Promoter Knock-In Mutations Reveal a Role of Mcl-1 in Thymocyte-Positive Selection and Tissue or Cell Lineage-Specific Regulation of Mcl-1 Expression

Autor: Chia-Yu Yang, Jeffrey J.Y. Yen, Nan-Shih Liao, Hsiang-Ju Min, Ching-Yu Huang, Jan-Mou Lee, Hsin-Fang Yang-Yen, Nai-Hui Lin
Rok vydání: 2009
Předmět:
Zdroj: The Journal of Immunology. 182:2959-2968
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.0803550
Popis: 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.
Databáze: OpenAIRE