Logo of embojLink to Publisher's site
EMBO J. 1999 Jun 15; 18(12): 3419–3430.
PMCID: PMC1171421

Aiolos transcription factor controls cell death in T cells by regulating Bcl-2 expression and its cellular localization.


We searched for proteins that interact with Ras in interleukin (IL)-2-stimulated or IL-2-deprived cells, and found that the transcription factor Aiolos interacts with Ras. The Ras-Aiolos interaction was confirmed in vitro and in vivo by co-immunoprecipitation. Indirect immunofluorescence shows that IL-2 controls the cellular distribution of Aiolos and induces its tyrosine phosphorylation, required for dissociation from Ras. We also identified functional Aiolos-binding sites in the Bcl-2 promoter, which are able to activate the luciferase reporter gene. Mutation of Aiolos-binding sites within the Bcl-2 promoter inhibits transactivation of the reporter gene luciferase, suggesting direct control of Bcl-2 expression by Aiolos. Co-transfection experiments confirm that Aiolos induces Bcl-2 expression and prevents apoptosis in IL-2-deprived cells. We propose a model for the regulation of Bcl-2 expression via Aiolos.

Full Text

The Full Text of this article is available as a PDF (460K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Benhamou LE, Cazenave PA, Sarthou P. Anti-immunoglobulins induce death by apoptosis in WEHI-231 B lymphoma cells. Eur J Immunol. 1990 Jun;20(6):1405–1407. [PubMed]
  • Boguski MS, McCormick F. Proteins regulating Ras and its relatives. Nature. 1993 Dec 16;366(6456):643–654. [PubMed]
  • Broome HE, Dargan CM, Bessent EF, Krajewski S, Reed JC. Apoptosis and Bcl-2 expression in cultured murine splenic T cells. Immunology. 1995 Mar;84(3):375–382. [PMC free article] [PubMed]
  • Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998;16:395–419. [PubMed]
  • Chen CY, Faller DV. Phosphorylation of Bcl-2 protein and association with p21Ras in Ras-induced apoptosis. J Biol Chem. 1996 Feb 2;271(5):2376–2379. [PubMed]
  • Chen HM, Boxer LM. Pi 1 binding sites are negative regulators of bcl-2 expression in pre-B cells. Mol Cell Biol. 1995 Jul;15(7):3840–3847. [PMC free article] [PubMed]
  • di Jeso B, Ulianich L, Racioppi L, D'Armiento F, Feliciello A, Pacifico F, Consiglio E, Formisano S. Serum withdrawal induces apoptotic cell death in Ki-ras transformed but not in normal differentiated thyroid cells. Biochem Biophys Res Commun. 1995 Sep 25;214(3):819–824. [PubMed]
  • Dobrowolski S, Harter M, Stacey DW. Cellular ras activity is required for passage through multiple points of the G0/G1 phase in BALB/c 3T3 cells. Mol Cell Biol. 1994 Aug;14(8):5441–5449. [PMC free article] [PubMed]
  • Duke RC, Cohen JJ. IL-2 addiction: withdrawal of growth factor activates a suicide program in dependent T cells. Lymphokine Res. 1986 Fall;5(4):289–299. [PubMed]
  • Fairbairn LJ, Cowling GJ, Reipert BM, Dexter TM. Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors. Cell. 1993 Sep 10;74(5):823–832. [PubMed]
  • Fernandez-Sarabia MJ, Bischoff JR. Bcl-2 associates with the ras-related protein R-ras p23. Nature. 1993 Nov 18;366(6452):274–275. [PubMed]
  • Ferrari G, Greene LA. Proliferative inhibition by dominant-negative Ras rescues naive and neuronally differentiated PC12 cells from apoptotic death. EMBO J. 1994 Dec 15;13(24):5922–5928. [PMC free article] [PubMed]
