Positive and negative regulation of the composite octamer motif of the interleukin 2 enhancer by AP-1, OCT-2, and retinoic acid receptor

Ugo De Grazia, Maria Pia Felli, Alessandra Vacca, Antonietta R. Farina, Marella Maroder, Lucia Cappabianca, Daniela Meco, Monica Farina, Isabella Screpanti, Luigi Frati, Alberto Gulino

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The differentiating agent retinoic acid (RA) has been previously reported to interfere with 12-O-tetradecanoyl-phorbol-13-acetate (TPA)/Ca2+-induced signals for the regulation of the -96 to -66-bp octamer motif found in the enhancer for the interleukin (IL)-2 gene, which encodes a major T lymphocyte growth factor. The IL-2 octamer motif is a composite cis-element which binds Oct-1 and Oct-2 as well as a TPA/Ca2+-inducible nuclear factor, previously termed octamer-associated protein (OAP40). We show here that Oct-2, despite the presence of an active transcriptional activation domain, requires TPA/Ca2+-induced signals to strongly transactivate the IL-2 octamer motif in Jurkat T cells. This Oct-2-dependent transactivation is inhibited by RA. The presence of an intact COOH-terminal domain of Oct-2 contributes to both TPA/Ca2+-induced transactivation and the RA-mediated repression. We also show that both Fos and Jun components of the AP-1 factors participate in the OAP40 complex. Furthermore, transfected c-jun, jun-B, jun-D, c-fos, or Fos- B expression vectors partially substitute for TPA and Ca2+ and cooperate with Oct-2 for the transactivation of the combined OAP/octamer cis-element. Mutations of the genuine octamer-binding site abrogate both the binding of Oct-1 and Oct-2 and the TPA/Ca2+-induced transactivation of the OAP/octamer motif. OAP confers to Oct-2 responsivity to both TPA/Ca2+ and RA, since specific mutations of the AP-1/OAP-binding site significantly reduce the transactivation by Oct-2 in response to TPA and Ca2+ and abolish the inhibition by RA. Furthermore, retinoic acid receptor (RAR) α is able to inhibit in vitro the formation of the complex between the nuclear AP-1/OAP and its specific binding site, resulting in the interference with Oct-2- dependent cis-regulatory function of this AP-1 element. Therefore, we propose that the TPA/calcium-activated AP-1/OAP element is the main target of positive or negative regulatory signals influencing the IL-2 octamer motif, through synergism with Oct-2 and antagonism by RAR.

Original languageEnglish
Pages (from-to)1485-1497
Number of pages13
JournalJournal of Experimental Medicine
Volume180
Issue number4
Publication statusPublished - Oct 1 1994

Fingerprint

Retinoic Acid Receptors
Transcription Factor AP-1
Tetradecanoylphorbol Acetate
Interleukin-2
Transcriptional Activation
Tretinoin
Binding Sites
T-Lymphocytes
Dilatation and Curettage
Mutation
Jurkat Cells
Intercellular Signaling Peptides and Proteins
Calcium

ASJC Scopus subject areas

  • Immunology

Cite this

Positive and negative regulation of the composite octamer motif of the interleukin 2 enhancer by AP-1, OCT-2, and retinoic acid receptor. / De Grazia, Ugo; Felli, Maria Pia; Vacca, Alessandra; Farina, Antonietta R.; Maroder, Marella; Cappabianca, Lucia; Meco, Daniela; Farina, Monica; Screpanti, Isabella; Frati, Luigi; Gulino, Alberto.

In: Journal of Experimental Medicine, Vol. 180, No. 4, 01.10.1994, p. 1485-1497.

