| First Author | Yang CY | Year | 2009 |
| Journal | J Immunol | Volume | 182 |
| Issue | 5 | Pages | 2959-68 |
| PubMed ID | 19234191 | Mgi Jnum | J:146246 |
| Mgi Id | MGI:3837084 | Doi | 10.4049/jimmunol.0803550 |
| Citation | Yang CY, et al. (2009) 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. J Immunol 182(5):2959-68 |
| abstractText | 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. |
