Down-regulation of Runx1 Expression by TCR Signal Involves an Autoregulatory Mechanism and Contributes to IL-2 Production
Runx1 transcription factor plays multiple roles in T cell development, differentiation, and function. However, the regulatory mechanisms and functional significance of high Runx1 protein expression in resting peripheral CD4+ T cells is not well understood. Here, we demonstrate that T-cell receptor (...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Published: |
American Society for Biochemistry and Molecular Biology
2011
|
| Subjects: |
| _version_ | 1825720278475341824 |
|---|---|
| author | Wong, W.F. Kurokawa, M. Satake, M. Kohu, K. |
| author_facet | Wong, W.F. Kurokawa, M. Satake, M. Kohu, K. |
| author_sort | Wong, W.F. |
| collection | UM |
| description | Runx1 transcription factor plays multiple roles in T cell development, differentiation, and function. However, the regulatory mechanisms and functional significance of high Runx1 protein expression in resting peripheral CD4+ T cells is not well understood. Here, we demonstrate that T-cell receptor (TCR) activation down-regulates distal Runx1 transcription, resulting in a significant reduction of Runx1 protein. Interestingly, this down-regulation of distal Runx1 transcription appears to be mediated through a negative auto-regulatory mechanism, whereby Runx1 protein binds to a Runx consensus site in the distal promoter. Through the use of Runx1-overexpressing cells from transgenic mice, we demonstrate that interference with TCR-mediated Runx1 down-regulation inhibits IL-2 production and proliferation in activated CD4+ T cells. In contrast, using Runx1-deficient cells prepared from targeted mice, we show that the absence of Runx1 in unstimulated CD4+ T cells results in IL-2 derepression. In summary, we propose that high levels of Runx1 in resting CD4+ T cells functions negatively in the regulation of IL-2 transcription, and that TCR activation-mediated down-regulation of Runx1 involves negative auto-regulation of the distal Runx1 promoter and contributes to IL-2 production. |
| first_indexed | 2024-03-06T05:32:41Z |
| format | Article |
| id | um.eprints-13024 |
| institution | Universiti Malaya |
| last_indexed | 2024-03-06T05:32:41Z |
| publishDate | 2011 |
| publisher | American Society for Biochemistry and Molecular Biology |
| record_format | dspace |
| spelling | um.eprints-130242015-03-13T01:32:10Z http://eprints.um.edu.my/13024/ Down-regulation of Runx1 Expression by TCR Signal Involves an Autoregulatory Mechanism and Contributes to IL-2 Production Wong, W.F. Kurokawa, M. Satake, M. Kohu, K. R Medicine Runx1 transcription factor plays multiple roles in T cell development, differentiation, and function. However, the regulatory mechanisms and functional significance of high Runx1 protein expression in resting peripheral CD4+ T cells is not well understood. Here, we demonstrate that T-cell receptor (TCR) activation down-regulates distal Runx1 transcription, resulting in a significant reduction of Runx1 protein. Interestingly, this down-regulation of distal Runx1 transcription appears to be mediated through a negative auto-regulatory mechanism, whereby Runx1 protein binds to a Runx consensus site in the distal promoter. Through the use of Runx1-overexpressing cells from transgenic mice, we demonstrate that interference with TCR-mediated Runx1 down-regulation inhibits IL-2 production and proliferation in activated CD4+ T cells. In contrast, using Runx1-deficient cells prepared from targeted mice, we show that the absence of Runx1 in unstimulated CD4+ T cells results in IL-2 derepression. In summary, we propose that high levels of Runx1 in resting CD4+ T cells functions negatively in the regulation of IL-2 transcription, and that TCR activation-mediated down-regulation of Runx1 involves negative auto-regulation of the distal Runx1 promoter and contributes to IL-2 production. American Society for Biochemistry and Molecular Biology 2011-04-01 Article PeerReviewed Wong, W.F. and Kurokawa, M. and Satake, M. and Kohu, K. (2011) Down-regulation of Runx1 Expression by TCR Signal Involves an Autoregulatory Mechanism and Contributes to IL-2 Production. The Journal of Biological Chemistry, 286. pp. 11110-11118. ISSN 0021-9258, DOI https://doi.org/10.1074/jbc.M110.166694 <https://doi.org/10.1074/jbc.M110.166694>. http://www.jbc.org/content/286/13/11110.long http://dx.doi.org/10.1074/jbc.M110.166694 |
| spellingShingle | R Medicine Wong, W.F. Kurokawa, M. Satake, M. Kohu, K. Down-regulation of Runx1 Expression by TCR Signal Involves an Autoregulatory Mechanism and Contributes to IL-2 Production |
| title | Down-regulation of Runx1 Expression by TCR Signal Involves an Autoregulatory Mechanism and Contributes to IL-2 Production |
| title_full | Down-regulation of Runx1 Expression by TCR Signal Involves an Autoregulatory Mechanism and Contributes to IL-2 Production |
| title_fullStr | Down-regulation of Runx1 Expression by TCR Signal Involves an Autoregulatory Mechanism and Contributes to IL-2 Production |
| title_full_unstemmed | Down-regulation of Runx1 Expression by TCR Signal Involves an Autoregulatory Mechanism and Contributes to IL-2 Production |
| title_short | Down-regulation of Runx1 Expression by TCR Signal Involves an Autoregulatory Mechanism and Contributes to IL-2 Production |
| title_sort | down regulation of runx1 expression by tcr signal involves an autoregulatory mechanism and contributes to il 2 production |
| topic | R Medicine |
| work_keys_str_mv | AT wongwf downregulationofrunx1expressionbytcrsignalinvolvesanautoregulatorymechanismandcontributestoil2production AT kurokawam downregulationofrunx1expressionbytcrsignalinvolvesanautoregulatorymechanismandcontributestoil2production AT satakem downregulationofrunx1expressionbytcrsignalinvolvesanautoregulatorymechanismandcontributestoil2production AT kohuk downregulationofrunx1expressionbytcrsignalinvolvesanautoregulatorymechanismandcontributestoil2production |