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

Rajesh P. Singh, Punita Dhawan, Carmen Golden, Gurpreet S. Kapoor, Kamal D. Mehta

Research output: Contribution to journalArticle

148 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)19593-19600
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number28
DOIs
StatePublished - Jul 9 1999
Externally publishedYes

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LDL Receptors
Mitogen-Activated Protein Kinase 1
p38 Mitogen-Activated Protein Kinases
Chemical activation
Protein Isoforms
Phosphotransferases
Inhibition (Psychology)
Hep G2 Cells
Sterols
Cues
Tuning
Communication
Cholesterol
Modulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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. / Singh, Rajesh P.; Dhawan, Punita; Golden, Carmen; Kapoor, Gurpreet S.; Mehta, Kamal D.

In: Journal of Biological Chemistry, Vol. 274, No. 28, 09.07.1999, p. 19593-19600.

Research output: Contribution to journalArticle

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abstract = "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.",
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