The VP16 Paradox: Herpes Simplex Virus VP16 Contains a Long-range Activation Domain but Within the Natural Multiprotein Complex Activates Only from Promoter-proximal Positions

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 1997 Aug 1

PMID 9223485

Citations 14

Authors

M Hagmann

O Georgiev

W Schaffner

Affiliations

Soon will be listed here.

Abstract

Removal of core promoter elements like the TATA box converts several regulatory upstream regions of viral and cellular genes into classical enhancers, i.e., cis-regulatory elements capable of activating transcription over long distances in an orientation-independent manner. This is not the case with herpes simplex virus (HSV) immediate-early gene promoters, which are strongly induced by the viral transactivator VP16 (Vmw65, alphaTIF, ICP25) complexed with the cellular factors Oct-1 and HCF. Here we report that the VP16 complex can readily bring about strong activation from a promoter-proximal position but fails to induce transcription from a distal downstream enhancer position. This is in striking contrast to results obtained with GAL fusion proteins: in this context, the C-terminal "general" activation domain of VP16 activates transcription to high levels over long distances. Thus, this paradoxical behavior suggests that the VP16 activation domain is not accessible to the transcription machinery when the VP16-Oct-1-HCF complex is bound in a remote position. Only upon specific interactions in a promoter-proximal position, perhaps with the basal transcription factors, can transcription be strongly induced. In agreement with such a proposed mechanism, VP16 proteins to which a heterologous general activation domain has been added strongly activate transcription from a downstream position. The biological role of this unexpected and sophisticated mechanism is most probably a limitation of the VP16 activity to the associated immediate-early genes, without undesired long-range effects on other viral promoters within the tightly packed HSV genome.

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References

Seipel K, Georgiev O, Schaffner W . Different activation domains stimulate transcription from remote ('enhancer') and proximal ('promoter') positions. EMBO J. 1992; 11(13):4961-8. PMC: 556974. DOI: 10.1002/j.1460-2075.1992.tb05603.x. View

Emami K, Carey M . A synergistic increase in potency of a multimerized VP16 transcriptional activation domain. EMBO J. 1992; 11(13):5005-12. PMC: 556978. DOI: 10.1002/j.1460-2075.1992.tb05607.x. View

Cleary M, Stern S, Tanaka M, Herr W . Differential positive control by Oct-1 and Oct-2: activation of a transcriptionally silent motif through Oct-1 and VP16 corecruitment. Genes Dev. 1993; 7(1):72-83. DOI: 10.1101/gad.7.1.72. View

Hahn S . Structure(?) and function of acidic transcription activators. Cell. 1993; 72(4):481-3. DOI: 10.1016/0092-8674(93)90064-w. View

Roberts S, Ha I, Maldonado E, Reinberg D, Green M . Interaction between an acidic activator and transcription factor TFIIB is required for transcriptional activation. Nature. 1993; 363(6431):741-4. DOI: 10.1038/363741a0. View

Wilson A, LaMarco K, Peterson M, Herr W . The VP16 accessory protein HCF is a family of polypeptides processed from a large precursor protein. Cell. 1993; 74(1):115-25. DOI: 10.1016/0092-8674(93)90299-6. View

Myrset A, Bostad A, Jamin N, Lirsac P, Toma F, Gabrielsen O . DNA and redox state induced conformational changes in the DNA-binding domain of the Myb oncoprotein. EMBO J. 1993; 12(12):4625-33. PMC: 413899. DOI: 10.1002/j.1460-2075.1993.tb06151.x. View

Arnosti D, Preston C, Hagmann M, Schaffner W, Hope R, Laughlan G . Specific transcriptional activation in vitro by the herpes simplex virus protein VP16. Nucleic Acids Res. 1993; 21(24):5570-6. PMC: 310517. DOI: 10.1093/nar/21.24.5570. View

Gerber H, Seipel K, Georgiev O, Hofferer M, Hug M, Rusconi S . Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science. 1994; 263(5148):808-11. DOI: 10.1126/science.8303297. View

10.

Kunzler M, Braus G, Georgiev O, Seipel K, Schaffner W . Functional differences between mammalian transcription activation domains at the yeast GAL1 promoter. EMBO J. 1994; 13(3):641-5. PMC: 394854. DOI: 10.1002/j.1460-2075.1994.tb06302.x. View

11.

Zhu H, Joliot V, Prywes R . Role of transcription factor TFIIF in serum response factor-activated transcription. J Biol Chem. 1994; 269(5):3489-97. View

12.

Wu T, Monokian G, Mark D, Wobbe C . Transcriptional activation by herpes simplex virus type 1 VP16 in vitro and its inhibition by oligopeptides. Mol Cell Biol. 1994; 14(5):3484-93. PMC: 358712. DOI: 10.1128/mcb.14.5.3484-3493.1994. View

13.

Yankulov K, Blau J, Purton T, Roberts S, Bentley D . Transcriptional elongation by RNA polymerase II is stimulated by transactivators. Cell. 1994; 77(5):749-59. DOI: 10.1016/0092-8674(94)90058-2. View

14.

Beijersbergen R, Hijmans E, Zhu L, Bernards R . Interaction of c-Myc with the pRb-related protein p107 results in inhibition of c-Myc-mediated transactivation. EMBO J. 1994; 13(17):4080-6. PMC: 395329. DOI: 10.1002/j.1460-2075.1994.tb06725.x. View

15.

Xiao H, Pearson A, Coulombe B, Truant R, Zhang S, Regier J . Binding of basal transcription factor TFIIH to the acidic activation domains of VP16 and p53. Mol Cell Biol. 1994; 14(10):7013-24. PMC: 359231. DOI: 10.1128/mcb.14.10.7013-7024.1994. View

16.

Roberts S, Green M . Activator-induced conformational change in general transcription factor TFIIB. Nature. 1994; 371(6499):717-20. DOI: 10.1038/371717a0. View

17.

Gstaiger M, Schaffner W . Strong transcriptional activators isolated from viral DNA by the 'activator trap', a novel selection system in mammalian cells. Nucleic Acids Res. 1994; 22(20):4031-8. PMC: 331886. DOI: 10.1093/nar/22.20.4031. View

18.

Ward P, Roizman B . Herpes simplex genes: the blueprint of a successful human pathogen. Trends Genet. 1994; 10(8):267-74. DOI: 10.1016/0168-9525(90)90009-u. View

19.

Gstaiger M, Knoepfel L, Georgiev O, Schaffner W, Hovens C . A B-cell coactivator of octamer-binding transcription factors. Nature. 1995; 373(6512):360-2. DOI: 10.1038/373360a0. View

20.

Strubin M, NEWELL J, Matthias P . OBF-1, a novel B cell-specific coactivator that stimulates immunoglobulin promoter activity through association with octamer-binding proteins. Cell. 1995; 80(3):497-506. DOI: 10.1016/0092-8674(95)90500-6. View