Role for Ets-2Thr-72 Transcription Factor in Stage-specific Thymocyte Development and Survival

Fisher, Ian; Ostrowski, Michael C.; Muthusamy, Natarajan

doi:10.1074/jbc.m111.242602

Cited by 9 publications

(10 citation statements)

References 47 publications

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“…Although the majority of previous studies and our study confirmed the anti-apoptotic function of Ets-2, Ets-2 can also mediate the survival and proliferation of normal and cancer cells (51,52), suggesting that Ets-2 may play a double role in regulating cell death and survival. Whether Ets-2 pro-survival pathway is activated in VSMCs and cardiomyocytes in allografts needs further study.…”

Section: Discussionsupporting

confidence: 43%

Erythroblast transformation-specific 2 correlates with vascular smooth muscle cell apoptosis in rat heterotopic heart transplantation model

Liu

Yan

et al. 2016

J. Thorac. Dis.

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Section: Discussionsupporting

confidence: 43%

Erythroblast transformation-specific 2 correlates with vascular smooth muscle cell apoptosis in rat heterotopic heart transplantation model

Liu

Yan

et al. 2016

J. Thorac. Dis.

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“…Alternative and not mutually exclusive mechanisms of oncogenic cooperation could also imply posttranslational modifications, such as phosphorylation of the threonine 72 residue of Ets2 via the Ras/MAPK pathway, a downstream effector of Jak3 KI/KI known to regulate T-cell survival. 48 Additional experiments are warranted to better understand the molecular bases of the cooperation between trisomy 21 and endogenous JAK3 activation.…”

Section: Discussionmentioning

confidence: 99%

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

et al. 2018

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JAK3-activating mutations are commonly seen in chronic or acute hematologic malignancies affecting the myeloid, megakaryocytic, lymphoid, and natural killer (NK) cell compartment. Overexpression models of mutant JAK3 or pharmacologic inhibition of its kinase activity have highlighted the role that these constitutively activated mutants play in the T-cell, NK cell, and megakaryocytic lineages, but to date, the functional impact of JAK3 mutations at an endogenous level remains unknown. Here, we report a JAK3 knockin mouse model and demonstrate that activated JAK3 leads to a progressive and dose-dependent expansion of CD8 T cells in the periphery before colonization of the bone marrow. This phenotype is dependent on the γc chain of cytokine receptors and presents several features of the human leukemic form of cutaneous T-cell lymphoma (L-CTCL), including skin involvements. We also showed that the JAK3-positive malignant cells are transplantable and phenotypically heterogeneous in bone marrow transplantation assays. Interestingly, we revealed that activated JAK3 functionally cooperates with partial trisomy 21 in vivo to enhance the L-CTCL phenotype, ultimately leading to a lethal and fully penetrant disorder. Finally, we assessed the efficacy of JAK3 inhibition and showed that CTCL JAK3-positive T cells are sensitive to tofacitinib, which provides additional preclinical insights into the use of JAK3 inhibitors in these disorders. Altogether, this JAK3 knockin model is a relevant new tool for testing the efficacy of JAK inhibitors in JAK3-related hematopoietic malignancies.

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“…For example, PU.1 is critical for progression from the DN1 to DN2 stage, as loss of PU.1 in murine thymocytes was shown to result in serious developmental defect . Ets‐2 is critical for the DN2 and DN3 cells, as Ets‐2 overexpression in murine thymocytes was shown to lead to a partial development defect at DN2 and DN3 stages and increases the apoptosis of thymocytes . The Ets at 97D (ELG) subfamily member GABPΑ is critical for the DN3 and DN4 cells, as loss of GABPΑ was shown to arrest murine thymocyte development at the DN3 stage and result in a reduced TCR‐β chain expression level in murine DN4 thymocytes .…”

Section: Ets Family Members Regulate the Development And Survival Of mentioning

confidence: 99%

Role of Ets Proteins in Development, Differentiation, and Function of T‐Cell Subsets

Liu

Gao

Velkinburgh³

et al. 2015

Medicinal Research Reviews

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Through positive selection, double-positive cells in the thymus differentiate into CD4(+) or CD8(+) T single-positive cells that subsequently develop into different types of effective T cells, such as T-helper and cytotoxic T lymphocyte cells, that play distinctive roles in the immune system. Development, differentiation, and function of thymocytes and CD4(+) and CD8(+) T cells are controlled by a multitude of secreted and intracellular factors, ranging from cytokine signaling modules to transcription factors and epigenetic modifiers. Members of the E26 transformation specific (Ets) family of transcription factors, in particular, are potent regulators of these CD4(+) or CD8(+) T-cell processes. In this review, we summarize and discuss the functions and underlying mechanisms of the Ets family members that have been characterized as involved in these processes. Ongoing research of these factors is expected to identify practical applications for the Ets family members as novel therapeutic targets for inflammation-related diseases.

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Role for Ets-2Thr-72 Transcription Factor in Stage-specific Thymocyte Development and Survival

Cited by 9 publications

References 47 publications

Erythroblast transformation-specific 2 correlates with vascular smooth muscle cell apoptosis in rat heterotopic heart transplantation model

Erythroblast transformation-specific 2 correlates with vascular smooth muscle cell apoptosis in rat heterotopic heart transplantation model

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

Role of Ets Proteins in Development, Differentiation, and Function of T‐Cell Subsets

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