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. 1995 Jun;15(6):3179–3186. doi: 10.1128/mcb.15.6.3179

A Myc-associated zinc finger protein binding site is one of four important functional regions in the CD4 promoter.

D D Duncan 1, A Stupakoff 1, S M Hedrick 1, K B Marcu 1, G Siu 1
PMCID: PMC230550  PMID: 7760814

Abstract

The CD4 promoter plays an important role in the developmental control of CD4 transcription. In this report, we show that the minimal CD4 promoter has four factor binding sites, each of which is required for full function. Using biochemical and mutagenesis analyses, we determined that multiple nuclear factors bind to these independent sites. We determined that an initiator-like sequence present at the cap site and an Ets consensus sequence are required for full promoter function. We also demonstrate that the Myc-associated zinc finger protein (MAZ) appears to be the predominant factor binding to one of these sites. This last site closely resembles the ME1a1 G3AG4AG3 motif previously shown to be a critical element in the P2 promoter of the c-myc gene. We therefore believe that the MAZ transcription factor is also likely to play an important role in the control of developmental expression of the CD4 gene.

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Selected References

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  1. Ashfield R., Patel A. J., Bossone S. A., Brown H., Campbell R. D., Marcu K. B., Proudfoot N. J. MAZ-dependent termination between closely spaced human complement genes. EMBO J. 1994 Dec 1;13(23):5656–5667. doi: 10.1002/j.1460-2075.1994.tb06904.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Asselin C., Nepveu A., Marcu K. B. Molecular requirements for transcriptional initiation of the murine c-myc gene. Oncogene. 1989 May;4(5):549–558. [PubMed] [Google Scholar]
  3. Badiani P., Corbella P., Kioussis D., Marvel J., Weston K. Dominant interfering alleles define a role for c-Myb in T-cell development. Genes Dev. 1994 Apr 1;8(7):770–782. doi: 10.1101/gad.8.7.770. [DOI] [PubMed] [Google Scholar]
  4. Blum M. D., Wong G. T., Higgins K. M., Sunshine M. J., Lacy E. Reconstitution of the subclass-specific expression of CD4 in thymocytes and peripheral T cells of transgenic mice: identification of a human CD4 enhancer. J Exp Med. 1993 May 1;177(5):1343–1358. doi: 10.1084/jem.177.5.1343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bossone S. A., Asselin C., Patel A. J., Marcu K. B. MAZ, a zinc finger protein, binds to c-MYC and C2 gene sequences regulating transcriptional initiation and termination. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7452–7456. doi: 10.1073/pnas.89.16.7452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chan S. H., Cosgrove D., Waltzinger C., Benoist C., Mathis D. Another view of the selective model of thymocyte selection. Cell. 1993 Apr 23;73(2):225–236. doi: 10.1016/0092-8674(93)90225-f. [DOI] [PubMed] [Google Scholar]
  7. Davis C. B., Killeen N., Crooks M. E., Raulet D., Littman D. R. Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes. Cell. 1993 Apr 23;73(2):237–247. doi: 10.1016/0092-8674(93)90226-g. [DOI] [PubMed] [Google Scholar]
  8. Dufort D., Nepveu A. The human cut homeodomain protein represses transcription from the c-myc promoter. Mol Cell Biol. 1994 Jun;14(6):4251–4257. doi: 10.1128/mcb.14.6.4251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fowlkes B. J., Pardoll D. M. Molecular and cellular events of T cell development. Adv Immunol. 1989;44:207–264. doi: 10.1016/s0065-2776(08)60643-4. [DOI] [PubMed] [Google Scholar]
  10. Germain R. N. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell. 1994 Jan 28;76(2):287–299. doi: 10.1016/0092-8674(94)90336-0. [DOI] [PubMed] [Google Scholar]
