Nucleic Acids Research, 1990, Vol. 18, No. 15 4523-4533
© 1990
MOLECULAR BIOLOGY |
Regulatory anatomy of the murine interleukin-2 gene
Division of Biology, 156-29, California Institute of Technology Pasadena, CA 91125, USA
Received April 4, 1990. Revised June 11, 1990. Accepted June 11, 1990.
We have cloned the mouse IL2 gene and sequenced 2800 bp of 5' flanking DNA. Comparison to the previously reported human sequence revealed extensive identity (–86%) between the two genes from +1 to – 580 with additional small islands of homology further upstream. Proximal sites which have been shown to be important in regulation of the human IL2 gene are well conserved in sequence and location. Transfection experiments using hybrid gene constructs containing varying lengths of the mouse 5' flanking DNA linked to a CAT reporter gene have demonstrated the presence of several novel positive and negative regulatory elements. One negative regulatory region lying between –750 and –1000 consists primarily of alternating purines and pyrimidines and is absent from the human gene. The conserved region from – 321 and -578, an upstream segment from –1219 to –1332, and another region of –450 bp from –1449 to –1890, which contained a well-conserved sequence of 60 bp, were each associated with enhanced levels of expression. We found no evidence for intragenic or downstream enhancer elements in this gene. All the elements identified affect only the magnitude of the inducible response, for no region when deleted had the effect of altering either the need for induction, the kinetics of stimulation, or the cell-type specificity of expression. Deletion studies suggest a strong requirement for NFAT binding even in the presence of extensive 5' flanking sequence. Therefore we conclude that IL2 gene expression is controlled primarily through a central TH1-specific signaling pathway, which acts through proximal elements, while distal cis-elements exert a secondary modulating effect.
*Present address: Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, PO Box 3333, New Haven, CT 06510, USA
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Touma, V. Antonini, M. Kumar, S. L. Osborn, A. M. Bobenchik, D. B. Keskin, J. E. Connolly, M. J. Grusby, E. L. Reinherz, and L. K. Clayton Functional Role for I{kappa}BNS in T Cell Cytokine Regulation As Revealed by Targeted Gene Disruption J. Immunol., August 1, 2007; 179(3): 1681 - 1692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Hwang, J.-H. Hong, and L. H. Glimcher IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508 J. Exp. Med., November 7, 2005; 202(9): 1289 - 1300. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Kittel, B. Ferko, M. Kurz, R. Voglauer, S. Sereinig, J. Romanova, G. Stiegler, H. Katinger, and A. Egorov Generation of an Influenza A Virus Vector Expressing Biologically Active Human Interleukin-2 from the NS Gene Segment J. Virol., August 15, 2005; 79(16): 10672 - 10677. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. P. Hermann and L. L. Heckert Silencing of Fshr Occurs through a Conserved, Hypersensitive Site in the First Intron Mol. Endocrinol., August 1, 2005; 19(8): 2112 - 2131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Adachi and E. V. Rothenberg Cell-type-specific epigenetic marking of the IL2 gene at a distal cis-regulatory region in competent, nontranscribing T-cells Nucleic Acids Res., June 3, 2005; 33(10): 3200 - 3210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Chen, J. Wang, D. Woltring, S. Gerondakis, and M. F. Shannon Histone Dynamics on the Interleukin-2 Gene in Response to T-Cell Activation Mol. Cell. Biol., April 15, 2005; 25(8): 3209 - 3219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-H. Liu and M.-Z. Lai Deltex Regulates T-Cell Activation by Targeted Degradation of Active MEKK1 Mol. Cell. Biol., February 15, 2005; 25(4): 1367 - 1378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Simmons, M. Koneru, M. Mohindru, R. Thomas, S. Cutro, P. Singh, R. H. DeKruyff, G. Inghirami, A. J. Coyle, B. S. Kim, et al. Tim-3+ T-bet+ Tumor-Specific Th1 Cells Colocalize with and Inhibit Development and Growth of Murine Neoplasms J. Immunol., February 1, 2005; 174(3): 1405 - 1415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Y. Kang, S.-C. Miaw, and I-C. Ho ROG Negatively Regulates T-Cell Activation but Is Dispensable for Th-Cell Differentiation Mol. Cell. Biol., January 15, 2005; 25(2): 554 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hawwari, J. Burrows, M. A. Vadas, and P. N. Cockerill The Human IL-3 Locus Is Regulated Cooperatively by Two NFAT-Dependent Enhancers That Have Distinct Tissue-Specific Activities J. Immunol., August 15, 2002; 169(4): 1876 - 1886. