection, our results reveal PP2A enzymes and PI-3 kinase to be novel intracellular regulators of Sp1-dependent gene expression.

      DISCUSSION

      We have previously reported that, in quiescent CV-1 cells, interaction of SV40 small t with endogenous AC and ABαC forms of PP2A (
      • Sontag E.
      • Fedorov S.
      • Kamibayashi C.
      • Robbins D.
      • Cobb M.
      • Mumby M.
      ) activates HIV-1 LTR and NF-κB, and these effects are dependent on both functional PI 3-kinase and PKC ζ (
      • Sontag E.
      • Sontag J.M.
      • Garcia A.
      ). Since both NF-κB and Sp1 regulate HIV-1 LTR activity (
      • Gaynor R.
      ), we investigated here the effects of small t, PI 3-kinase, and PKC ζ on Sp1 regulation. We first show (Fig. 1) that small t and okadaic acid induce Sp1 transactivation in CV-1 cells. Significantly, okadaic acid has similar effects in J. Jhan cells (
      • Vlach J.
      • Garcia A.
      • Jacqué J.-M.
      • Rodriguez M.S.
      • Michelson S.
      • Virelizier J.-L.
      ). Consistent with a specific involvement of PP2A in Sp1 regulation, all three B56 (α, β, γ1) regulatory subunits of PP2A counteracted the transactivation of Sp1 induced by small t, but not okadaic acid (Fig. 2). When present in excess, B56 regulatory subunits of PP2A can displace small t from AC-small t complexes in vitro (
      • Kamibayashi C.
      • Mumby M.C.
      ). We therefore propose that, following overexpression of B56, the displacement of small t and subsequent formation of AB56C heterotrimers simply reverse PP2A inhibition by small t. Interestingly, in CV-1 cells, AC and ABαC are present in both cytoplasm and nuclear subcellular compartments, whereas AB56αC and AB56βC are concentrated in the cytoplasm, and AB56 γ1C is targeted to the nucleus (
      • Kamibayashi C.
      • Mumby M.C.
      ,
      • McCright B.
      • Rivers A.M.
      • Audin S.
      • Virshup D.M.
      ,
      • Sontag E.
      • Fedorov S.
      • Kamibayashi C.
      • Robbins D.
      • Cobb M.
      • Mumby M.
      ). Results from our overexpression studies imply that both cytosolic and nuclear forms of PP2A have the potential to regulate Sp1, either directly or indirectly. Thus, any alterations in the subcellular distribution and ratio between the endogenous AC core enzyme and PP2A holoenzymes could affect Sp1-dependent promoter transactivation. Beside PP2A, we have identified PI 3-kinase and atypical PKC ζ as novel regulators of Sp1-responsive promoter activity in CV-1 cells (Fig. 3). Although not presented here, we found similar results in mouse NIH 3T3 and human J. Jhan cells, suggesting that the regulatory mechanisms described in CV-1 cells are not restricted to this unique cell type. The existence of a nuclear pool of PKC ζ in CV-1 cells
      E. Sontag, unpublished data.
      suggests that PKC ζ could directly regulate Sp1. Indeed, PKC ζ has been recently reported to bind to and phosphorylate the zinc finger region of Sp1 in vitro and in carcinoma cell lines (
      • Pal S.
      • Claffey K.P.
      • Cohen H.T.
      • Mukhopadhyay D.
      ).
      Our findings are clearly important for understanding the biology of SV40. First, small t transactivates SV40 early and late promoters (
      • Bikel I.
      • Loeken M.R.
      ). Next, infection of CV-1 cells with SV40 leads to a ∼10-fold increase in the intracellular levels of Sp1 mRNA and proteins, and this effect can be attributed to expression of an early viral protein (
      • Saffer J.D.
      • Jackson S.P.
      • Thurston S.J.
      ). Since Sp1 stimulates the activity of the SV40 early promoter, its enhanced expression may be critical for the viral life cycle (
      • Dynan W.S.
      • Tjian R.
      ). Mutant SV40 viruses that lack small t antigen replicate less efficiently than the wild-type virus, and microinjection of small t in CV-1 cells stimulates the replication of wild-type and small t deletion mutant viruses (
      • Cicala C.
      • Avantaggiati M.L.
      • Graessmann A.
      • Rundell K.
      • Levine A.S.
      • Carbone M.
      ). In agreement with these observations, we found in this study that two PI 3-kinase inhibitors, which are potent suppressors of small t signaling (
      • Sontag E.
      • Sontag J.M.
      • Garcia A.
      ), also inhibit the initiation of SV40 DNA replication (Fig. 4). Based on our data (Ref.
      • Sontag E.
      • Sontag J.M.
      • Garcia A.
      and Fig. 1), we propose that transactivation of NF-κB and Sp1-dependent SV40 viral promoters by small t is involved in the initiation of SV40 DNA replication. In this context, it is noteworthy that expression of large T correlates with induction of Sp1 during the early phase of viral infection (
      • Jackson S.P.
      • MacDonald J.J.
      • Lees-Miller S.
      • Tjian R.
      ). Large T plays a critical function in the initiation of viral DNA synthesis by unwinding the SV40 origin of replication (
