Interplay between RORγt, Egr3, and E Proteins Controls Proliferation in Response to Pre-TCR Signals

Xi, Hongkang; Schwartz, Ruth; Engel, Isaac; Murre, Cornelis; Kersh, Gilbert J.

doi:10.1016/j.immuni.2006.03.023

Cited by 99 publications

(123 citation statements)

References 47 publications

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“…The data presented herein suggest that the proliferative response itself is only mildly decreased by Akt loss, consistent with previous studies demonstrating distinct pathways for survival versus proliferation at the ␤-selection checkpoint (2). Signaling by the pre-TCR has been shown to directly influence cell cycle regulation through activation of the Ras-MAPK pathway (23,24). Overexpression studies using myr-Akt show that activated Akt1 leads to enhanced Erk phosphorylation, providing evidence for cross-talk between the pathways (25).…”

Section: Discussionsupporting

confidence: 90%

Akt1 and Akt2 are required for αβ thymocyte survival and differentiation

Juntilla

Wofford

Birnbaum

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

127

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The ␤-selection checkpoint in ␣␤T lymphocyte development occurs at the double negative (DN) 3 (CD4 ؊ CD8 ؊ CD25 ؉ c-kit ؊ ) stage, when further differentiation requires a signal from the newly rearranged TCR ␤ chain. Thymocytes with mutations in key signaling molecules in the phosphatidylinositol 3-kinase-Akt pathway manifest defects in survival, proliferation, and differentiation past the ␤-selection checkpoint. However, little information is available regarding the role of Akt itself in thymocyte development. In this study, we explore the role of the two Akt isoforms most highly expressed in the thymus, Akt1 and Akt2, in early T cell development. Using several complementary approaches, we find that deletion of Akt1 results in only minor defects in thymocyte development. The Akt1 ؊/؊ Akt2 ؊/؊ thymocytes manifest a severe developmental block at the DN3 stage and ultimately fail to repopulate the T cell compartment of an irradiated host. Further, we show that Akt1 ؊/؊ Akt2 ؊/؊ DN3 cells have decreased glucose uptake and die in response to TCR stimulation in vitro. Study of thymocytes from the genetically altered mice suggests that the cause of the developmental defect is due to apoptosis, partially caused by decreased cellular growth and metabolism at the DN3 stage. Our results show that Akt protects thymocytes from cell death during the ␤-selection checkpoint.apoptosis ͉ metabolism ͉ thymic development

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Section: Discussionsupporting

confidence: 90%

Akt1 and Akt2 are required for αβ thymocyte survival and differentiation

Juntilla

Wofford

Birnbaum

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

127

143

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“…Presumably, Egr3 is required to maintain constitutive survival mechanisms, but is dispensable for VEGF-induced survival pathways. Egr3 is important for proliferative and survival signals in thymocytes (Xi and Kersh, 2004a,b;Xi et al, 2006;Carter and Tourtellotte, 2007), but has not previously been implicated in endothelial cell responses. Furthermore, Egr3 knockdown also strongly inhibited tubulogenesis and proliferation induced by the angiogenic factor FGF-2.…”

Section: Vegf Regulation Of Egr3 D Liu Et Almentioning

confidence: 99%

The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis

et al. 2007

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“…The early growth response (Egr) transcription factors Egr1 [7], Egr2 [8] and Egr3 [9] are central players throughout the development of T lymphocytes. All three are induced upon activation of the pre-TCR [10][11][12], and their overexpression can force progression through b-selection [10,13]. Egr1 and Egr3 promote survival at b-selection [14], and Egr3 is also required for the post-b-selection proliferative burst to occur [12].…”

Section: Introductionmentioning

confidence: 99%

“…All three are induced upon activation of the pre-TCR [10][11][12], and their overexpression can force progression through b-selection [10,13]. Egr1 and Egr3 promote survival at b-selection [14], and Egr3 is also required for the post-b-selection proliferative burst to occur [12]. These transcription factors are also induced rapidly following ligation of the abTCR, both during thymocyte selection [15] and in mature T cells responding to antigen-MHC, where Egr1 has a role in upregulation of IL2 transcription [16], and Egr2 and Egr3 are required for induction of anergy [17,18], and regulate expression of FasL [19,20].…”

Section: Introductionmentioning

confidence: 99%

Early growth response 2 regulates the survival of thymocytes during positive selection

2009

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The early growth response (Egr) transcription factor family regulates multiple steps during T-cell development. We examine here the role played by Egr2 in positive selection. In double-positive cells, Egr2 is upregulated immediately following TCR ligation, and its expression requires both the MAPK and calcineurin signaling pathways. Inducible transgenic and knockout mice were generated to cause gain-or loss-of-function of Egr2 in double-positive cells, and had reciprocal effects; more mature single-positive cells were made when Egr2 was overexpressed, and fewer when Egr2 was absent. These defects were associated with changes in the survival of positively selected cells rather than perturbation of positive selection or immediate post-selection signaling. The survival function of Egr2 at least partly depends upon its ability to activate the cytokine-mediated survival pathway, likely through negative regulation of both the IL-7R and suppressor of cytokine signaling 1 (Socs1), the molecular switch whose downregulation normally results in restored responsiveness to cytokine signaling following selection. While gain of Egr2 caused a decrease in Socs1 mRNA, loss of Egr2 resulted in downregulation of IL-7R, upregulation of Socs1, and inhibition of Stat5 phosphorylation and IL-7-mediated survival post-selection. Therefore, expression of Egr2 following positive selection links the initial TCR signaling event to subsequent survival of signaled cells. , and Egr3 is also required for the post-b-selection proliferative burst to occur [12]. These transcription factors are also induced rapidly following ligation of the abTCR, both during thymocyte selection [15] and in mature T cells responding to antigen-MHC, where Egr1 has a role in upregulation of IL2 transcription [16], and Egr2 and Egr3 are required for induction of anergy [17,18], and regulate expression of FasL [19,20]. Through its control of self-tolerance, Egr2 has also been implicated in the development of late-onset autoimmune disease [21] and is required for the development and maturation of NKT cells [22].Upregulation of Egr proteins during positive selection is dependent upon the Ras/MAPK pathway [13]. Egr proteins are direct transcriptional targets of ternary complex factor Sap-1, which is itself a substrate of Erk and essential for positive selection [23]. In addition, Egr2 and Egr3 are regulated by calcineurin signaling, likely via NFAT [13,20,22]. Both Egr1 and Egr3 have roles in positive selection. Egr1 overexpression enhances positive selection of cells with low affinity TCR [24]. Conversely, Egr1-deficient mice have impaired positive selection [25]; although the initial TCR signal is transduced, cells stall at the DP to SP transition, resulting in a numerical decrease in CD4 and CD8 SP. Animals doubly deficient for both Egr1 and Egr3 have a similar but more marked selection phenotype, and CD8 differentiation is significantly impaired [14]. For both Egr1 and Egr3, the principal reason for the alterations in SP cell number is a change in the cells' susceptibi...

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Interplay between RORγt, Egr3, and E Proteins Controls Proliferation in Response to Pre-TCR Signals

Cited by 99 publications

References 47 publications

Akt1 and Akt2 are required for αβ thymocyte survival and differentiation

Akt1 and Akt2 are required for αβ thymocyte survival and differentiation

The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis

Early growth response 2 regulates the survival of thymocytes during positive selection

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