Post-receptor signals that modulate growth-related gene expression
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Abstract
Polypeptide growth factors regulate cell proliferation by binding to cell surface receptors. Cytoplasmic second messengers are activated and induce the mRNAs of the c-fos and c-myc protooncogenes. In Swiss 3T3 cells, these mRNAs were induced by platelet extract (PE), bombesin and epidermal growth factor (EGF). Inactivation of protein kinase C (PKC), greatly reduced the induction of c-myc and c-fos mRNA by PE or bombesin but not by EGF. Therefore, a kinase other than PKC may mediate EGF-induced gene expression.
In confluent Balb/c 3T3 cells, c-myc and c-fos mRNAs were induced by tetradecanoyl phorbol acetate (TPA), a direct activator of PKC, but not by EGF. By contrast, TPA was a poor inducer of these mRNAs in serum deprived, subconfluent cells, whereas EGF was a more potent inducer. Responsiveness to EGF was associated with elevated levels of intracellular cAMP. First, serum-deprived cells had intracellular cAMP levels that were 2-fold higher than the level in confluent cells. Second, EGF's ability to induce protooncogene mRNA in confluent cells was enhanced by agents that raised intracellular cAMP. In addition, the calcium ionophore, A23187, mimicked the ability of EGF to induce c-fos and c-myc mRNA in a cAMP-dependent manner.
These results demonstrate that c-fos and c-myc mRNA can be induced by two different post-receptor pathways: a PKC-dependent pathway and a cAMP-dependent, calcium sensitive pathway. In Balb/c 3T3 cells, the preferential use of one pathway over the other depended upon the method used to growth arrest the cells.
During asynchronous growth, cells require only insulin or IGF-1 to progress through G1. The mRNA levels of c-myc and ornithine decarboxylase declined in the absence of growth factors and the cells underwent a transient change in cell shape. My results demonstrate that: 1) the removal of growth factors rather than the change in cell shape mediates the decline in these mRNAs, 2) TPA or EGF and insulin partially prevented c-myc mRNA decay in serum-free medium and 3) insulin-mediated G1 transit is not dependent upon the presence of c-myc transcripts.
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Dissertation (Ph.D.)--Boston University
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