Dexamethasone modulates ErbB tyrosine kinase expression and signaling through multiple and redundant mechanisms in cultured rat hepatocytes.

Scheving LA, Buchanan R, Krause MA, Zhang X, Stevenson MC, Russell WE
Am J Physiol Gastrointest Liver Physiol. 2007 293 (3): G552-9

PMID: 17585012 · DOI:10.1152/ajpgi.00140.2007

Glucocorticoids paradoxically exert both stimulatory and inhibitory effects on the proliferation of cultured rat hepatocytes. We studied the effects of dexamethasone, a synthetic glucocorticoid, on the proliferation of cultured rat hepatocytes. The timing of growth factor addition modified the action of high-dose dexamethasone (10(-6) M) on DNA synthesis. When we added transforming growth factor-alpha at the time of plating, 10(-6) M dexamethasone weakly stimulated DNA synthesis by 26% relative to cells cultured in dexamethasone-free media. When we delayed growth factor addition until 24-48 h after plating, 10(-6) M dexamethasone inhibited DNA synthesis by 50%. Using immunological methods, we analyzed the expression and signaling patterns of the ErbB kinases in dexamethasone-treated cells. High-dose dexamethasone stabilized the expression of epidermal growth factor receptor (EGFr) and ErbB3, and it suppressed the de novo expression of ErbB2 that occurs during the third and fourth day of culture in 10(-8) M dexamethasone. High-dose dexamethasone by 72 h suppressed basal and EGF-associated phosphorylation of ERK and Akt. The reduction in ERK1/2 phosphorylation correlated with suppression of a culture-dependent increase in Son-of sevenless 1 (Sos1) and ERK1/2 expression. High-dose dexamethasone in hepatocytes stabilized or upregulated several inhibitory effectors of EGFr/ErbB2 and ERK, including receptor-associated late transducer (RALT) and MKP-1, respectively. Thus 10(-6) M dexamethasone exerts a time-dependent and redundant inhibitory effect on EGFr-mediated proliferative signaling in hepatocytes, targeting not only the ErbB proteins but also their various positive and negative effectors.

MeSH Terms (30)

Adaptor Proteins, Signal Transducing Animals Cell Cycle Proteins Cell Proliferation Cells, Cultured Dexamethasone DNA Replication Dose-Response Relationship, Drug Dual Specificity Phosphatase 1 ErbB Receptors Glucocorticoids Hepatocytes Immediate-Early Proteins Male Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Phosphatidylinositol 3-Kinases Phosphoprotein Phosphatases Phosphorylation Protein Phosphatase 1 Protein Tyrosine Phosphatases Proto-Oncogene Proteins c-akt Rats Rats, Sprague-Dawley Receptor, ErbB-2 Receptor, ErbB-3 Signal Transduction SOS1 Protein Time Factors Transforming Growth Factor alpha

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