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,¶,¶
* Graduate Institute of Life Sciences, National Defense Medical Center;
Institute of Molecular Biology and
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan;
Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan; and
¶ Graduate Institute of Cell and Molecular Biology, Taipei Medical University, Taipei, Taiwan
We previously demonstrated that IL-3 stimulates transcription of the antiapoptotic gene mcl-1 via two promoter elements designated as the SIE and CRE-2 sites. To further study the functional role of these two DNA elements, mutant mice with targeted mutations of both SIE and CRE-2 sites (SC mutants) were generated. Homozygous SC mutants manifested a markedly reduced level of Mcl-1 in thymus but not in other major organs such as spleen, liver, lung, or heart. Reduced expression of Mcl-1 in SC mutant thymus resulted in attenuated positive selection of double-positive thymocytes into both CD4 and CD8 lineages, a result likely due to reduced survival of SC mutant double-positive thymocytes that were supposed to be positively selected. In contrast, in the peripheral lymphoid organs, only CD8+ but not CD4+ T cells were significantly reduced in homozygous SC mutant mice, a result consistent with a more dramatic decrease both of Mcl-1 expression and cell viability in mutant CD8+ compared with mutant CD4+ T cells. Impaired T cell development and peripheral CD8+ lymphopenia in homozygous SC mutant mice were both cell autonomous and could be rescued by enforced expression of human Mcl-1. Together, the promoter-knock-in mouse model generated in this study not only revealed a role of Mcl-1 in thymocyte-positive selection, but also uncovered that Mcl-1 expression is regulated in a tissue or cell lineage-specific manner.
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1 This study was supported in part by an intramural fund from Academia Sinica and by grants (NSC 93-2320-B-001-042; 94-2320-B-001-017; 95-2320-B-001-006) from the National Science Council of Taiwan.
2 Address correspondence and reprint requests to Dr. Hsin-Fang Yang-Yen, Institute of Molecular Biology, Academia Sinica, 128 Yen-Jiou Yuan Road, Section 2, Taipei, Taiwan. E-mail address: imbyy{at}gate.sinica.edu.tw
3 Abbreviations used in this paper: DN, double negative; DP, double positive; SP, single positive; WT, wild type; hMcl-1, human Mcl-1; LN, lymph node; HPRT, hypoxanthine phosphoribosyltransferase; CMFDA, 5-chloromethylfluorescein diacetate.
4 The online version of this article contains supplemental material.
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