  11. Ghosh D. TFD: the transcription factors database. Nucleic Acids Res. 1992 May 11;20 (Suppl):2091–2093. doi: 10.1093/nar/20.suppl.2091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gillespie F. P., Doros L., Vitale J., Blackwell C., Gosselin J., Snyder B. W., Wadsworth S. C. Tissue-specific expression of human CD4 in transgenic mice. Mol Cell Biol. 1993 May;13(5):2952–2958. doi: 10.1128/mcb.13.5.2952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hanna Z., Simard C., Laperrière A., Jolicoeur P. Specific expression of the human CD4 gene in mature CD4+ CD8- and immature CD4+ CD8+ T cells and in macrophages of transgenic mice. Mol Cell Biol. 1994 Feb;14(2):1084–1094. doi: 10.1128/mcb.14.2.1084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Javahery R., Khachi A., Lo K., Zenzie-Gregory B., Smale S. T. DNA sequence requirements for transcriptional initiator activity in mammalian cells. Mol Cell Biol. 1994 Jan;14(1):116–127. doi: 10.1128/mcb.14.1.116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jones N. C., Rigby P. W., Ziff E. B. Trans-acting protein factors and the regulation of eukaryotic transcription: lessons from studies on DNA tumor viruses. Genes Dev. 1988 Mar;2(3):267–281. doi: 10.1101/gad.2.3.267. [DOI] [PubMed] [Google Scholar]
  16. Kennedy G. C., Rutter W. J. Pur-1, a zinc-finger protein that binds to purine-rich sequences, transactivates an insulin promoter in heterologous cells. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11498–11502. doi: 10.1073/pnas.89.23.11498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Killeen N., Sawada S., Littman D. R. Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4. EMBO J. 1993 Apr;12(4):1547–1553. doi: 10.1002/j.1460-2075.1993.tb05798.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kunkel T. A., Roberts J. D., Zakour R. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Methods Enzymol. 1987;154:367–382. doi: 10.1016/0076-6879(87)54085-x. [DOI] [PubMed] [Google Scholar]
  19. Littman D. R. The structure of the CD4 and CD8 genes. Annu Rev Immunol. 1987;5:561–584. doi: 10.1146/annurev.iy.05.040187.003021. [DOI] [PubMed] [Google Scholar]
  20. Miller H., Asselin C., Dufort D., Yang J. Q., Gupta K., Marcu K. B., Nepveu A. A cis-acting element in the promoter region of the murine c-myc gene is necessary for transcriptional block. Mol Cell Biol. 1989 Dec;9(12):5340–5349. doi: 10.1128/mcb.9.12.5340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Natesan S., Gilman M. Z. DNA bending and orientation-dependent function of YY1 in the c-fos promoter. Genes Dev. 1993 Dec;7(12B):2497–2509. doi: 10.1101/gad.7.12b.2497. [DOI] [PubMed] [Google Scholar]
  22. Nossal G. J. Negative selection of lymphocytes. Cell. 1994 Jan 28;76(2):229–239. doi: 10.1016/0092-8674(94)90331-x. [DOI] [PubMed] [Google Scholar]
  23. Paillard F., Sterkers G., Vaquero C. Transcriptional and post-transcriptional regulation of TcR, CD4 and CD8 gene expression during activation of normal human T lymphocytes. EMBO J. 1990 Jun;9(6):1867–1872. doi: 10.1002/j.1460-2075.1990.tb08312.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Parnes J. R. Molecular biology and function of CD4 and CD8. Adv Immunol. 1989;44:265–311. doi: 10.1016/s0065-2776(08)60644-6. [DOI] [PubMed] [Google Scholar]
  25. Pugh B. F., Tjian R. Transcription from a TATA-less promoter requires a multisubunit TFIID complex. Genes Dev. 1991 Nov;5(11):1935–1945. doi: 10.1101/gad.5.11.1935. [DOI] [PubMed] [Google Scholar]
  26. Pyrc J. J., Moberg K. H., Hall D. J. Isolation of a novel cDNA encoding a zinc-finger protein that binds to two sites within the c-myc promoter. Biochemistry. 1992 Apr 28;31(16):4102–4110. doi: 10.1021/bi00131a029. [DOI] [PubMed] [Google Scholar]
  27. Robey E. A., Fowlkes B. J., Gordon J. W., Kioussis D., von Boehmer H., Ramsdell F., Axel R. Thymic selection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage. Cell. 1991 Jan 11;64(1):99–107. doi: 10.1016/0092-8674(91)90212-h. [DOI] [PubMed] [Google Scholar]