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-R. Jan, G. K. Rao, and N. E. Kaminski Cannabinol Enhancement of Interleukin-2 (IL-2) Expression by T Cells Is Associated with an Increase in IL-2 Distal Nuclear Factor of Activated T Cell Activity Mol. Pharmacol., February 1, 2002; 61(2): 446 - 454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-M. Oh, D. H. Hahm, I.-H. Kim, and S.-Y. Choi Human Neutrophil Lactoferrin trans-Activates the Matrix Metalloproteinase 1 Gene through Stress-activated MAPK Signaling Modules J. Biol. Chem., November 2, 2001; 276(45): 42575 - 42579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Mestas and C. C. W. Hughes Endothelial Cell Costimulation of T Cell Activation Through CD58-CD2 Interactions Involves Lipid Raft Aggregation J. Immunol., October 15, 2001; 167(8): 4378 - 4385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E. Solomou, Y.-T. Juang, and G. C. Tsokos Protein Kinase C-{{theta}} Participates in the Activation of Cyclic AMP-Responsive Element-Binding Protein and Its Subsequent Binding to the -180 Site of the IL-2 Promoter in Normal Human T Lymphocytes J. Immunol., May 1, 2001; 166(9): 5665 - 5674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Yui, G. Hernandez-Hoyos, and E. V. Rothenberg A New Regulatory Region of the IL-2 Locus That Confers Position-Independent Transgene Expression J. Immunol., February 1, 2001; 166(3): 1730 - 1739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-S. Jeon and C. Esser The Murine IL-2 Promoter Contains Distal Regulatory Elements Responsive to the Ah Receptor, a Member of the Evolutionarily Conserved bHLH-PAS Transcription Factor Family J. Immunol., December 15, 2000; 165(12): 6975 - 6983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Himes, R. Reeves, J. Attema, M. Nissen, Y. Li, and M. F. Shannon The Role of High-Mobility Group I(Y) Proteins in Expression of IL-2 and T Cell Proliferation J. Immunol., March 15, 2000; 164(6): 3157 - 3168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Yea, K.-H. Yang, and N. E. Kaminski Role of Nuclear Factor of Activated T-Cells and Activator Protein-1 in the Inhibition of Interleukin-2 Gene Transcription by Cannabinol in EL4 T-Cells J. Pharmacol. Exp. Ther., February 1, 2000; 292(2): 597 - 605. [Abstract] [Full Text]
|
|
|
|
|
|
J. D. Powell, C. G. Lerner, G. R. Ewoldt, and R. H. Schwartz The -180 Site of the IL-2 Promoter Is the Target of CREB/CREM Binding in T Cell Anergy J. Immunol., December 15, 1999; 163(12): 6631 - 6639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Ragheb, M. Deen, and R. H. Schwartz CD28-Mediated Regulation of mRNA Stability Requires Sequences Within the Coding Region of the IL-2 mRNA J. Immunol., July 1, 1999; 163(1): 120 - 129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Gonsky, R. L. Deem, D. H. Lee, A. Chen, and S. R. Targan CD28 Costimulation Augments IL-2 Secretion of Activated Lamina Propria T Cells by Increasing mRNA Stability Without Enhancing IL-2 Gene Transactivation J. Immunol., June 1, 1999; 162(11): 6621 - 6629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Brunner, C. A. Chambers, F. K.-M. Chan, J. Hanke, A. Winoto, and J. P. Allison CTLA-4-Mediated Inhibition of Early Events of T Cell Proliferation J. Immunol., May 15, 1999; 162(10): 5813 - 5820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Han, S. S. Yea, Y. J. Jeon, K.-H. Yang, and N. E. Kaminski Transforming Growth Factor-Beta 1 (TGF-beta 1) Promotes IL-2 mRNA Expression Through the Up-regulation of NF-kappa B, AP-1 and NF-AT in EL4 Cells J. Pharmacol. Exp. Ther., December 1, 1998; 287(3): 1105 - 1112. [Abstract] [Full Text]
|
|
|
|
|
|
A. P. Kennedy, A. Sekulic, B. J. Irvin, A. E. Nilson, S. M. Dilworth, and R. T. Abraham Polyomavirus Middle T Antigen as a Probe for T Cell Antigen Receptor-coupled Signaling Pathways J. Biol. Chem., May 8, 1998; 273(19): 11505 - 11513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Mathisen, M. Yu, J. M. Johnson, J. A. Drazba, and V. K. Tuohy Treatment of Experimental Autoimmune Encephalomyelitis with Genetically Modified Memory T Cells J. Exp. Med., July 7, 1997; 186(1): 159 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. W. Hughes and J. S. Pober Transcriptional Regulation of the Interleukin-2 Gene in Normal Human Peripheral Blood T Cells J. Biol. Chem., March 8, 1996; 271(10): 5369 - 5377. [Abstract] [Full Text] [PDF]
|
|