Transcriptional Regulation of CD28 Expression by CD28GR, a Novel Promoter Element Located in Exon 1 of the CD28 Gene

Lin, Catherine J.; Tam, Robert C.

doi:10.4049/jimmunol.166.10.6134

Cited by 18 publications

(11 citation statements)

References 38 publications

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“…It contained additional 5Ј sequences flanking the minimal CD28 promoter sequences in the p42 and p52 reporters (3). We had reported previously that the activity of the CD28 minimal promoter was regulated by the CD28 INR (33), which functioned independently of a downstream GR element (41). To further validate that the CD28 INR comprised the minimal promoter, the GR element was deleted in the RV construct, the shortest of the reporters.…”

Section: Methodsmentioning

confidence: 99%

Tumor Necrosis Factor-α and CD80 Modulate CD28 Expression through a Similar Mechanism of T-cell Receptor-independent Inhibition of Transcription

Lewis

Merched-Sauvage

Goronzy

et al. 2004

Journal of Biological Chemistry

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Replicative senescence of human T cells is characterized by the loss of CD28 expression, exemplified by the clonal expansion of CD28null T cells during repeated stimulation in vitro as well as in chronic inflammatory and infectious diseases and in the normal course of aging. Because CD28 is the major costimulatory receptor for the induction of T cell-mediated immunity, the mechanism(s) underlying CD28 loss is of paramount interest. Current models of replicative senescence involve protracted procedures to generate CD28 null cells from CD28 ؉ precursors; hence, a T-cell line model was used to examine the dynamics of CD28 expression. Here, we show the versatility of the JT and Jtag cell lines in tracking CD28 null 7 CD28 hi phenotypic transitions. JT and Jtag cells were CD28 null and CD28 lo , respectively, but expressed high levels of CD28 when exposed to phorbol 12-myristate 13-acetate. This was a result of the reconstitution of the CD28 gene transcriptional initiator (INR). Tumor necrosis factor-␣ reduced CD28 expression because of the inhibition of INR-driven transcription. Ligation of CD28 by an antibody or by CD80 also down-regulated CD28 transcription through the same mechanism, providing evidence that CD28 can generate a T cell receptor-independent signal with a unique biological outcome. Collectively, these data unequivocally demonstrate the critical role of the INR in the regulation of CD28 expression. T cell lines with transient expression of CD28 are invaluable in the dissection of the biochemical processes involved in the transactivation of the CD28 INR, the silencing of which is a key event in the ontogenesis of senescent T cells.

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Section: Methodsmentioning

confidence: 99%

Tumor Necrosis Factor-α and CD80 Modulate CD28 Expression through a Similar Mechanism of T-cell Receptor-independent Inhibition of Transcription

Lewis

Merched-Sauvage

Goronzy

et al. 2004

Journal of Biological Chemistry

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“…Our data indicate that enforced expression of Egr1, 2, and 3 increases the surface expression of CD28. It was recently demonstrated that Egr1 can transactivate reporter constructs containing G-rich CD28, a novel promoter element within CD28 exon 1 which serves as the predominant cis-acting element for regulating CD28 expression (46). Consequently, induction of the Egr factors during traversal of the ␤-selection checkpoint is likely to play an important role in the transactivation of CD28 during development of DN thymocytes to the DP stage.…”

Section: Discussionmentioning

confidence: 99%

Early Growth Response Transcription Factors Are Required for Development of CD4−CD8− Thymocytes to the CD4+CD8+ Stage

