c‐Fos is essential for the response of the tyrosine hydroxylase gene to depolarization or phorbol ester

Tyrosine hydroxylase (TH) gene transcription rate increases in response to numerous pharmacological and physiological stimuli. The AP1 site within the TH gene proximal promoter is thought to play an important role in mediating many of these responses; however, it is unclear which AP1 factors are required. To investigate whether c‐Fos is essential for the response of the TH gene to different stimuli, c‐Fos‐deficient PC12 cell lines were produced utilizing an antisense RNA strategy. In these cell lines, stimulus‐induced increases in c‐Fos protein levels were dramatically attenuated, while c‐Jun and CREB levels remained unchanged. TH gene transcription rate increased from four‐ to eight‐fold in control cells after treatment with either 50 mm KCl or TPA. These responses were dramatically decreased in the c‐Fos‐deficient cell lines. In contrast, c‐Fos down‐regulation had little effect on the response of the TH gene to forskolin. Stimulation of TH gene promoter activity, which was observed in control cell lines treated with either 50 mm KCl or TPA was also dramatically inhibited in the c‐Fos‐deficient cells. These results suggest that c‐Fos induction is essential for maximal stimulation of the TH gene in response to either depolarization or PKC activation in PC12 cells.