This, in turn, results in the activation of gene transcription. We have tested whether histone acetylation participates in the regulation of dexamethasone induced PTEN transcrip tion. As shown in Figure 3, the histone acetylase inhibitor anacardic acid inhibited dexamethasone induced PTEN up regulation in mRNA levels, indicating that histone acetylase inhibition is associated with transcriptional sti mulation of the PTEN gene by dexamethasone. Our results are supported by the findings of Ito et al. that high concentrations dexamethasone produce a time and concentration dependent increase in histone acetylation in A549 cells, resulting in the recruitment of the activated transcription complex, and the subsequent increase in the expression of several genes.

The direct effect of glucocorticoids on transcript acti vation occurs through binding and activation glucocorti coid receptors, which results in the translocation of glucocorticoid receptor complexes to the nucleus and binding to glucocorticoid response elements in the promoter region of target genes. GREs are short sequences of DNA within the promoter that are able to bind glucocorticoid receptor complexes and therefore regulate gene transcription. The typical DNA sequence of the GRE is 5 GGTACAnnnTGTTCT 3. However, this typical response element could not be found in the 5 upstream region of the PTEN gene. Several studies have reported several alternative GREs, in addition to the typical GRE. These GREs have some variability at several nucleotide positions. Among them, the sequence 5 TGTNC 3 was reported to be a pentamer GRE core sequence.

We screened the promoter region of PTEN for homology to this sequence. Two regions with the high est homology are at positions 1360 Cilengitide to 1364, and 1604 to 1608, both with the sequence 5 TGTGC 3. Further investigations are necessary to answer whether gluco corticoids increase PTEN expression by direct binding to these two putative GREs in the PTEN promoter region, or by interfering with the binding of other tran scription factors. In fact, the number of genes directly regulated by glu cocorticoids was limited, whereas many genes were indirectly regulated through an interaction with other transcription factors and coactivators. Pan et al. reported that p300 could promote PTEN expression. Wang et al. reported that dexamethasone treatment increased SRC 1, CBP and p300 recruited to the PEPCK gene pro moter. Recruitment of these transcription factors promotesd large protein complexes such as RNApoly merase II binding to the promoter region. Therefore it was very likely that these transcription factors partici pated in dexamethasone induced PTEN regulation. Here we propose a new signaling pathway of anti inflammatory responses.