  28. Salmon P., Giovane A., Wasylyk B., Klatzmann D. Characterization of the human CD4 gene promoter: transcription from the CD4 gene core promoter is tissue-specific and is activated by Ets proteins. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7739–7743. doi: 10.1073/pnas.90.16.7739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sawada S., Littman D. R. A heterodimer of HEB and an E12-related protein interacts with the CD4 enhancer and regulates its activity in T-cell lines. Mol Cell Biol. 1993 Sep;13(9):5620–5628. doi: 10.1128/mcb.13.9.5620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sawada S., Littman D. R. Identification and characterization of a T-cell-specific enhancer adjacent to the murine CD4 gene. Mol Cell Biol. 1991 Nov;11(11):5506–5515. doi: 10.1128/mcb.11.11.5506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sawada S., Scarborough J. D., Killeen N., Littman D. R. A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development. Cell. 1994 Jun 17;77(6):917–929. doi: 10.1016/0092-8674(94)90140-6. [DOI] [PubMed] [Google Scholar]
  32. Siu G., Wurster A. L., Duncan D. D., Soliman T. M., Hedrick S. M. A transcriptional silencer controls the developmental expression of the CD4 gene. EMBO J. 1994 Aug 1;13(15):3570–3579. doi: 10.1002/j.1460-2075.1994.tb06664.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Siu G., Wurster A. L., Lipsick J. S., Hedrick S. M. Expression of the CD4 gene requires a Myb transcription factor. Mol Cell Biol. 1992 Apr;12(4):1592–1604. doi: 10.1128/mcb.12.4.1592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Swain S. L. T cell subsets and the recognition of MHC class. Immunol Rev. 1983;74:129–142. doi: 10.1111/j.1600-065x.1983.tb01087.x. [DOI] [PubMed] [Google Scholar]
  35. Takahama Y., Singer A. Post-transcriptional regulation of early T cell development by T cell receptor signals. Science. 1992 Nov 27;258(5087):1456–1462. doi: 10.1126/science.1439838. [DOI] [PubMed] [Google Scholar]
  36. Thanos D., Maniatis T. The high mobility group protein HMG I(Y) is required for NF-kappa B-dependent virus induction of the human IFN-beta gene. Cell. 1992 Nov 27;71(5):777–789. doi: 10.1016/0092-8674(92)90554-p. [DOI] [PubMed] [Google Scholar]
  37. Travis A., Amsterdam A., Belanger C., Grosschedl R. LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected]. Genes Dev. 1991 May;5(5):880–894. doi: 10.1101/gad.5.5.880. [DOI] [PubMed] [Google Scholar]
  38. Waterman M. L., Fischer W. H., Jones K. A. A thymus-specific member of the HMG protein family regulates the human T cell receptor C alpha enhancer. Genes Dev. 1991 Apr;5(4):656–669. doi: 10.1101/gad.5.4.656. [DOI] [PubMed] [Google Scholar]
  39. Waterman M. L., Jones K. A. Purification of TCF-1 alpha, a T-cell-specific transcription factor that activates the T-cell receptor C alpha gene enhancer in a context-dependent manner. New Biol. 1990 Jul;2(7):621–636. [PubMed] [Google Scholar]
  40. Wright S., Bishop J. M. DNA sequences that mediate attenuation of transcription from the mouse protooncogene myc. Proc Natl Acad Sci U S A. 1989 Jan;86(2):505–509. doi: 10.1073/pnas.86.2.505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wu L., Scollay R., Egerton M., Pearse M., Spangrude G. J., Shortman K. CD4 expressed on earliest T-lineage precursor cells in the adult murine thymus. Nature. 1991 Jan 3;349(6304):71–74. doi: 10.1038/349071a0. [DOI] [PubMed] [Google Scholar]
  42. Wurster A. L., Siu G., Leiden J. M., Hedrick S. M. Elf-1 binds to a critical element in a second CD4 enhancer. Mol Cell Biol. 1994 Oct;14(10):6452–6463. doi: 10.1128/mcb.14.10.6452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. de Wet J. R., Wood K. V., DeLuca M., Helinski D. R., Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. doi: 10.1128/mcb.7.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. von Boehmer H., Kisielow P. Lymphocyte lineage commitment: instruction versus selection. Cell. 1993 Apr 23;73(2):207–208. doi: 10.1016/0092-8674(93)90220-k. [DOI] [PubMed] [Google Scholar]
  45. von Boehmer H. Positive selection of lymphocytes. Cell. 1994 Jan 28;76(2):219–228. doi: 10.1016/0092-8674(94)90330-1. [DOI] [PubMed] [Google Scholar]
  46. von Boehmer H. The developmental biology of T lymphocytes. Annu Rev Immunol. 1988;6:309–326. doi: 10.1146/annurev.iy.06.040188.001521. [DOI] [PubMed] [Google Scholar]

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