Research output: Contribution to journalArticle

De Grazia, U, Felli, MP, Vacca, A, Farina, AR, Maroder, M, Cappabianca, L, Meco, D, Farina, M, Screpanti, I, Frati, L & Gulino, A 1994, 'Positive and negative regulation of the composite octamer motif of the interleukin 2 enhancer by AP-1, OCT-2, and retinoic acid receptor', Journal of Experimental Medicine, vol. 180, no. 4, pp. 1485-1497.
De Grazia, Ugo ; Felli, Maria Pia ; Vacca, Alessandra ; Farina, Antonietta R. ; Maroder, Marella ; Cappabianca, Lucia ; Meco, Daniela ; Farina, Monica ; Screpanti, Isabella ; Frati, Luigi ; Gulino, Alberto. / Positive and negative regulation of the composite octamer motif of the interleukin 2 enhancer by AP-1, OCT-2, and retinoic acid receptor. In: Journal of Experimental Medicine. 1994 ; Vol. 180, No. 4. pp. 1485-1497.
@article{965882f158dd45849da1d05706421478,
title = "Positive and negative regulation of the composite octamer motif of the interleukin 2 enhancer by AP-1, OCT-2, and retinoic acid receptor",
abstract = "The differentiating agent retinoic acid (RA) has been previously reported to interfere with 12-O-tetradecanoyl-phorbol-13-acetate (TPA)/Ca2+-induced signals for the regulation of the -96 to -66-bp octamer motif found in the enhancer for the interleukin (IL)-2 gene, which encodes a major T lymphocyte growth factor. The IL-2 octamer motif is a composite cis-element which binds Oct-1 and Oct-2 as well as a TPA/Ca2+-inducible nuclear factor, previously termed octamer-associated protein (OAP40). We show here that Oct-2, despite the presence of an active transcriptional activation domain, requires TPA/Ca2+-induced signals to strongly transactivate the IL-2 octamer motif in Jurkat T cells. This Oct-2-dependent transactivation is inhibited by RA. The presence of an intact COOH-terminal domain of Oct-2 contributes to both TPA/Ca2+-induced transactivation and the RA-mediated repression. We also show that both Fos and Jun components of the AP-1 factors participate in the OAP40 complex. Furthermore, transfected c-jun, jun-B, jun-D, c-fos, or Fos- B expression vectors partially substitute for TPA and Ca2+ and cooperate with Oct-2 for the transactivation of the combined OAP/octamer cis-element. Mutations of the genuine octamer-binding site abrogate both the binding of Oct-1 and Oct-2 and the TPA/Ca2+-induced transactivation of the OAP/octamer motif. OAP confers to Oct-2 responsivity to both TPA/Ca2+ and RA, since specific mutations of the AP-1/OAP-binding site significantly reduce the transactivation by Oct-2 in response to TPA and Ca2+ and abolish the inhibition by RA. Furthermore, retinoic acid receptor (RAR) α is able to inhibit in vitro the formation of the complex between the nuclear AP-1/OAP and its specific binding site, resulting in the interference with Oct-2- dependent cis-regulatory function of this AP-1 element. Therefore, we propose that the TPA/calcium-activated AP-1/OAP element is the main target of positive or negative regulatory signals influencing the IL-2 octamer motif, through synergism with Oct-2 and antagonism by RAR.",
author = "{De Grazia}, Ugo and Felli, {Maria Pia} and Alessandra Vacca and Farina, {Antonietta R.} and Marella Maroder and Lucia Cappabianca and Daniela Meco and Monica Farina and Isabella Screpanti and Luigi Frati and Alberto Gulino",
year = "1994",
month = "10",
day = "1",
language = "English",
volume = "180",
pages = "1485--1497",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "4",

}

TY - JOUR

T1 - Positive and negative regulation of the composite octamer motif of the interleukin 2 enhancer by AP-1, OCT-2, and retinoic acid receptor

AU - De Grazia, Ugo

AU - Felli, Maria Pia

AU - Vacca, Alessandra

AU - Farina, Antonietta R.

