Regulation of oncogene expression in cultured aortic smooth muscle cells. Post-transcriptional control of c-myc mRNA.

Proliferation of normally quiescent vascular smooth muscle cells plays a major role in the development of an atherosclerotic lesion. Since cellular homologues of oncogenes have been implicated in the control of normal cell proliferation, we have analyzed the regulation of expression of two proto-oncogenes (c-fos and c-myc) in primary cultures of calf aortic smooth muscle cells during the transition from quiescence to proliferation. Quiescent (serum-deprived) smooth muscle cells were stimulated to proliferative by serum addition. DNA synthesis began 12 h post-serum addition and peaked between 16 and 20 h. Following addition of serum, c-fos mRNA levels increased rapidly from an undetectable amount to the maximal level at 30 min after serum addition and then rapidly returned to the levels found in quiescent cells. Changes in the rate of c-fos gene transcription, as measured by nuclear "runoff" assays, paralleled the alterations in mRNA levels, indicating that regulation of c-fos was at the level of mRNA synthesis. The mRNA for the c-myc oncogene was expressed at a detectable level in quiescent cells, peaked in abundance at approximately 2 h after stimulation, and then returned to the level found in quiescent cells. No significant change in the rate of c-myc gene transcription was detectable over the time course. The rate of decay of c-myc mRNA following the inhibition of transcription by actinomycin D was measured at the 1- and 4-h time points and in exponentially growing cells. There was a transient stabilization of the normally labile c-myc mRNA at 1 h after serum stimulation. Thus c-myc gene expression was regulated at the level of mRNA turnover.