One-way cross-talk between p38(MAPK) and p42/44(MAPK). Inhibition of p38(MAPK) induces low density lipoprotein receptor expression through activation of the p42/44(MAPK) cascade

• Published in: The Journal of biological chemistry Vol. 274; no. 28; p. 19593
• Main Authors: Singh, R P, Dhawan, P, Golden, C, Kapoor, G S, Mehta, K D
• Format: Journal Article
• Language: English
• Published: United States 09.07.1999
• Subjects: Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cholesterol - analogs & derivatives; Cholesterol - pharmacology; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Gene Expression Regulation - drug effects; Humans; Imidazoles - pharmacology; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Promoter Regions, Genetic; Pyridines - pharmacology; Receptors, LDL - genetics; Signal Transduction; Tumor Cells, Cultured
• ISSN: 0021-9258
• DOI: 10.1074/jbc.274.28.19593

In this paper, we report that SB202190 alone, a specific inhibitor of p38(MAPK), induces low density lipoprotein (LDL) receptor expression (6-8-fold) in a sterol-sensitive manner in HepG2 cells. Consistent with this finding, selective activation of the p38(MAPK) signaling pathway by expression of MKK6b(E), a constitutive activator of p38(MAPK), significantly reduced LDL receptor promoter activity. Expression of the p38(MAPK) alpha-isoform had a similar effect, whereas expression of the p38(MAPK) betaII-isoform had no significant effect on LDL receptor promoter activity. SB202190-dependent increase in LDL receptor expression was accompanied by induction of p42/44(MAPK), and inhibition of this pathway completely prevented SB202190-induced LDL receptor expression, suggesting that p38(MAPK) negatively regulates the p42/44(MAPK) cascade and the responses mediated by this kinase. Cross-talk between these kinases appears to be one-way because modulation of p42/44(MAPK) activity did not affect p38(MAPK) activation by a variety of stress inducers. Taken together, these findings reveal a hitherto unrecognized one-way communication that exists between p38(MAPK) and p42/44(MAPK) and provide the first evidence that through the p42/44(MAPK) signaling cascade, the p38(MAPK) alpha-isoform negatively regulates LDL receptor expression, thus representing a novel mechanism of fine tuning cellular levels of cholesterol in response to a diverse set of environmental cues.