TY - JOUR
T1 - Cholesterol depletion upregulates involucrin expression in epidermal keratinocytes through activation of p38
AU - Jans, Ralph
AU - Atanasova, Ganka
AU - Jadot, Michel
AU - Poumay, Yves
PY - 2004/9/1
Y1 - 2004/9/1
N2 - Cholesterol has been recently suggested to regulate the early steps of keratinocyte differentiation through lipid rafts. In many cell types, depletion of cholesterol activates signaling proteins like epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), or extracellular signal-regulated kinase (ERK) known to affect cell differentiation. In this study, we explored the effects of cholesterol depletion on the phenotype of cultured keratinocytes, using a treatment with methyl-β-cyclodextrin (MβCD) to extract cholesterol and a treatment with lovastatin to inhibit cholesterol neosynthesis. Analysis of the expression of differentiation marker genes in early differentiating confluent cultures reveals that cholesterol depletion induces downregulation of keratin 14 (K14) and keratin 10 (K10) and upregulation of involucrin. MβCD treatment induces phosphorylation of EGFR, HER2, and ERK, but not KER3. Inhibition of EGFR with PD153035 impairs the MβCD-induced phosphorylation of EGFR, HER2, and ERK, but does not impair the alteration of K14, K10, or involucrin gene expression, indicating that other signaling proteins regulate this phenomenon. p38 has been suggested to regulate the expression of involucrin during keratinocyte differentiation. We found that MβCD treatment induces a prolonged phosphorylation of p38 in general and p38α in particular. An inhibition of p38 with PD169316 impairs the upregulation of involucrin mRNAs by a treatment with MβCD, but not by a p38δ-activating TPA treatment, which might suggest that cholesterol depletion alters involucrin gene expression through activation of p38α/β.
AB - Cholesterol has been recently suggested to regulate the early steps of keratinocyte differentiation through lipid rafts. In many cell types, depletion of cholesterol activates signaling proteins like epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), or extracellular signal-regulated kinase (ERK) known to affect cell differentiation. In this study, we explored the effects of cholesterol depletion on the phenotype of cultured keratinocytes, using a treatment with methyl-β-cyclodextrin (MβCD) to extract cholesterol and a treatment with lovastatin to inhibit cholesterol neosynthesis. Analysis of the expression of differentiation marker genes in early differentiating confluent cultures reveals that cholesterol depletion induces downregulation of keratin 14 (K14) and keratin 10 (K10) and upregulation of involucrin. MβCD treatment induces phosphorylation of EGFR, HER2, and ERK, but not KER3. Inhibition of EGFR with PD153035 impairs the MβCD-induced phosphorylation of EGFR, HER2, and ERK, but does not impair the alteration of K14, K10, or involucrin gene expression, indicating that other signaling proteins regulate this phenomenon. p38 has been suggested to regulate the expression of involucrin during keratinocyte differentiation. We found that MβCD treatment induces a prolonged phosphorylation of p38 in general and p38α in particular. An inhibition of p38 with PD169316 impairs the upregulation of involucrin mRNAs by a treatment with MβCD, but not by a p38δ-activating TPA treatment, which might suggest that cholesterol depletion alters involucrin gene expression through activation of p38α/β.
KW - Cholesterol
KW - Gene expression
KW - Keratinocytes
KW - MAPK
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=4143139930&partnerID=8YFLogxK
U2 - 10.1111/j.0022-202X.2004.23221.x
DO - 10.1111/j.0022-202X.2004.23221.x
M3 - Article
C2 - 15304097
AN - SCOPUS:4143139930
SN - 0022-202X
VL - 123
SP - 564
EP - 573
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 3
ER -