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Promoter-dependent Synergy between Glucocorticoid Receptor and Stat5 in the Activation of β-Casein Gene Transcription*

Open AccessPublished:August 15, 1997DOI:https://doi.org/10.1074/jbc.272.33.20954
      Steroid hormone receptors and Stat factors comprise two distinct families of inducible transcription factors. Activation of a member of each family, namely the glucocorticoid receptor by glucocorticoids and Stat5 by prolactin, is required for the efficient induction of the expression of milk protein genes in the mammary epithelium. We have studied the mode of interaction between Stat5 and the glucocorticoid receptor in the activation of β-casein gene transcription. The functional role of potential half-palindromic glucocorticoid receptor-binding sites mapped previously in the promoter region was investigated. β-Casein gene promoter chloramphenicol acetyltransferase constructs containing mutations and deletions in these sites were tested for their responsiveness to the synergistic effect of prolactin and dexamethasone employing COS-7 cells or HC11 mammary epithelial cells. Synergism depended on promoter regions containing intact binding sites for the glucocorticoid receptor and Stat5. The carboxyl-terminal transactivation domains of Stat5a and Stat5b were not required for this synergism. Our results suggest that in lactogenic hormone response elements glucocorticoid receptor molecules bound to nonclassical half-palindromic sites gain competence as transcriptional activators by the interaction with Stat5 molecules binding to vicinal sites.
      The stage-specific regulation of milk protein gene expression is controlled by the lactogenic hormones glucocorticoids and prolactin. Both hormones have been documented to synergistically induce the expression of these genes at the level of transcription initiation (
      • Doppler W.
      • Groner B.
      • Ball R.K.
      ). Lactogenic hormone response elements have been defined in the promoter region and upstream enhancer regions of the genes encoding the milk proteins αS1-casein (
      • Pierre S.
      • Jolivet G.
      • Devinoy E.
      • Houdebine L.M.
      ), β-casein (
      • Doppler W.
      • Groner B.
      • Ball R.K.
      ,
      • Yoshimura M.
      • Oka T.
      ,
      • Schmidhauser C.
      • Casperson G.F.
      • Myers C.A.
      • Sanzo K.T.
      • Bolten S.
      • Bissell M.J.
      ), whey acidic protein (
      • Doppler W.
      • Villunger A.
      • Jennewein P.
      • Brduscha A.
      • Groner B.
      • Ball R.K.
      ,
      • Goldberg Y.
      • Treier M.
      • Ghysdael J.
      • Bohmann D.
      ,
      • Devinoy E.
      • Maliénou-N′Gassa R.
      • Thépot D.
      • Puissant C.
      • Houdebine L.M.
      ), and β-lactoglobulin (
      • Burdon T.G.
      • Maitland K.A.
      • Clark A.J.
      • Wallace R.
      • Watson C.J.
      ). They all contain binding sites for the prolactin inducible transcription factor MGF/Stat5
      The abbreviations used are: MGF/Stat5, mammary gland specific factor/signal transducer and activator of transcription 5; GR, glucocorticoid receptor; CAT, chloramphenicol acetyltransferase; GR-DBD, glucocorticoid receptor DNA-binding domain.
      1The abbreviations used are: MGF/Stat5, mammary gland specific factor/signal transducer and activator of transcription 5; GR, glucocorticoid receptor; CAT, chloramphenicol acetyltransferase; GR-DBD, glucocorticoid receptor DNA-binding domain.
      (
      • Pierre S.
      • Jolivet G.
      • Devinoy E.
      • Houdebine L.M.
      ,
      • Burdon T.G.
      • Maitland K.A.
      • Clark A.J.
      • Wallace R.
      • Watson C.J.
      ,
      • Schmitt-Ney M.
      • Doppler W.
      • Ball R.K.
      • Groner B.
      ,
      • Li S.
      • Rosen J.M.
