Alternative modes of c-myc regulation in growth factor-stimulated and differentiating cells.
We have analysed the regulation of c-myc expression in murine fibroblasts and F9 teratocarcinoma cells. The initiation of c-myc transcription is induced to similar levels after serum stimulation of confluent and subconfluent Balb/c A31 fibroblasts while intragenic pausing within the gene's first exon remains unaffected. Sense c-myc transcription continues unabated for at least 18 hours in subconfluent cells, whereas in confluent cells it rapidly falls to pre-induced levels. Cytoplasmic c-myc mRNAs accumulate within 1-2 hours of serum addition to subconfluent cells and reach a higher level than expected from the degree of induction of sense transcription. However, c-myc mRNA levels fall close to pre-induced levels by 18 hours demonstrating that c-myc expression is initially subject to strong positive and then eventually strong negative post-transcriptional control. Anti-sense transcription within the c-myc locus was found to be constitutive under all these physiological states, thereby demonstrating that c-myc transcriptional control is strand specific. Epidermal growth factor stimulates c-myc transcription in a way different from that of serum: (1) initiation of transcription is not significantly enhanced, but intragenic pausing is significantly abrogated; and (2) post-transcriptional mechanisms do not enhance the degree of c-myc mRNA accumulation. In contrast to our results in fibroblastic cells, differentiating F9 teratocarcinoma cells down-regulate c-myc expression entirely at the post-transcriptional level. Our findings indicate that different cell types preferentially employ different modes of myc control depending on their physiological status.
Nepveu
A
A
Department of Biochemistry, SUNY at Stony Brook 11794-5215.
Levine
R A
RA
Campisi
J
J
Greenberg
M E
ME
Ziff
E B
EB
Marcu
K B
KB
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005786:Gene Expression Regulation; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011519:Proto-Oncogenes; D012313:RNA / Q000502:physiology; D016372:RNA, Antisense; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic
D011518:Proto-Oncogene Proteins; D016372:RNA, Antisense; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D012313:RNA