Role for transcription factor TFII-I in the suppression of SSeCKS/Gravin/Akap12 transcription by Src

The SSeCKS/Gravin/AKAP12 gene, encoding a kinase scaffolding protein with metastasis- suppressing activity, is transcriptionally downregulated in Src- transformed cells through the recruitment of HDAC1 to a Src- responsive proximal promoter site charged with Sp1, Sp3 and USF1. However, the ectopic expression of these proteins formed a suppressive complex in Src- transformed but not in parental NIH3T3 cells, suggesting the involvement of additional repressor factors. Transcription factor II-I (TFII-I) [ general transcription factor 2i (Gtf2i)] was identified by mass spectrometry as being associated with the SSeCKS promoter complex in NIH3T3/Src cells, and moreover, the Src- induced tyrosine phosphorylation of TFII-I significantly increased its binding to the SSeCKS proximal promoter. siRNA- mediated knockdown of TFII-I or the expression of TFII- I Y248/249F caused the derepression of SSeCKS in NIH3T3/Src cells. Taken with previous data showing that the tyrosine phosphorylation of TFII- I facilitates its nuclear translocation, these data suggest that Src- family kinase- mediated phosphorylation converts a portion of TFII- I into a transcriptional repressor. Cancer Genetics