      ). A mutation introduced into the Stat5-binding site has been shown to destroy the response of the promoter not only to prolactin but also to glucocorticoids (
      • Schmitt-Ney M.
      • Happ B.
      • Ball R.K.
      • Groner B.
      ), indicating that Stat5 is necessary for mediating the effects of prolactin and glucocorticoids. Glucocorticoids do not significantly change the binding activity of MGF/Stat5 to lactogenic hormone response elements (
      • Welte T.
      • Garimorth K.
      • Philipp S.
      • Doppler W.
      ), ruling out the possibility that they act synergistically with prolactin simply by enhancing the effect of prolactin on the activation of Stat5 DNA binding.
      In vitro binding studies with purified preparations of the glucocorticoid receptor revealed the presence of multiple GR-binding sites in the lactogenic response elements of the rat β-casein gene promoter (
      • Welte T.
      • Philipp S.
      • Cairns C.
      • Gustafsson J.-Å.
      • Doppler W.
      ), the proximal mouse whey acidic protein gene promoter (
      • Welte T.
      • Philipp S.
      • Cairns C.
      • Gustafsson J.-Å.
      • Doppler W.
      ), and the distal rat whey acidic protein gene promoter (
      • Li S.
      • Rosen J.M.
      ). Interestingly, only sequence motifs resembling half-palindromic GR-binding sites were contained within the footprinted regions. Transactivation mediated by the glucocorticoid receptor usually requires the binding of dimeric receptor molecules to palindromic DNA-binding sites (,
      • Truss M.
      • Chalepakis G.
      • Slater E.P.
      • Mader S.
      • Beato M.
      ,
      • Drouin J.
      • Sun Y.L.
      • Tremblay S.
      • Lavender P.
      • Schmidt T.J.
      • de Léan A.
      • Nemer M.
      ), whereas half-sites binding monomeric GR complexes have been reported to be insufficient by themselves to confer hormone responsiveness (
      • Drouin J.
      • Sun Y.L.
      • Tremblay S.
      • Lavender P.
      • Schmidt T.J.
      • de Léan A.
      • Nemer M.
      ). However, monomeric GR molecules binding to receptor half-palindromic sites were proposed to gain competence as transcriptional activators by interacting with other transcription factors (
      • Slater E.P.
      • Hesse H.
      • Müller J.M.
      • Beato M.
      ).
      We tested whether GR molecules binding to half-palindromic sites in the rat β-casein gene promoter can functionally interact with MGF/Stat5 in the activation of milk protein gene transcription. COS-7 cells were employed in transient co-transfection assays using wild-type and mutated β-casein gene promoter CAT constructs. These cells allow the reconstitution of prolactin-dependent signaling cascades by transfection of prolactin receptor and Stat5 expression vectors (
      • Wakao H.
      • Gouilleux F.
      • Groner B.
      ). They also can be used to study the synergy between Stat5 and GR in cotransfection experiments (
      • Stöcklin E.
      • Wissler M.
      • Gouilleux F.
      • Groner B.
      ). The results presented here suggest that GR half-palindromic sites serve to recruit GR molecules to the β-casein gene promoter and are instrumental for mediating the synergistic effect between glucocorticoids and prolactin. Experiments with stably transfected HC11 mammary epithelial cells, which do not overexpress Stat5 and GR molecules, lead to the same conclusion. Efficient transactivation by GR molecules was dependent on the activation and binding of Stat5 to its recognition site. Interestingly, transactivation was also possible with Stat5 molecules devoid of their carboxyl-terminal transactivation domain.

      DISCUSSION

      The steroid receptor superfamily and Stat molecules represent two archetypal families of signaling molecules which evolved to meet the requirement of cells to respond differentially to diverse extracellular stimuli. The specificity of the response is controlled at two levels (,
      • Schindler U.
      • Wu P.
      • Rothe M.
      • Brasseur M.
      • McKnight S.L.