  • Fields S, Song O. A novel genetic system to detect protein-protein interactions. Nature. 1989 Jul 20;340(6230):245–246. [PubMed]
  • Frampton J, Ramqvist T, Graf T. v-Myb of E26 leukemia virus up-regulates bcl-2 and suppresses apoptosis in myeloid cells. Genes Dev. 1996 Nov 1;10(21):2720–2731. [PubMed]
  • Gómez J, Martínez C, Fernández B, García A, Rebollo A. Ras activation leads to cell proliferation or apoptotic cell death upon interleukin-2 stimulation or lymphokine deprivation, respectively. Eur J Immunol. 1997 Jul;27(7):1610–1618. [PubMed]
  • Gómez J, Martínez-A C, González A, García A, Rebollo A. The Bcl-2 gene is differentially regulated by IL-2 and IL-4: role of the transcription factor NF-AT. Oncogene. 1998 Sep 10;17(10):1235–1243. [PubMed]
  • Gómez J, Martínez-A C, González A, Rebollo A. Dual role of Ras and Rho proteins: at the cutting edge of life and death. Immunol Cell Biol. 1998 Apr;76(2):125–134. [PubMed]
  • Gratiot-Deans J, Ding L, Turka LA, Nuñez G. bcl-2 proto-oncogene expression during human T cell development. Evidence for biphasic regulation. J Immunol. 1993 Jul 1;151(1):83–91. [PubMed]
  • Gulbins E, Bissonnette R, Mahboubi A, Martin S, Nishioka W, Brunner T, Baier G, Baier-Bitterlich G, Byrd C, Lang F, et al. FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity. 1995 Apr;2(4):341–351. [PubMed]
  • Hannon GJ, Demetrick D, Beach D. Isolation of the Rb-related p130 through its interaction with CDK2 and cyclins. Genes Dev. 1993 Dec;7(12A):2378–2391. [PubMed]
  • Heckman C, Mochon E, Arcinas M, Boxer LM. The WT1 protein is a negative regulator of the normal bcl-2 allele in t(14;18) lymphomas. J Biol Chem. 1997 Aug 1;272(31):19609–19614. [PubMed]
  • Hewitt SM, Hamada S, McDonnell TJ, Rauscher FJ, 3rd, Saunders GF. Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms' tumor suppressor gene WT1. Cancer Res. 1995 Nov 15;55(22):5386–5389. [PubMed]
  • Kinoshita T, Yokota T, Arai K, Miyajima A. Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells. Oncogene. 1995 Jun 1;10(11):2207–2212. [PubMed]
  • Lai CC, Boguski M, Broek D, Powers S. Influence of guanine nucleotides on complex formation between Ras and CDC25 proteins. Mol Cell Biol. 1993 Mar;13(3):1345–1352. [PMC free article] [PubMed]
  • Pownall ME, Isaacs HV, Slack JM. Two phases of Hox gene regulation during early Xenopus development. Curr Biol. 1998 May 21;8(11):673–676. [PubMed]
  • Minami Y, Taniguchi T. IL-2 signaling: recruitment and activation of multiple protein tyrosine kinases by the components of the IL-2 receptor. Curr Opin Cell Biol. 1995 Apr;7(2):156–162. [PubMed]
  • Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995 Jan 27;80(2):293–299. [PubMed]
  • Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 1994 Jun 15;54(12):3131–3135. [PubMed]
  • Miyazaki T, Liu ZJ, Kawahara A, Minami Y, Yamada K, Tsujimoto Y, Barsoumian EL, Permutter RM, Taniguchi T. Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. Cell. 1995 Apr 21;81(2):223–231. [PubMed]
  • Morgan B, Sun L, Avitahl N, Andrikopoulos K, Ikeda T, Gonzales E, Wu P, Neben S, Georgopoulos K. Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J. 1997 Apr 15;16(8):2004–2013. [PMC free article] [PubMed]