Carleton

Haks

Smeele

et al. 2002

The Journal of Immunology

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Progression of immature CD4−CD8− thymocytes beyond the β-selection checkpoint to the CD4+CD8+ stage requires activation of the pre-TCR complex; however, few of the DNA-binding proteins that serve as molecular effectors of those pre-TCR signals have been identified. We demonstrate in this study that members of the early growth response (Egr) family of transcription factors are critical effectors of the signals that promote this developmental transition. Specifically, the induction of three Egr family members (Egr1, 2, and 3) correlates with pre-TCR activation and development of CD4−CD8− thymocytes beyond the β-selection checkpoint. Enforced expression of each of these Egr factors is able to bypass the block in thymocyte development associated with defective pre-TCR function. However, Egr family members may play somewhat distinct roles in promoting thymocyte development, because there are differences in the genes modulated by enforced expression of particular Egr factors. Finally, interfering with Egr function using dominant-negative proteins disrupts thymocyte development from the CD4−CD8− to the CD4+CD8+ stage. Taken together, these data demonstrate that the Egr proteins play an essential role in executing the differentiation program initiated by pre-TCR signaling.

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“…Previous studies have indicated that CD28 transcription may also be regulated by Sp1 and Egr-1 proteins, which bind to a so-called GR element situated in the first exon of the gene (49). The GR sequence is likely an enhancer element as evidenced by observations that the pharmacologic agent phytohemagglutinin increases the activity of GR-driven reporter gene constructs.…”

Section: Fig 11 Nucleolin⅐hnrnp-d0a⅐site ␣-Complex Formation Is Permentioning

confidence: 99%

“…The GR sequence is likely an enhancer element as evidenced by observations that the pharmacologic agent phytohemagglutinin increases the activity of GR-driven reporter gene constructs. It may be noted that the GR element is 30-bp upstream from the first translation codon (49), whereas the ␣␤-INR is situated 130-bp further upstream in the 5Ј-untranslated region (10) and coincides with the transcription initiation site (50). Unlike the enhancer activity of the GR sequence, the ␣␤-INR is a core promoter element regulating the constitutive transcription of CD28 (18).…”

Section: Fig 11 Nucleolin⅐hnrnp-d0a⅐site ␣-Complex Formation Is Permentioning

confidence: 99%

Molecular Basis for the Loss of CD28 Expression in Senescent T Cells

Vallejo¹,

Bryl²,

Klarskov

et al. 2002

Journal of Biological Chemistry

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CD28null T cells are the most consistent biological indicator of the aging immune system in humans and are predictors of immunoincompetence in the elderly. The loss of CD28 is the result of an inoperative transcriptional initiator (INR), which consists of two nonoverlapping ␣ and ␤ motifs that have distinct protein binding profiles but function as a unit. In CD28 null T cells, there is a coordinate loss of ␣-/␤-bound complexes, hence the ␣␤-INR is inactive. In the present work therefore, studies were conducted to identify the components of such complexes that may account for the trans-activation of the ␣␤-INR. By affinity chromatography and tandem mass spectrometry, two proteins, namely, nucleolin and the A isoform of heterogeneous nuclear ribonucleoprotein-D0 (hnRNP-D0A), were identified to be among the key components of the site ␣ complex. In DNA binding assays, specific antibodies indicated their antigenic presence in ␣-bound complexes. Transcription assays showed that they are both required in the trans-activation of ␣␤-INR-driven DNA templates. Because CD28 is T cell-restricted, and nucleolin and hnRNP-D0A are ubiquitous proteins, these results support the notion that cellspecific functions can be regulated by commonly expressed proteins. The present data also provide evidence for INR-regulated transcription that is independent of the known components of the basal transcription complex.

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Transcriptional Regulation of CD28 Expression by CD28GR, a Novel Promoter Element Located in Exon 1 of the CD28 Gene

Cited by 18 publications

References 38 publications

Tumor Necrosis Factor-α and CD80 Modulate CD28 Expression through a Similar Mechanism of T-cell Receptor-independent Inhibition of Transcription

Tumor Necrosis Factor-α and CD80 Modulate CD28 Expression through a Similar Mechanism of T-cell Receptor-independent Inhibition of Transcription

Early Growth Response Transcription Factors Are Required for Development of CD4−CD8− Thymocytes to the CD4+CD8+ Stage

Molecular Basis for the Loss of CD28 Expression in Senescent T Cells

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