T cells are derived from progenitor thymocytes, of which only a minority receive the appropriate TCR signal, undergo positive selection and mature. Owing to the very short lifespan of thymocytes, the prerequisite for ...T cells are derived from progenitor thymocytes, of which only a minority receive the appropriate TCR signal, undergo positive selection and mature. Owing to the very short lifespan of thymocytes, the prerequisite for posi- tive selection is survival. TCR signal-induced Bcl-2 expression is believed to play a dominant role in the survival of positively selecting thymocytes, but how Bcl-2 is directly regulated is unknown. Here we report that the immediate early gene （IEG） c-Fos can stimulate the expression of Bcl-2, depending on a specific AP-l-binding site in the Bcl-2 promoter. In c-Fos transgenic （Fos-Tg） mice, c-Fos binds to this site and promotes the expression of Bcl-2. As a result, Fos-Tg thymocytes exhibited enhanced survival, and more mature single-positive （SP） thymocytes were generated, even on a unique TCR background. The TCR repertoire remained normal in Fos-Tg mice. Our results identified c-Fos as the mediator of the stimulatory effect of TCR signaling on Bcl-2 expression. Therefore, c-Fos, as an IEG, because of its early response ability, can quickly rescue the survival of short-lived thymocytes during positive selection. Our results provide novel insight into the mechanism regulating the survival of positively selecting thymocytes.展开更多
Organic compounds containing the thiazol-2-yl-lH-pyrazol-5（4H）-one moiety are known to be associated with versatile pharmacological applications. In this study, we describe the methods for preparing 4-（2-phenylhydr...Organic compounds containing the thiazol-2-yl-lH-pyrazol-5（4H）-one moiety are known to be associated with versatile pharmacological applications. In this study, we describe the methods for preparing 4-（2-phenylhydrazono）- l-（4-phenylthiazol-2-yl）-1H-pyrazol-5（4H）-one compounds. A set of 26 compounds were synthesized with overall yields ranging between 37%-92%. They were tested in a fluorescence polarization-based binding assay against three anti-apoptotic Bcl-2 family proteins, including Bcl-xL, Bcl-2, and Mcl-1. Our results indicate that this class of compounds are not effective inhibitors of these anti-apoptotic Bcl-2 family proteins. Their apoptosis-inducing ef- fects are possibly due to BAX activation as suggested by Gavathiotis et al. in their recent study. However, other possibilities should not be ignored. In addition, a crystal structure obtained by us reveals that the exocyclic double bond in the molecular structure of this class of compounds is in the （Z）-configuration.展开更多
文摘T cells are derived from progenitor thymocytes, of which only a minority receive the appropriate TCR signal, undergo positive selection and mature. Owing to the very short lifespan of thymocytes, the prerequisite for posi- tive selection is survival. TCR signal-induced Bcl-2 expression is believed to play a dominant role in the survival of positively selecting thymocytes, but how Bcl-2 is directly regulated is unknown. Here we report that the immediate early gene （IEG） c-Fos can stimulate the expression of Bcl-2, depending on a specific AP-l-binding site in the Bcl-2 promoter. In c-Fos transgenic （Fos-Tg） mice, c-Fos binds to this site and promotes the expression of Bcl-2. As a result, Fos-Tg thymocytes exhibited enhanced survival, and more mature single-positive （SP） thymocytes were generated, even on a unique TCR background. The TCR repertoire remained normal in Fos-Tg mice. Our results identified c-Fos as the mediator of the stimulatory effect of TCR signaling on Bcl-2 expression. Therefore, c-Fos, as an IEG, because of its early response ability, can quickly rescue the survival of short-lived thymocytes during positive selection. Our results provide novel insight into the mechanism regulating the survival of positively selecting thymocytes.
基金The authors are grateful to the financial supports from the Chinese National Natural Science Foundation，the Chinese Ministry of Science and Technology，the Chinese Academy of Sciences
文摘Organic compounds containing the thiazol-2-yl-lH-pyrazol-5（4H）-one moiety are known to be associated with versatile pharmacological applications. In this study, we describe the methods for preparing 4-（2-phenylhydrazono）- l-（4-phenylthiazol-2-yl）-1H-pyrazol-5（4H）-one compounds. A set of 26 compounds were synthesized with overall yields ranging between 37%-92%. They were tested in a fluorescence polarization-based binding assay against three anti-apoptotic Bcl-2 family proteins, including Bcl-xL, Bcl-2, and Mcl-1. Our results indicate that this class of compounds are not effective inhibitors of these anti-apoptotic Bcl-2 family proteins. Their apoptosis-inducing ef- fects are possibly due to BAX activation as suggested by Gavathiotis et al. in their recent study. However, other possibilities should not be ignored. In addition, a crystal structure obtained by us reveals that the exocyclic double bond in the molecular structure of this class of compounds is in the （Z）-configuration.
