Regulation of the Expression of Caspase-9 by the Transcription Factor Activator Protein-4 in Glucocorticoid-induced Apoptosis

Abstract

Caspase-9 (Casp-9) induces death signals by triggering other types of caspase activation, and its expression greatly influences the onset of apoptosis. During the isolation of apoptosis-related genes involved in glucocorticoid (GC)-induced cell death in murine thymic lymphomas, we found that the antisense gene of the transcription factor activator protein-4 (AP-4) inhibited dexamethasone-induced apoptosis. Western blot analysis revealed that the expression of Bcl-x L , Bax, and Apaf-1 was not affected in cells transfected with sense or antisense AP-4 genes. In contrast, both the expression and activation of Casp-9 were inhibited in the antisense AP-4 transfectants. We isolated the 2.4-kb 5-flanking region of Casp-9, and the promoter activity was investigated. We found the AP-4-binding sites at ؊1.55 and ؊1.38 kb to be responsible for the promoter activity. Furthermore, a negative cis-element was expected to exist between bases ؊1140 and ؊944. When the cells were treated with dexamethasone, a rapid down-regulation of AP-4 and Casp-9 was observed whether the cells were GC-sensitive lymphomas or GC-insensitive L929 fibroblast cells. In addition, L929 cells pretreated with dexamethasone were found to be resistant to subsequent treatment with etoposide, an apoptosis-inducing reagent. GC has a two-sided effect on apoptosis, i.e. a pro-apoptotic effect on certain cell types and a prosurvival effect on other cell types. Our findings will explain, at least in part, this effect.

Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

“…A component of AP-1 the oncoprotein c-jun has been shown to be hyperactivated by JNK in epithelial cells (43). Our observations showing JNK involvement in the regulation of AP-4 activity following IGF-1 stimulation are supported by a study wherein AP-4 was shown to be downregulated by glucocorticoids (44). Although the AP-1 binding site is present in the E1 oligonucleotides, mutation of this site or inclusion of anti-c-jun antibody did not diminish E1 binding to IGF-1-stimulated nuclear proteins, suggesting that AP-1 may not play a role in JNK-activated SHP1 expression in MCF-7 cells.…”

Selective Regulation of Bone Cell Apoptosis by Translational Isoforms of the Glucocorticoid Receptor

“…In agreement with data in the literature, there is a delayed onset of cell death in our model system, suggesting that the proapoptotic action of glucocorticoids requires GR-mediated transcription (22,29,35). Several genes, including GZMA and CASP6, have been suggested to participate in glucocorticoid-induced killing of osteoblasts, chondrocytes, and lymphocytes (4,28,30,35). Using siRNA technology, we clearly show that these executionstage molecules are critical in glucocorticoid-induced bone cell apoptosis.…”

Co-expression of IGFs and GH receptors (GHRs) in gilthead sea bream (Sparus aurata L.): sequence analysis of the GHR-flanking region

“…The regulation of CREB (Hai & Hartman 2001) and AP-1 (Prabhakar 2001, Kim et al 2002 have been extensively studied in mammals, and serve as models of stress-and redox-sensitive transcription factors. Of note, AP-4 is a closely related transcription factor that is rapidly downregulated by glucocorticoids (Tsujimoto et al 2005), and various AP-4 sequence elements were retrieved in the proximal 5 0 -flanking region of gilthead sea bream GHR-II, although its functional relevance remains still to be demonstrated. Figure 5 Summer age-related changes in the tissue-specific expression (relative units) of GHR-I and GHR-II.…”