AU - Maroder, Marella

AU - Cappabianca, Lucia

AU - Meco, Daniela

AU - Farina, Monica

AU - Screpanti, Isabella

AU - Frati, Luigi

AU - Gulino, Alberto

PY - 1994/10/1

Y1 - 1994/10/1

N2 - The differentiating agent retinoic acid (RA) has been previously reported to interfere with 12-O-tetradecanoyl-phorbol-13-acetate (TPA)/Ca2+-induced signals for the regulation of the -96 to -66-bp octamer motif found in the enhancer for the interleukin (IL)-2 gene, which encodes a major T lymphocyte growth factor. The IL-2 octamer motif is a composite cis-element which binds Oct-1 and Oct-2 as well as a TPA/Ca2+-inducible nuclear factor, previously termed octamer-associated protein (OAP40). We show here that Oct-2, despite the presence of an active transcriptional activation domain, requires TPA/Ca2+-induced signals to strongly transactivate the IL-2 octamer motif in Jurkat T cells. This Oct-2-dependent transactivation is inhibited by RA. The presence of an intact COOH-terminal domain of Oct-2 contributes to both TPA/Ca2+-induced transactivation and the RA-mediated repression. We also show that both Fos and Jun components of the AP-1 factors participate in the OAP40 complex. Furthermore, transfected c-jun, jun-B, jun-D, c-fos, or Fos- B expression vectors partially substitute for TPA and Ca2+ and cooperate with Oct-2 for the transactivation of the combined OAP/octamer cis-element. Mutations of the genuine octamer-binding site abrogate both the binding of Oct-1 and Oct-2 and the TPA/Ca2+-induced transactivation of the OAP/octamer motif. OAP confers to Oct-2 responsivity to both TPA/Ca2+ and RA, since specific mutations of the AP-1/OAP-binding site significantly reduce the transactivation by Oct-2 in response to TPA and Ca2+ and abolish the inhibition by RA. Furthermore, retinoic acid receptor (RAR) α is able to inhibit in vitro the formation of the complex between the nuclear AP-1/OAP and its specific binding site, resulting in the interference with Oct-2- dependent cis-regulatory function of this AP-1 element. Therefore, we propose that the TPA/calcium-activated AP-1/OAP element is the main target of positive or negative regulatory signals influencing the IL-2 octamer motif, through synergism with Oct-2 and antagonism by RAR.

AB - The differentiating agent retinoic acid (RA) has been previously reported to interfere with 12-O-tetradecanoyl-phorbol-13-acetate (TPA)/Ca2+-induced signals for the regulation of the -96 to -66-bp octamer motif found in the enhancer for the interleukin (IL)-2 gene, which encodes a major T lymphocyte growth factor. The IL-2 octamer motif is a composite cis-element which binds Oct-1 and Oct-2 as well as a TPA/Ca2+-inducible nuclear factor, previously termed octamer-associated protein (OAP40). We show here that Oct-2, despite the presence of an active transcriptional activation domain, requires TPA/Ca2+-induced signals to strongly transactivate the IL-2 octamer motif in Jurkat T cells. This Oct-2-dependent transactivation is inhibited by RA. The presence of an intact COOH-terminal domain of Oct-2 contributes to both TPA/Ca2+-induced transactivation and the RA-mediated repression. We also show that both Fos and Jun components of the AP-1 factors participate in the OAP40 complex. Furthermore, transfected c-jun, jun-B, jun-D, c-fos, or Fos- B expression vectors partially substitute for TPA and Ca2+ and cooperate with Oct-2 for the transactivation of the combined OAP/octamer cis-element. Mutations of the genuine octamer-binding site abrogate both the binding of Oct-1 and Oct-2 and the TPA/Ca2+-induced transactivation of the OAP/octamer motif. OAP confers to Oct-2 responsivity to both TPA/Ca2+ and RA, since specific mutations of the AP-1/OAP-binding site significantly reduce the transactivation by Oct-2 in response to TPA and Ca2+ and abolish the inhibition by RA. Furthermore, retinoic acid receptor (RAR) α is able to inhibit in vitro the formation of the complex between the nuclear AP-1/OAP and its specific binding site, resulting in the interference with Oct-2- dependent cis-regulatory function of this AP-1 element. Therefore, we propose that the TPA/calcium-activated AP-1/OAP element is the main target of positive or negative regulatory signals influencing the IL-2 octamer motif, through synergism with Oct-2 and antagonism by RAR.

UR - http://www.scopus.com/inward/record.url?scp=0028018364&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028018364&partnerID=8YFLogxK

M3 - Article

VL - 180

SP - 1485

EP - 1497

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 4

ER -