  • Nagata S. Apoptosis by death factor. Cell. 1997 Feb 7;88(3):355–365. [PubMed]
  • Nuñez G, London L, Hockenbery D, Alexander M, McKearn JP, Korsmeyer SJ. Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol. 1990 May 1;144(9):3602–3610. [PubMed]
  • Pan BT, Chen CT, Lin SM. Oncogenic Ras blocks cell cycle progression and inhibits p34cdc2 kinase in activated Xenopus egg extracts. J Biol Chem. 1994 Feb 25;269(8):5968–5975. [PubMed]
  • Park JR, Hockenbery DM. BCL-2, a novel regulator of apoptosis. J Cell Biochem. 1996 Jan;60(1):12–17. [PubMed]
  • Pitton C, Rebollo A, Van Snick J, Thèze J, Garcia A. High-affinity and intermediate-affinity forms of the human interleukin 2 receptor, expressed in an interleukin 9-dependent murine T cell line, deliver proliferative signals via differences in their transduction pathways. Cytokine. 1993 Jul;5(4):362–371. [PubMed]
  • Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994 Jan;124(1-2):1–6. [PMC free article] [PubMed]
  • Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJ. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. [PubMed]
  • Smith MD, Ensor EA, Coffin RS, Boxer LM, Latchman DS. Bcl-2 transcription from the proximal P2 promoter is activated in neuronal cells by the Brn-3a POU family transcription factor. J Biol Chem. 1998 Jul 3;273(27):16715–16722. [PubMed]
  • Taylor D, Badiani P, Weston K. A dominant interfering Myb mutant causes apoptosis in T cells. Genes Dev. 1996 Nov 1;10(21):2732–2744. [PubMed]
  • Taylor SJ, Shalloway D. Cell cycle-dependent activation of Ras. Curr Biol. 1996 Dec 1;6(12):1621–1627. [PubMed]
  • Veis DJ, Sentman CL, Bach EA, Korsmeyer SJ. Expression of the Bcl-2 protein in murine and human thymocytes and in peripheral T lymphocytes. J Immunol. 1993 Sep 1;151(5):2546–2554. [PubMed]
  • Vojtek AB, Hollenberg SM, Cooper JA. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell. 1993 Jul 16;74(1):205–214. [PubMed]
  • Wang HG, Millan JA, Cox AD, Der CJ, Rapp UR, Beck T, Zha H, Reed JC. R-Ras promotes apoptosis caused by growth factor deprivation via a Bcl-2 suppressible mechanism. J Cell Biol. 1995 May;129(4):1103–1114. [PMC free article] [PubMed]
  • Wang JH, Avitahl N, Cariappa A, Friedrich C, Ikeda T, Renold A, Andrikopoulos K, Liang L, Pillai S, Morgan BA, et al. Aiolos regulates B cell activation and maturation to effector state. Immunity. 1998 Oct;9(4):543–553. [PubMed]
  • White E. Life, death, and the pursuit of apoptosis. Genes Dev. 1996 Jan 1;10(1):1–15. [PubMed]
  • Williams GT, Smith CA, Spooncer E, Dexter TM, Taylor DR. Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis. Nature. 1990 Jan 4;343(6253):76–79. [PubMed]
  • Wilson BE, Mochon E, Boxer LM. Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis. Mol Cell Biol. 1996 Oct;16(10):5546–5556. [PMC free article] [PubMed]
  • Wilson DJ, Fortner KA, Lynch DH, Mattingly RR, Macara IG, Posada JA, Budd RC. JNK, but not MAPK, activation is associated with Fas-mediated apoptosis in human T cells. Eur J Immunol. 1996 May;26(5):989–994. [PubMed]
  • Winston JT, Coats SR, Wang YZ, Pledger WJ. Regulation of the cell cycle machinery by oncogenic ras. Oncogene. 1996 Jan 4;12(1):127–134. [PubMed]
  • Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980 Apr 10;284(5756):555–556. [PubMed]
