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Complementary roles of retinoic acid and TGF-?1 in coordinated expression of mucosal integrins by T cells.

ABSTRACT: ?(4) and ?(7) integrins, such as ?(4)?(1), ?(4)?(7), and ?(E)?(7), are major integrins required for migration of leukocytes into mucosal tissues. The mechanisms responsible for coordinated expression of these three integrins have been poorly elucidated to date. We report that expression of the Itg-?(4) subunit by both CD4(+) and CD8(+) T cells requires the retinoic acid signal. In contrast, transcription of Itg-?(E) genes is induced by the transforming growth factor-?1 (TGF?1) signal. Expression of Itg-?(7) is constitutive but can be further increased by TGF?1. Consistently, expression of ?(4)-containing integrins is severely suppressed in vitamin A deficiency with a compensatory increase of ?(E)?(7), whereas expression of Itg-?(E) and Itg-?(7) is decreased in TGF?-signal deficiency with a compensatory increase in ?(4)?(1). The retinoic acid-mediated regulation of ?(4) integrins is required for specific migration of T cells in vitro and in vivo. These results provide central regulatory mechanisms for coordinated expression of the major mucosal integrins.

SUBMITTER: Kang SG

PROVIDER: S-EPMC3012787 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Complementary roles of retinoic acid and TGF-β1 in coordinated expression of mucosal integrins by T cells.

Kang S G SG Park J J Cho J Y JY Ulrich B B Kim C H CH

Mucosal immunology 20100721 1

α(4) and β(7) integrins, such as α(4)β(1), α(4)β(7), and α(E)β(7), are major integrins required for migration of leukocytes into mucosal tissues. The mechanisms responsible for coordinated expression of these three integrins have been poorly elucidated to date. We report that expression of the Itg-α(4) subunit by both CD4(+) and CD8(+) T cells requires the retinoic acid signal. In contrast, transcription of Itg-α(E) genes is induced by the transforming growth factor-β1 (TGFβ1) signal. Expression ...[more]

PMID: 20664575

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Project description:The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. RA is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by RA. The RA-treated HL-60 cells used here expressed all RA receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by RA. Within this sequence DNase I footprinting revealed that RA induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without RA there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by RA. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to RA also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. RA upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel RA response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites.

Project description:Retinoid therapy is widely employed in clinical oncology to differentiate malignant cells into their more benign counterparts. However, certain high-risk cohorts, such as patients with MYCN-amplified neuroblastoma, are innately resistant to retinoid therapy. Therefore, we employed a precision medicine approach to globally profile the retinoid signalling response and to determine how an excess of cellular MYCN antagonises these signalling events to prevent differentiation and confer resistance.We applied RNA sequencing (RNA-seq) and interaction proteomics coupled with network-based systems level analysis to identify targetable vulnerabilities of MYCN-mediated retinoid resistance. We altered MYCN expression levels in a MYCN-inducible neuroblastoma cell line to facilitate or block retinoic acid (RA)-mediated neuronal differentiation. The relevance of differentially expressed genes and transcriptional regulators for neuroblastoma outcome were then confirmed using existing patient microarray datasets.We determined the signalling networks through which RA mediates neuroblastoma differentiation and the inhibitory perturbations to these networks upon MYCN overexpression. We revealed opposing regulation of RA and MYCN on a number of differentiation-relevant genes, including LMO4, CYP26A1, ASCL1, RET, FZD7 and DKK1. Furthermore, we revealed a broad network of transcriptional regulators involved in regulating retinoid responsiveness, such as Neurotrophin, PI3K, Wnt and MAPK, and epigenetic signalling. Of these regulators, we functionally confirmed that MYCN-driven inhibition of transforming growth factor beta (TGF-?) signalling is a vulnerable node of the MYCN network and that multiple levels of cross-talk exist between MYCN and TGF-?. Co-targeting of the retinoic acid and TGF-? pathways, through RA and kartogenin (KGN; a TGF-? signalling activating small molecule) combination treatment, induced the loss of viability of MYCN-amplified retinoid-resistant neuroblastoma cells.Our approach provides a powerful precision oncology tool for identifying the driving signalling networks for malignancies not primarily driven by somatic mutations, such as paediatric cancers. By applying global omics approaches to the signalling networks regulating neuroblastoma differentiation and stemness, we have determined the pathways involved in the MYCN-mediated retinoid resistance, with TGF-? signalling being a key regulator. These findings revealed a number of combination treatments likely to improve clinical response to retinoid therapy, including co-treatment with retinoids and KGN, which may prove valuable in the treatment of high-risk MYCN-amplified neuroblastoma.

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Complementary roles of retinoic acid and TGF-?1 in coordinated expression of mucosal integrins by T cells.

Publications

Complementary roles of retinoic acid and TGF-β1 in coordinated expression of mucosal integrins by T cells.

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