Effects of chronic phorbol ester treatment on protein kinase C activity, content, and gene expression in the human monoblastoid U937 cell.

Feb 1, 1994Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research

Long-term phorbol ester treatment changes protein kinase C activity, amount, and gene expression in human immune-like U937 cells

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Abstract

Sustained activation of protein kinase C (PKC) is essential for phorbol ester-induced differentiation of U937 cells into monocyte/macrophage-like cells.

Chronic activation of the PKC pathway alters the signal transduction profile compared to initial phorbol ester application.
AP-1 binding activity increased in response to 12-O-tetradecanoylphorbol-13-acetate (TPA), showing a temporal dependency with a notable shift after 12 hours.
Maximal enhancement of AP-1 binding activity occurred with 1 nM TPA after 72 hours, remaining elevated despite higher concentrations.
Sustained TPA exposure was crucial for enhanced AP-1 binding activity, which was not a result of cellular differentiation.
A 72-hour treatment with 1 nM TPA significantly boosted the expression of c-jun, krox-24, and jun-B mRNA transcripts, while higher concentrations reduced their levels.
Higher TPA concentrations (100 nM) were required for maximal expression of collagenase and plasminogen activator receptor transcripts.

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Immediate and sustained signal transduction is involved in mediating phorbol ester-induced changes in growth and differentiation. Activation of protein kinase C (PKC) is the initial step in phorbol ester-induced signal transduction. By virtue of preferential down-regulation of individual isoforms and generation of proteolytically derived kinase activities, the signal transduced by sustained activation of this pathway may differ substantially from that generated initially upon application of the phorbol ester. To examine the effect of chronic phorbol ester-induced activation of this pathway, the relationship between PKC activity/content and AP-1 binding activity and gene expression was studied in the U937 cell. Phorbol ester-induced differentiation of the U937 cell into a monocyte/macrophage-like cell requires sustained activation of the PKC pathway. AP-1 binding activity was enhanced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and in a temporally dependent manner, with conversion of a high to low mobility band shift occurring after a 12-h exposure to TPA. After a 72-h exposure, AP-1 binding activity was maximally increased by 1 nM TPA and remained elevated to a similar degree even after treatment with 600 nM TPA. Enhanced AP-1 binding activity was dependent upon continuous exposure to TPA and was not secondary to differentiation. A 72-h treatment with one nM TPA maximally increased expression of c-jun, krox-24, and jun-B mRNA transcripts. Exposure to higher TPA concentrations decreased the content of these transcripts. Maximal expression of collagenase and plasminogen activator receptor transcripts required exposure to much higher TPA concentrations (100 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of chronic phorbol ester treatment on protein kinase C activity, content, and gene expression in the human monoblastoid U937 cell.

Abstract

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