  • Yang E, Korsmeyer SJ. Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood. 1996 Jul 15;88(2):386–401. [PubMed]
  • Young RL, Korsmeyer SJ. A negative regulatory element in the bcl-2 5'-untranslated region inhibits expression from an upstream promoter. Mol Cell Biol. 1993 Jun;13(6):3686–3697. [PMC free article] [PubMed]
  • Zubiaga AM, Munoz E, Huber BT. IL-4 and IL-2 selectively rescue Th cell subsets from glucocorticoid-induced apoptosis. J Immunol. 1992 Jul 1;149(1):107–112. [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

    Holmfeldt L, Wei L, Diaz-Flores E, Walsh M, Zhang J, Ding L, Payne-Turner D, Churchman M, Andersson A, Chen SC, McCastlain K, Becksfort J, Ma J, Wu G, Patel SN, Heatley SL, Phillips LA, Song G, Easton J, Parker M, Chen X, Rusch M, Boggs K, Vadodaria B, Hedlund E, Drenberg C, Baker S, Pei D, Cheng C, Huether R, Lu C, Fulton RS, Fulton LL, Tabib Y, Dooling DJ, Ochoa K, Minden M, Lewis ID, To LB, Marlton P, Roberts AW, Raca G, Stock W, Neale G, Drexler HG, Dickins RA, Ellison DW, Shurtleff SA, Pui CH, Ribeiro RC, Devidas M, Carroll AJ, Heerema NA, Wood B, Borowitz MJ, Gastier-Foster JM, Raimondi SC, Mardis ER, Wilson RK, Downing JR, Hunger SP, Loh ML, Mullighan CG. Nature genetics. 2013 Mar; 45(3)242-252
  • Regulation of host gene expression by HIV-1 TAR microRNAs[Retrovirology. ]
    Ouellet DL, Vigneault-Edwards J, Létourneau K, Gobeil LA, Plante I, Burnett JC, Rossi JJ, Provost P. Retrovirology. 1086
  • PKCδ is Required for Survival of Cells Expressing Activated p21Ras[The Journal of biological chemistry. 2007]
    Xia S, Forman LW, Faller DV. The Journal of biological chemistry. 2007 May 4; 282(18)13199-13210
  • Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis[Nature genetics. 2010]
    Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I, Podda M, Xu C, Xie G, Macciardi F, Selmi C, Lupoli S, Shigeta R, Ransom M, Lleo A, Lee AT, Mason AL, Myers RP, Peltekian KM, Ghent CN, Bernuzzi F, Zuin M, Rosina F, Borghesio E, Floreani A, Lazzari R, Niro G, Andriulli A, Muratori L, Muratori P, Almasio PL, Andreone P, Margotti M, Brunetto M, Coco B, Alvaro D, Bragazzi MC, Marra F, Pisano A, Rigamonti C, Colombo M, Marzioni M, Benedetti A, Fabris L, Strazzabosco M, Portincasa P, Palmieri VO, Tiribelli C, Croce L, Bruno S, Rossi S, Vinci M, Prisco C, Mattalia A, Toniutto P, Picciotto A, Galli A, Ferrari C, Colombo S, Casella G, Morini L, Caporaso N, Colli A, Spinzi G, Montanari R, Gregersen PK, Heathcote EJ, Hirschfield GM, Siminovitch KA, Amos CI, Gershwin ME, Seldin MF. Nature genetics. 2010 Aug; 42(8)658-660
  • Identification of fusion genes in breast cancer by paired-end RNA-sequencing[Genome Biology. 2011]
    Edgren H, Murumagi A, Kangaspeska S, Nicorici D, Hongisto V, Kleivi K, Rye IH, Nyberg S, Wolf M, Borresen-Dale AL, Kallioniemi O. Genome Biology. 2011; 12(1)R6
See all...


  • Compound
    PubChem Compound links
  • Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene links
  • MedGen
    Related information in MedGen
  • Nucleotide
    Published Nucleotide sequences
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • Protein
    Published protein sequences
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...