Abstract
The mechanism by which phorbol esters induce hypertrophic growth of cardiomyocytes was investigated. Control and 4 alpha-phorbol 12,13-didecanoate-treated myocytes demonstrated a slow rate of growth as measured by the protein/DNA ratio and cell area. In contrast, treatment with phorbol 12-myristate 13-acetate (PMA) stimulated protein accumulation by 34%, while cell area was increased by 68% over control myocytes after 72 h. RNA content in PMA-treated myocytes was 33% higher than in control cells and 4 alpha-phorbol 12,13-didecanoate-treated cells after 72 h. Membrane-associated protein kinase C activity was transiently increased after PMA treatment but returned to normal by 48 h. Cytosolic protein kinase C activity was not significantly altered by PMA. Membrane-associated and cytosolic protein kinase C activities were not altered by 4 alpha-phorbol 12,13-didecanoate. Protein kinase C activity, RNA polymerase I activity, and the transcriptional rate of ribosomal DNA (rDNA) were increased in nuclei isolated from PMA-treated cells. However, consistent with a high rate of processing of pre-ribosomal RNA (pre-rRNA), the pool size of pre-rRNA relative to the 28 S rRNA was unaltered by PMA treatment. These data demonstrated that PMA-induced hypertrophic growth of cardiomyocytes was due to an increase in the capacity for protein synthesis (rRNA), and suggest that this results from protein kinase C mediated increase in the rate of transcription of rDNA.
Highlights
The mechanism by which phorbol esters induce 1987; Komura et al, 1991)
In is the primary mechanism by which protein synthesis is contrast, treatment with phorboll2-myristate 13-ace-accelerated during hypertrophic growth (Morgan et al, 1987; tate (PMA) stimulated protein accumulation by 3490, while cell area was increased by 68% over control myocytes after 72 h.RNA content in PMA-treated myocytes was 33%higher than in control cells and 4aphorbol 12,13-didecanoate-treatedcells after72 h
Ribosome accumulation can be due to changes at thelevel of ribosomal DNA (rDNA) transcription, processing of the 45 S rRNA precursor, synthesis of ribosomal proteins, and assembly intomaturesubunits (Sollner-Webb and Tower, 1986;Mager, 1988).In a recent study, the contraction-induced increase in RNA content in cultured cardiomyocytes was shown to be due to anaccelerated rate of 18S and 28 S rRNA
Summary
The mechanism by which phorbol esters induce 1987; Komura et al, 1991). In all of these models of hyperhypertrophicgrowth of cardiomyocytes wasinves- trophic growth, increases in total protein and RNA content tigated. In is the primary mechanism by which protein synthesis is contrast, treatment with phorboll2-myristate 13-ace-accelerated during hypertrophic growth (Morgan et al, 1987; tate (PMA) stimulated protein accumulation by 3490, while cell area was increased by 68% over control myocytes after 72 h.RNA content in PMA-treated myocytes was 33%higher than in control cells and 4aphorbol 12,13-didecanoate-treatedcells after h. Ribosome accumulation can be due to changes at thelevel of rDNA transcription, processing of the 45 S rRNA precursor, synthesis of ribosomal proteins, and assembly intomaturesubunits (Sollner-Webb and Tower, 1986;Mager, 1988).In a recent study, the contraction-induced increase in RNA content in cultured cardiomyocytes was shown to be due to anaccelerated rate of 18S and 28 S rRNA brane-associated andcytosolic protein kinaseC activi- synthesis rather than a decrease in the rate of degradation ties werenot altered by 4c~-phorbol12,13-didecanoate.(McDermott et al, 1989). Ing of pre-ribosomal RNA (pre-rRNA), thepool size of Since its discovery by Nishizuka and colleagues (Takai et pre-rRNA relative to th2e 8 S rRNA was unalteredby al., 1977; Inoue et al, 1977), protein kinase Chas been
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