      ): At the first level, there is a selective activation of steroid receptors or Stat factors by different extracellular signals. This is achieved by the specific binding of the steroid receptors to their ligands and the selective recruitment of Stat factors by their activating receptors. The second level of specificity is brought about by the recognition of distinct DNA-binding sites by the activated steroid receptors and Stat factors.
      Integration of different signaling pathways is a further means to increase the versatility of the response to extracellular stimuli (
      • Lucas P.C.
      • Granner D.K.
      ,
      • Doppler W.
      ,
      • Bamberger C.M.
      • Schulte H.M.
      • Chrousos G.P.
      ). In this study we have investigated how integration of the signaling pathways triggered by the two pleiotropic hormones prolactin and glucocorticoids leads to the specific activation of milk protein gene transcription.
      When this article was in preparation, Stöcklin et al.(
      • Stöcklin E.
      • Wissler M.
      • Gouilleux F.
      • Groner B.
      ) reported a direct interaction between Stat5 and the GR overexpressed in COS-7 cells. A model was proposed where the GR acts as a co-activator of Stat5 in a mode which is independent of a GRE. The results presented in our study do not support this model, since they provide clear evidence that GR and Stat5 molecules, activated by the two hormones, interact in a lactogenic hormone response element dependent fashion. DNA-binding sites for both the GR and Stat5 were demonstrated to be essential in mediating their synergism on β-casein gene induction. However, protein-protein interactions between GR and Stat5, as the one observed by Stöcklin et al. (
      • Stöcklin E.
      • Wissler M.
      • Gouilleux F.
      • Groner B.
      ), might also be important for a productive functional interaction of GR and Stat5 molecules, recruited to the lactogenic hormone response elements of milk protein gene promoters. In fact, a role for both DNA-template dependent and independent interactions of the GR or Stat5 with other transcription factors has been demonstrated frequently. GR homodimers bound to palindromic GR consensus sites were described to interact with several unrelated transcription factors bound to vicinal sites (,
      • Lucas P.C.
      • Granner D.K.
      ,
      • Schüle R.
      • Muller M.
      • Kaltschmidt C.
      • Renkawitz R.
      ). In addition, direct DNA-template independent interactions of the GR with the transcription factors NFκB (
      • Ray A.
      • Prefontaine K.E.
      ), NF-IL6 (
      • Nishio Y.
      • Isshiki H.
      • Kishimoto T.
      • Akira S.
      ), and AP-1 (reviewed in Ref.
      • Ponta H.
      • Cato A.C.
      • Herrlich P.
      ) have been reported. Protein-protein interactions of GR monomers and AP-1 were suggested to be involved in the repression of transcription factor AP-1 activity (
      • Heck S.
      • Kullmann M.
      • Gast A.
      • Ponta H.
      • Rahmsdorf H.J.
      • Herrlich P.
      • Cato A.C.
      ). Interactions involving both DNA binding and protein-protein contacts are the hallmark of composite glucocorticoid response elements (
      • Diamond M.I.
      • Miner J.N.
      • Yoshinaga S.K.
      • Yamamoto K.R.
      ), which mediate a positive or negative effect of glucocorticoids on transcription depending on the type of the cooperating transcription factor.
      For Stat factors, DNA template-dependent synergy with members of the Ets family and C/EBP has been described. In the c-fos gene promoter, Stat1 and Stat3 cooperate with ternary complex factors (
      • Hill C.S.
      • Treisman R.
      ); in the Fcγ receptor gene, Stat1 cooperates with PU.1 (
      • Perez C.
      • Coeffier E.
      • Moreau-Gachelin F.
      • Wietzerbin J.
      • Benech P.D.
      ); for the induction of the interleukin-4 gene vicinal sites of Stat6 and C/EBP have been found to be important (
      • Mikita T.
      • Campbell D.
      • Wu P.
      • Williamson K.
      • Schindler U.
