One-way Cross-talk between p38MAPK and p42/44MAPK

• Published in: The Journal of biological chemistry Vol. 274; no. 28; pp. 19593 - 19600
• Main Authors: Singh, Rajesh P., Dhawan, Punita, Golden, Carmen, Kapoor, Gurpreet S., Mehta, Kamal D.
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 01.07.1999
• ISSN: 0021-9258; 1083-351X
• 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 α-isoform had a similar effect, whereas expression of the p38 MAPK βII-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 α-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.