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To understand the tumor-suppressing mechanism of the SWI/SNF chromatin remodeling complex, we investigated its molecular relationship with p53. Using the pREP4-luc episomal reporter, we first demonstrated that p53 utilizes the chromatin remodeling activity of the SWI/SNF complex to initiate transcription from the chromatin-structured promoter. Among the components of the SWI/SNF complex, we identified BAF60a as a mediator of the interaction with p53 by the yeast two-hybrid assay. p53 directly interacted only with BAF60a, but not with other components of the SWI/SNF complex, such as BRG1, SRG3, SNF5, or BAF57. We found out that multiple residues at the amino acid 108 -150 region of BAF60a were involved in the interaction with the tetramerization domain of p53. The N-terminal fragment of BAF60a containing the p53-interacting region as well as small interfering RNA for baf60a inhibited the SWI/SNF complex-mediated transcriptional activity of p53. The uncoupling of p53 with the SWI/SNF complex resulted in the repression of both p53-dependent apoptosis and cell cycle arrest by the regulation of target genes. These results suggest that the SWI/SNF chromatin remodeling complex is involved in the suppression of tumors by the interaction with p53. [ABSTRACT FROM AUTHOR]

Activation of T cell antigen receptor (TCR) signaling inhibits glucocorticoid (GC)-induced apoptosis of T cells. However, the detailed mechanism regarding how activated T cells are protected from GC-induced apoptosis is unclear. Previously, we have shown that the expression level of SRG3, a murine homolog of BAF155 in humans, correlated well with the GC sensitivity of T cells either in vitro or in vivo. Intriguingly, the expression of SRG3 decreased upon positive selection in the thymus. Here we have shown that TCR signaling inhibits the SRG3 expression via Ras activation and thereby renders primary thymocytes and some thymoma cells resistant to GC-mediated apoptosis. By using pharmacological inhibitors, we have shown that Ras-mediated down-regulation of the SRG3 gene expression is mediated by MEK/ERK and phosphatidylinositol 3-kinase pathways. Moreover, TCR signals repressed the SRG3 transcription through the putative binding sites for E proteins and Ets family transcription factors in the proximal region of the SRG3 promoter. Introduction of mutations in these elements rendered the SRG3 promoter immune to the Ras or TCR signals. Taken together, these observations suggest that TCR signals result in GC desensitization in immature T cells by repressing SRG3 gene expression via Ras activation. [ABSTRACT FROM AUTHOR]

CD7, one of the galectin-1 receptors, has crucial roles in galectin-1-mediated apoptosis of activated T-cells and T-lymphoma progression in peripheral tissues. In this study, we showed that CD7 promoter activity was increased by NF-kappaB and that this activity was synergistic when Sp1 was co-expressed in the immature T-cell line L7. Site-directed mutagenesis analysis of the CD7 promoter indicated that NF-kappaB specifically bound to the NF-kappaE2 site in cooperation with Sp1. Overexpression of E12 or Twist2 proteins negatively regulated NF-kappaB-mediated activity of the CD7 proximal promoter. In addition, CD7 expression was down-regulated by treatment with the p38 MAPK inhibitor SB20358, or the MSK1 inhibitor H-89. These signaling pathway inhibitors prevented galectin-1-mediated apoptosis of immature T-cells. From these results, we concluded that the regulation of CD7 gene expression through NF-kappaB activation induced by TCR/CD28 might have significant implications for T-cell homeostasis.