The association between hormone-induced changes in baseline QT interval and the mRNA level for these channels suggests that sex hormones may play a critical role in regulating cardiac repolarization. However, the changes in baseline QT and potassium channel mRNA after hormone treatment were not concordant with the changes in QT interval after the infusion of quinidine, after which E2-treated animals responded similarly to controls (18.4 +/- 4.6% and 19.3 +/- 4.6% increase in QT interval, respectively) and DHT-treated animals exhibited less QT prolongation (11.4 +/- 3.8% increase; P < .03).

Protein kinase Calpha (PKCalpha) is a phospholipid-dependent protein-serine/threonine kinase that plays a major role in intracellular signaling pathways associated with transformation and tumor progression. Glioblastoma multiforme (GBM) and GBM cell lines exhibit increased levels of PKCalpha compared to normal brain tissue that relates to their proliferative and invasive potential. To investigate the transcriptional regulation of PKCalpha, the 5'-flanking sequence of the human PKCalpha gene was cloned and its promoter activity assessed in U-87 GBM cells. This sequence contained a TATA-less promoter region and a single transcription start site within an initiator sequence. Basal promoter activity was restricted to a region spanning -227 to +77 relative to the transcription start site. DNase I footprinting revealed multiple activator protein-2 (AP-2) binding sites and one Sp1 binding site within this region, and point mutations of two AP-2 elements resulted in a loss of DNA binding and transcriptional activation. Overexpression of Sp1 in either U-87 or insect cells increased transcription from the -227/+77 promoter region, whereas overexpression of AP-2 increased transcription only in insect cells. Cis activation of the promoter in U-87 cells was increased by phorbol esters but not by cyclic AMP or phosphatidylinositol 3-kinase inhibitors. These results provide evidence that cis activation of the basal promoter of the human PKCalpha gene occurs through an AP-2-dependent, phorbol ester-responsive pathway, which suggests an autoregulatory manner of transcription in GBM.

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