      • Virshup D.M.
      • Russo A.A.R.
      • Kelly T.J.
      ). It has been previously documented that nuclear B56-containing holoenzymes activate large T by dephosphorylating Ser-120 and Ser-123 residues, whereas AC and ABαC inactivate large T by dephosphorylating Thr-124 (
      • Virshup D.M.
      • Russo A.A.R.
      • Kelly T.J.
      ,
      • Cegielska A.
      • Shaffer S.
      • Derua R.
      • Goris J.
      • Virshup D.M.
      ). Since small t can selectively bind to and inhibit AC and ABαC, but not AB56C (
      • Kamibayashi C.
      • Mumby M.C.
      ,
      • Sontag E.
      • Sontag J.M.
      • Garcia A.
      ), it could promote the activation of large T. Transactivation of Sp1 by AC-small t may represent a means for SV40 viruses to enhance transcription from the early SV40 promoter at times when large T levels are low. Together, these results support the notion that SV40 DNA replication is controlled by intricate mechanisms that depend on the concerted action of distinct hosts' PP2A isoforms and viral antigens.
      Besides regulating SV40, Sp1 elevates the expression of a large variety of viral and cellular promoters. Sp1 interacts with several components of the cell cycle machinery, including the transcription factor E2F (
      • Lin S.Y.
      • Black A.R.
      • Kostic D.
      • Pajovic S.
      • Hoover C.N.
      • Azizkhan J.C.
      ), and Rb-like proteins (
      • Shao Z.
      • Robbins P.D.
      ). Increased cellular levels of Sp1 proteins and activity have been linked to cell proliferation and tumor progression (
      • Gunther M.
      • Frebourg T.
      • Laithier M.
      • Fossar N.
      • Bouziane-Ouartini M.
      • Lavialle C.
      • Brison O.
      ,
      • Kitadai Y.
      • Yasui W.
      • Yokozaki H.
      • Kuniyasu H.
      • Haruma K.
      • Kajiyama G.
      • Tahara E.
      ,
      • Mortensen E.R.
      • Marks P.A.
      • Shiotani A.
      • Merchant J.L.
      ,
      • Saffer J.D.
      • Jackson S.P.
      • Annarella M.B.
      ). The transactivation of Sp1-driven cellular promoters by small t may therefore account for its ability to promote growth and transformation of quiescent CV-1 cells. It is also of particular interest that efficient viral transcription and replication of HIV-1 requires both Sp1 sites and the interaction of Sp1 proteins with the viral transcription factor HIV-1 Tat (
      • Sune C.
      • Garcia-Blanco M.A.
      ,
      • Chang L.J.
      • McNulty E.
      • Martin M.
      ,
      • Harrich D.
      • Garcia J.
      • Wu F.
      • Mitsuyasu R.
      • Gonzales J.
      • Gaynor R.
      ,
      • Ross E.K.
      • Buckler-White A.J.
      • Rabson A.B.
      • Englund G.
      • Martin M.A.
      ). Recently, changes in the ratio of PP2A core enzyme to holoenzyme were found to affect Tat-dependent HIV-1 transcription (
      • Ruediger R.
      • Brewis N.
      • Ohst K.
      • Walter G.
      ). Our results showing that overexpression of distinct PP2A subunits differentially deregulates Sp1-dependent HIV-1 LTR activity (Fig. 2) support these findings. We have demonstrated that, following expression of small t, PI-3 kinase-dependent activation of PKC ζ induces transactivation of NF-κB-responsive promoters, including HIV-1 LTR (
      • Sontag E.
      • Sontag J.M.
      • Garcia A.
      ). Remarkably, the cooperative interaction between NF-κB and Sp1 is crucial for transcriptional activation of HIV1-LTR (
      • Perkins N.D.
      • Edwards L.
      • Duckett C.S.
      • Agranoff A.B.
      • Schmid R.M.
      • Nabel G.J.
      ). Moreover, induction of Sp1 during cytomegalovirus infection mediates up-regulation of NF-κB promoters (
      • Yurochko A.D.
      • Mayo M.W.
      • Poma E.E.
      • Baldwin Jr., A.S.
      • Huang E.S.
      ). Indeed, Sp1 directly interacts with NF-κB-binding sites, providing a means to keep basal levels of NF-κB-dependent gene expression elevated in the absence of activated NF-κB (
      • Hirano F.
      • Tanaka H.
      • Hirano Y.
      • Hiramoto M.
      • Handa H.
      • Makino I.
      • Scheidereit C.
      ). By regulating both NF-κB and Sp1, the signaling involving PP2A, PI 3-kinase, and PKC ζ may play a critical role in the transcriptional regulation of not only SV40 but also HIV-1 promoters. Results obtained with small t suggest that deregulation of this signaling may be strategically targeted by viruses to elevate viral and cellular gene expression during infection of resting cells.

      Acknowledgments

      We thank Drs. C. L. White III and J.-M. Sontag for helpful suggestions and critical reading of the manuscript; Dr. M. Cobb for providing pCMV5-ERK2-Y185F; Dr. J. Moscat for pRcCMV-ζPKCmut; Dr. W. Ogawa for SRα-Δp85; and Dr. D. Virshup for B56 expression plasmids.

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