The Journal of Immunology, Vol 154, Issue 1 68-79, Copyright © 1995 by American Association of Immunologists

ARTICLES

Regulation of cAMP-responsive enhancer binding proteins during cell cycle progression in T lymphocytes stimulated by IL-2

N Feuerstein, D Huang, SH Hinrichs, DJ Orten, N Aiyar and MB Prystowsky
Center for Gerontologic Research, Medical College of Pennsylvania, Philadelphia 19129.

IL-2 stimulates the proliferative response of various lymphoid cells. Previous studies showed an increase in intracellular levels of cAMP concomitant with an increase in phosphorylation of discrete proteins by protein kinase A at late G1 phase in mitogen-stimulated lymphocytes. Thus, experiments were undertaken to study nuclear proteins that bind to the cAMP-responsive enhancer (CRE) in cloned T lymphocytes stimulated with IL-2. With the use of a 32P-labeled CRE consensus sequence in a DNA binding gel mobility shift assay, we showed that IL-2 stimulation resulted in the induction of two major DNA-protein complexes at late G1/S during the cell cycle. This binding was competed in a dose-dependent manner by a nonlabeled CRE oligonucleotide but was not competed by a nonlabeled AP-1 oligonucleotide. Rapamycin, a potent immunosuppressant, which arrests IL-2-stimulated T lymphocytes at G1/S, inhibited the IL-2-induced CRE binding activities concomitantly with inhibition of DNA synthesis. By using specific Abs in a gel mobility shift assay, we identified two known CREB/ATF transcription factors in the IL-2-induced CRE complexes: the CRE binding factor (CREB), and ATF1. The induction of CREB binding by IL-2 was not associated with an increase in its abundance but was associated with a major increase in CREB phosphorylation that was particularly prominent at late G1/S. However, we found that G1/S progression induced by IL-2 was not associated with an increase in the intracellular levels of cAMP. These results suggest that 1) the transcription factors CREB and ATF1 and possibly other CRE binding proteins may have an important role in the modulation of specific gene expression at G1/S during cell cycle progression induced by IL-2. 2) The involvement of these CRE binding transcription factors in IL-2-stimulated cells is regulated via a mechanism that is not cAMP dependent.

This article has been cited by other articles:

				A. M. Reimold, J. Kim, R. Finberg, and L. H. Glimcher Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice Int. Immunol., February 1, 2001; 13(2): 241 - 248. [Abstract] [Full Text] [PDF]

				N. Feuerstein, F. Chen, M. Madaio, M. Maldonado, and R. A. Eisenberg Induction of Autoimmunity in a Transgenic Model of B Cell Receptor Peripheral Tolerance: Changes in Coreceptors and B Cell Receptor-Induced Tyrosine-Phosphoproteins J. Immunol., November 15, 1999; 163(10): 5287 - 5297. [Abstract] [Full Text] [PDF]

				J. Zhang, I. Scordi, M. J. Smyth, and M. G. Lichtenheld Interleukin 2 Receptor Signaling Regulates the Perforin Gene through Signal Transducer and Activator of Transcription (Stat)5 Activation of Two Enhancers J. Exp. Med., November 1, 1999; 190(9): 1297 - 1308. [Abstract] [Full Text] [PDF]

				P. Hollsberg Mechanisms of T-Cell Activation by Human T-Cell Lymphotropic Virus Type I Microbiol. Mol. Biol. Rev., June 1, 1999; 63(2): 308 - 333. [Abstract] [Full Text] [PDF]

				N. Muthusamy and J. M. Leiden A Protein Kinase C-, Ras-, and RSK2-dependent Signal Transduction Pathway Activates the cAMP-responsive Element-binding Protein Transcription Factor following T Cell Receptor Engagement J. Biol. Chem., August 28, 1998; 273(35): 22841 - 22847. [Abstract] [Full Text] [PDF]

				S. M. Belkowski, C. S. Rubin, and M. B. Prystowsky Isolation and Analysis of a T Cell Clone Variant Exhibiting Constitutively Phosphorylated Ser133 cAMP Response Element-Binding Protein J. Immunol., July 15, 1998; 161(2): 659 - 665. [Abstract] [Full Text] [PDF]

				J. M. Bosilevac, C. A. Gilchrist, P. E. Jankowski, S. Paul, A. R. Rees, and S. H. Hinrichs Inhibition of Activating Transcription Factor 1- and cAMP-responsive Element-binding Protein-activated Transcription by an Intracellular Single Chain Fv Fragment J. Biol. Chem., July 3, 1998; 273(27): 16874 - 16879. [Abstract] [Full Text] [PDF]

				N. Ishiguro, G. D. Brown, A. Ishizu, and D. Meruelo The Regulation of Murine H-2Dd Expression by Activation Transcription Factor 1 and cAMP Response Element Binding Protein J. Immunol., June 15, 1998; 160(12): 5907 - 5914. [Abstract] [Full Text] [PDF]

				D. Gibellini, A. Bassini, S. Pierpaoli, L. Bertolaso, D. Milani, S. Capitani, M. La Placa, and G. Zauli Extracellular HIV-1 Tat Protein Induces the Rapid Ser133 Phosphorylation and Activation of CREB Transcription Factor in Both Jurkat Lymphoblastoid T Cells and Primary Peripheral Blood Mononuclear Cells J. Immunol., April 15, 1998; 160(8): 3891 - 3898. [Abstract] [Full Text] [PDF]

				R. Firestein and N. Feuerstein Association of Activating Transcription Factor 2 (ATF2) with the Ubiquitin-conjugating Enzyme hUBC9. IMPLICATION OF THE UBIQUITIN/PROTEASOME PATHWAY IN REGULATION OF ATF2 IN T CELLS J. Biol. Chem., March 6, 1998; 273(10): 5892 - 5902. [Abstract] [Full Text] [PDF]

				N. Ishiguro, G. D. Brown, and D. Meruelo Activation Transcription Factor 1 Involvement in the Regulation of Murine H-2Dd Expression J. Biol. Chem., June 20, 1997; 272(25): 15993 - 16001. [Abstract] [Full Text] [PDF]

				L. A. Penix, M. T. Sweetser, W. M. Weaver, J. P. Hoeffler, T. K. Kerppola, and C. B. Wilson The Proximal Regulatory Element of the Interferon-gamma Promoter Mediates Selective Expression in T Cells J. Biol. Chem., December 13, 1996; 271(50): 31964 - 31972. [Abstract] [Full Text] [PDF]