      ); activation of the lipopolysaccharide-binding protein required Stat3, C/EBP, and AP-1 sites (
      • Schumann R.R.
      • Kirschning C.J.
      • Unbehaun A.
      • Aberle H.
      • Knopf H.P.
      • Lamping N.
      • Ulevitch R.J.
      • Herrmann F.
      ). Examples of direct binding of Stats to other proteins involved in transcription are the interaction of the Stat3β splice variant with c-jun (
      • Schaefer T.S.
      • Sanders L.K.
      • Nathans D.
      ); the cooperative interactions of dimeric Stat molecules with themselves, mediated by the NH2-terminal domain of Stats (
      • Xu X.A.
      • Sun Y.L.
      • Hoey T.
      ); and the binding of the carboxyl-terminal domain of Stat2 to the p300/CBP transcriptional adaptor (
      • Bhattacharya S.
      • Eckner R.
      • Grossman S.
      • Oldread E.
      • Arany Z.
      • D'Andrea A.
      • Livingston D.M.
      ).
      GR molecules usually utilize palindromic sites for high affinity DNA binding. They are composed of hexameric half-sites with the consensus 5′-TGTTCT-3′ spaced by 3 nucleotides (). The GR-binding sites characterized in the lactogenic hormone response elements were non-classical sites. They represent half-palindromic sites (
      • Welte T.
      • Philipp S.
      • Cairns C.
      • Gustafsson J.-Å.
      • Doppler W.
      ,
      • Li S.
      • Rosen J.M.
      ). Half-sites binding monomeric GR molecules have been found to be unable to confer glucocorticoid-inducible transcription on a heterologous promoter by themselves (
      • Drouin J.
      • Sun Y.L.
      • Tremblay S.
      • Lavender P.
      • Schmidt T.J.
      • de Léan A.
      • Nemer M.
      ). However, in complex glucocorticoid response elements, half-palindromic sites have been mapped which are essential in mediating the effect of glucocorticoid hormones (
      • Drouin J.
      • Sun Y.L.
      • Tremblay S.
      • Lavender P.
      • Schmidt T.J.
      • de Léan A.
      • Nemer M.
      ,
      • Slater E.P.
      • Hesse H.
      • Müller J.M.
      • Beato M.
      ). Functional half-palindromic binding sites were also described for the estrogen receptor in the far upstream estrogen response element of the ovalbumin gene (
      • Kato S.
      • Tora L.
      • Yamauchi J.
      • Masushige S.
      • Bellard M.
      • Chambon P.
      ). Mutational analysis of the three proximal GR half-sites in the β-casein gene promoter (Fig. 5 A) revealed the functional importance of the half-palindromic sites in GRa, GRb, GRc, and GRe. In the lactogenic hormone response element the utilization of half-sites by the GR appears to be one important means for ensuring the stage-specific activation of milk protein expression: here, glucocorticoids are unable to induce transcription via the GR half-sites alone, but require the synergy with Stat5 activated by prolactin. Although the unusual spacing and orientation of GR half-sites in lactogenic hormone response elements would not allow a favorable steric alignment of GRs like the one observed with classical GREs, direct interactions between receptors bound to several sites might be important. In addition, or alternatively, interactions of the GR with other factors binding to neighboring sites could stabilize the binding of the GR to half-palindromes. For the β-casein gene a cooperative binding between C/EBP and GR could be important, since several binding sites for C/EBP were mapped vicinal to GR half-palindromic sites (
      • Doppler W.
      • Welte T.
      • Philipp S.
      ). In the case of the whey acidic protein gene promoter, CTF/NF-1 could be involved (
      • Li S.
      • Rosen J.M.
      ,
      • Li S.
      • Rosen J.M.
      ).
