|[Frontiers in Bioscience 2, d49-60, February 15, 1997]|
ROLE OF NF-KappaB IN THE CONTROL OF APOPTOTIC AND PROLIFERATIVE RESPONSES IN IL-2-RESPONSIVE T CELLS|
Javier Gómez, David García-Domingo, Carlos Martínez-A.1 and Angelita Rebollo
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Campus de Cantoblanco, E-28049 Madrid, Spain
Received 1/21/97; Accepted 1/30/97; On-line 2/15/97
The IL-2 receptor is composed of at least three distinct subunits, p55, p70 and p64, or alpha, ß and gamma chains, respectively; this trimolecular complex binds IL-2 with a high affinity (54-56). Expression of the p55 subunit is inducible in T cells by activation through the T cell receptor (57). The cytoplasmic region of p55 subunit has 13 amino acids, including serine and threonine residues as potential phosphorylation targets. Deletion of this region does not affect the capacity of the high affinity IL-2 receptor to transmit IL-2-mediated proliferative signals.
Previous studies demonstrated that inducible IL-2Ralpha expression is at least partially regulated by a potent enhancer located between nucleotide positions -299 and -228 relative to the major transcription initiation site (58). This enhancer is termed the positive regulatory region I (PRRI) and contains NF-kappaB, serum response factor (SRF), SP1 and UE-1 motifs (58-62). These binding sites are important in IL-2Ralpha gene activation in response to several stimuli, including the transactivator protein, Tax, of the human T cell lymphotropic virus type I, PMA, TNFalpha, IL-2 and IL-1 (19, 60, 62-67).
Internal deletions within the IL-2Ralpha promoter suggested the presence of other positive regulatory elements located between nucleotides -137 and -64, termed positive regulatory region II (PRRII). This region contains sites for at least two DNA-binding proteins, Elf-1 (68), a member of the Ets family, and the nonhistone chromatin-associated proteins, HMG-I(Y) (69-71). Deletion of the binding sites for these proteins profoundly reduced IL-2Ralpha gene transcription, even in the presence of an intact upstream enhancer (PRRI). Elf-1 specifically binds to p50 and c-Rel in vitro, suggesting that these protein-protein interactions may mediate the transcriptional coordination between PRRI and PRRII (72) (Fig. 2).
Figure 2. Schematic diagram of the IL-2 receptor, a 5' regulatory region, including positive regulatory regions PRRI and II.
Elf-1 is the first Ets family protein known to interact with NF-kappaB family members (73). Mapping of the Elf-1 interaction domain with c-Rel revealed that the Ets domain is necessary and sufficient to mediate this interaction (74). Elf-1 interaction with p50 is enhanced by the presence of HMG-I(Y), which has also been shown to associate with p50 (52, 75). Elf-1 may be involved in the selective binding and stabilization of specific NF-kappaB family proteins to PRRI during T cell activation. Elf-1 can interact with p50, but not with its precursor p105, suggesting that the interaction is masked in p105.
c-Rel/ p50 heterodimers also bind to the PRRI enhancer of the IL-2Ralpha gene and the amount of heterodimer present correlates with the level of IL-2Ra gene expression. c-Rel or p65 can cooperate with SRF in IL-2Ralpha promoter activation (76). Synergy of c-Rel and SRF may reflect interaction of these proteins with basal transcription factors. Finally, c-Rel can also associate with TATA binding proteins of the transcription factor IID complex to mediate transcription activation of IL-2Ralpha gene expression (50, 77).
The IL-2Ralpha gene is not only expressed in mature activated T cells, but is also found early in T cell ontogeny, before expression of TCR genes (78). It has been proposed that this early expression could involve the NF-kappaB/SRF interaction (79). The recent observation that NF-kappaB proteins can be found in thymocytes (80, 81) suggests that NF-kappaB/SRF interactions may also be important in early T cell development.