Opposite regulation of myc and p21waf1 transcription by STAT3 proteins.

Activated forms of STAT3 transcription factors are often found in various cancers and tumor cell lines, indicating that this signaling pathway is involved in tumorogenesis. At the molecular level, STAT3 proteins function as transcriptional activators and up-regulate several growth-promoting genes such as myc, pim-1, or cyclin D1. However, these transcription factors have also proapoptotic functions and can activate the expression of the cell-cycle inhibitor p21(waf1), suggesting that STAT3 can also block cell-cycle progression and prevent abnormal cell proliferation. To reconcile these observations, one would predict that the STAT3-mediated activation of p21(waf1) is lost during cell transformation. In this study, we show that upon IL-6 stimulation of glioblastoma cells, STAT3 does not activate the expression of the p21(waf1) gene, whereas the expression of the myc gene remains unaltered. Chromatin immunoprecipitation experiments show that STAT3 and its cofactor NcoA/SRC1a are effectively recruited to the p21(waf1) promoter but that this is not followed by the association of the CREB-binding protein (CBP) histone acetylase and the type II RNA polymerase as normally seen on the myc promoter. Whereas the PI-3K/Akt pathway is constitutively activated in these cells, inactivation of this pathway restores the loading of CBP and the RNA polymerase and the expression of the p21(waf1) gene without having any effect on myc regulation. Moreover, this effect was recapitulated in HepG2 cells expressing an activated form of the Akt kinase. In these cells, the kinase blocked the STAT3-mediated expression of the p21(waf1) gene by inhibiting the recruitment of CREB-binding protein and the type II RNA polymerase, without having any effects on the loading of STAT3 and its cofactor NcoA/SRC1a. Together, these findings suggest that the phosphatidylinositol 3-kinase/Akt pathway inhibits the transcriptional activation of the p21(waf1) gene by STAT3 proteins without altering the regulation of the myc promoter.