      Two cellular systems were employed in the present study. COS-7 cells allowed to assess directly the role of Stat5 in transient cotransfection experiments. However, a drawback of this system is that the cells are not of mammary epithelial origin and the expression levels of Stat5 and GR are very high, giving rise to the question whether the results obtained are relevant for the in vivoregulation of milk protein genes by lactogenic hormones. We thus also used HC11 mammary epithelial cells which can be induced by glucocorticoids and prolactin to express the endogenous β-casein gene. It was possible to demonstrate a functional role of GR half-sites in mediating the response of lactogenic hormones in this cell line (Fig. 5 B), suggesting that the mechanism of interaction between GR and Stat5 is the same in HC11 and COS-7 cells and thus of general relevance for the regulation of milk protein gene expression.
      In HC11 cells the action of lactogenic hormones on milk protein expression is slow (
      • Ball R.K.
      • Friis R.R.
      • Schoenenberger C.A.
      • Doppler W.
      • Groner B.
      ). An indirect effect of glucocorticoids on transcription, mediated by the activation or repression of a gene regulated by the GR has been described to account for the slow response (
      • Doppler W.
      • Höck W.
      • Hofer P.
      • Groner B.
      • Ball R.K.
      ). Our data presented here implicate that, in addition, the GR exerts a direct effect on the lactogenic hormone response element. Regulation of gene expression by direct and indirect mechanisms has also been reported to account for the action of glucocorticoids on the α2-uteroglobulin (
      • Chan G.C.-K.
      • Hess P.
      • Meenakshi T.
      • Carlstedt-Duke J.
      • Gustafsson J.-Å.
      • Payvar F.
      ) and the α-amylase 2 (
      • Slater E.P.
      • Hesse H.
      • Müller J.M.
      • Beato M.
      ) genes, which both contain functional GR half-sites similar as the lactogenic hormone response elements.
      Stat5a and Stat5b, which differ significantly in their carboxyl terminus, were equally potent in their cooperativity with the GR (Fig.6). Interestingly, Stat5 devoid of the carboxyl terminus was as efficient in mediating the synergism with the GR as full-length Stat5. The deleted region contains the major transactivation domain of Stat5 important for the response to prolactin alone (
      • Moriggl R.
      • Gouilleux-Gruart V.
      • Jähne R.
      • Berchtold S.
      • Gartmann C.
      • Liu X.
      • Henninghausen L.
      • Sotiropoulos A.
      • Groner B.
      • Gouilleux F.
      ). Thus, the finding implies that either the transcriptional activation in the synergistic response is predominantly mediated by the GR, or that a cryptic transactivation domain of Stat5 is unmasked by the interaction with the GR. Stat5 molecules lacking the carboxyl-terminal transactivation domain have been described as dominant negative (
      • Moriggl R.
      • Gouilleux-Gruart V.
      • Jähne R.
      • Berchtold S.
      • Gartmann C.
      • Liu X.
      • Henninghausen L.
      • Sotiropoulos A.
      • Groner B.
      • Gouilleux F.
      ). They efficiently inhibited the activation of prolactin-dependent genes, presumably because they retained the ability to bind DNA and thereby were able to compete with transcriptionally active, full-length Stat5 molecules. Since, as shown in Fig. 6, carboxyl-terminally deleted Stat5s are not impaired in their ability to synergize with the GR to activate transcription, these molecules should allow the specific repression of genes regulated by prolactin only, without affecting genes synergistically regulated by both dexamethasone and prolactin. Further mutation and deletion experiments will reveal the domains of Stat5 required for a functional interaction with GR. It will be interesting to see whether other steroid receptors can also interact with Stat5 and whether other members of the Stat family are able to cooperate with the glucocorticoid receptor.

      Acknowledgments

      We thank S. Philipp, N. Greier, and C. Soratroi for excellent technical assistance, Dr. R. K. Ball for the mouse prolactin receptor expression vector, Dr. T. Schlake for the luciferase expression vector, Dr. S. Rusconi for providing the rat glucocorticoid receptor expression vector, and Dr. H. Klocker and Dr. A. Helmberg for critical reading of the manuscript.

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