Multiple cis- and trans-acting elements mediate the transcriptional response to phorbol esters

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Abstract
Protein kinase C is important in the transduction of signals generated at the plasma membrane. The physiological activators of protein kinase C are diacylglycerols1, and the tumour-promoting phorbol esters, such as 12-O-tetradecanoyI-phorbol-14 acetate (TPA), constitute another group of specific activators1,2. Many cellular substrates for phosphorylation by protein kinase C have been described1,3, but proteins that directly control transcription in response to protein kinase C activation are yet to be identified. TPA treatment leads to induction of various proto-oncogenes4–7, growth factor genes7,8, and genes encoding secreted proteases9. In addition. TPA increases the activity of viral enhancer elements10–13. To identify trans-acting factors that mediate the transcriptional response to TPA we chose the simian virus 40 (SV40) enhancer14 as a model, because it is known to be composed of several discrete cis-acting elements15–18 which are recognized by multiple trans-acting factors19–21. We report here that the SV40 enhancer contains at least four different TPA responsive elements whose activity is dependent on cell-type. The induction response is likely to involve at least two distinct post-translational steps which modulate the activity of the proteins that recognize these elements.