p38 Mitogen-Activated Protein Kinases on the Body Surface – A Function for p38δ

Self Cite

Background: MAPK signaling is an important mechanism controlling keratinocyte differentiation. Results: PRMT5 and p38␦ interact as part of a multiprotein signaling complex, and PRMT5 and p38␦ produce opposing actions in regulating differentiation. Conclusion: PRMT5 modulates p38␦ MAPK kinase phosphorylation and signaling. Significance: This is a novel mechanism that links p38␦ MAPK signaling and PRMT5 signaling.

Section: Prmt5-dependent Covalent Modification Of Proteins In P38␦ Comentioning

confidence: 74%

“…Three p38 isoforms, p38␣, p38␤, and p38␦, are expressed in keratinocytes (5,8). Among these, p38␦ has a key role as a positive regulator of keratinocyte differentiation (7). p38␦ mediates the response to differentiating agents including phorbol ester, calcium, okadaic acid, and green tea polyphenol (7,10 -15).…”

mentioning

confidence: 99%

Protein Arginine Methyltransferase 5 (PRMT5) Signaling Suppresses Protein Kinase Cδ- and p38δ-dependent Signaling and Keratinocyte Differentiation

Kanade

Eckert

2012

Self Cite

“…Unexpectedly, we found that inhibition of the JNK, p38 MAPK, PKC␦/, and Notch signal pathways affected HO-1 expression in keratinocytes. Considering the fact that the activation of these pathways is tightly connected to keratinocyte differentiation (47)(48)(49)(50), the strict regulation of HO-1 may be critical for keratinocyte differentiation. Because the expression of epidermal proteins is precisely regulated in a temporal and spatial manner, HO-1 expression must be synchronized to that of other proteins during differentiation.…”

Section: Discussionmentioning

confidence: 99%

Bach1-dependent and -independent Regulation of Heme Oxygenase-1 in Keratinocytes

Okada

Muto

Ogawa

et al. 2010

Bach1 is a member of the basic leucine zipper transcription factor family, and the Bach1/small Maf heterodimer specifically represses transcriptional activity directed by the Maf recognition element (MARE). Because Bach1 is a repressor of the oxidative stress response, we examined the function(s) of Bach1 in keratinocytes subjected to oxidative stress. Oxidative stress induced by H 2 O 2 led to an increase in MARE activity and expression of heme oxygenase-1 (HO-1), an inducible antioxidant defense enzyme. Bach1 depletion by small interfering RNAs or by deletion of Bach1 enhanced HO-1 expression in the absence of H 2 O 2 , indicating that Bach1 is a critical repressor of HO-1 in keratinocytes. Although Bach1-deficient or -reduced keratinocytes expressed higher levels of HO-1 than control cells in response to H 2 O 2 , Bach1 down-regulation did not attenuate the production of reactive oxygen species by H 2 O 2 . In contrast, Bach1 overexpression abolished HO-1 induction by H 2 O 2 , which led to increased reactive oxygen species accumulation. HO-1 was induced during keratinocyte differentiation, but MARE activity did not change during differentiation. Furthermore, Bach1 overexpression did not inhibit differentiation-associated induction of HO-1 expression, suggesting that HO-1 induction in differentiation is independent of Bach1. Thus, in response to oxidative stress, Bach1 regulates the oxidation state through the negative control of HO-1 expression prior to terminal keratinocyte differentiation. However, Bach1-mediated repression is negated during keratinocyte differentiation.Redox regulation is critical to cell survival, because cells cannot avoid endogenous reactive oxygen species (ROS) 2 that are generated as by-products of respiration (1). The skin is constantly exposed to harmful ROS that are generated by prooxidant agents in the environment, as well as by endogenous cellular oxidants. Thus, keratinocytes strongly and constitutively express ROS-detoxifying enzymes, including superoxide dismutase, catalase, glutathione peroxidase, and reductase, and contain substantial levels of the antioxidants tocopherol and ubiquinol (2, 3). Additionally, these cells possess an inducible defense system that includes heme oxygenase-1 (HO-1) (3-5). An imbalance between ROS and antioxidants can lead to the generation of high oxidant levels, which play a pivotal role in skin aging and disease (6).The transcription factor Bach1 is a repressor of the oxidative stress response in higher eukaryotes (7,8) and, together with its paralogue Bach2, constitutes a subfamily of the basic leucine zipper family of proteins. Bach1 forms heterodimers with the basic leucine zipper subfamily of small Maf proteins (i.e. MafF, MafG, and MafK), which bind the Maf recognition element (MARE) in the promoter regions of genes such as HO-1, NADP(H) quinone (oxido)reductase, and ␤-globin (7, 9, 10), and thereby repress transcription in the absence of oxidative stress. In the presence of oxidative stress, Bach1 is inactivated (11, 12), which allows tran...

“…This may be important, as p38 is known to enhance differentiation in surface epithelia and may contribute to cell death (52,53). As the four p38 isoforms are known to have differential effects (52,53), additional studies will be required to identify which form is modified by EGCG in our system. Moreover, as noted above, phosphorylation of only selected targets downstream of ERK1/2 is suppressed by EGCG.…”

Section: Egcg Perturbs Cell Cycle Regulators-as Shown Inmentioning

confidence: 99%

Epigallocatechin-3-gallate Inhibits Epidermal Growth Factor Receptor Signaling Pathway

Sah

Balasubramanian

Eckert

et al. 2004

Self Cite

238

143

Epidermal growth factor receptor (EGFR) activation is absolutely required for cervical cell proliferation. This suggests that EGFR-inhibitory agents may be of therapeutic value. In the present study, we investigated the effects of epigallocatechin-3-gallate (EGCG), a bioactive green tea polyphenol, on EGFR signaling in cervical cells. EGCG inhibits epidermal growth factor-dependent activation of EGFR, and EGFR-dependent activation of the mitogen-activated protein kinases ERK1/2. EGCG also inhibits EGFR-dependent AKT activity. The EGCGdependent reduction in ERK and AKT activity is associated with reduced phosphorylation of downstream substrates, including p90RSK, FKHR, and BAD. These changes are associated with increased p53, p21 WAF-1 , and p27 KIP-1 levels, reduced cyclin E level, and reduced CDK2 kinase activity. Consistent with these findings, flow cytometry and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling) staining revealed EGCG-dependent G 1 arrest. Moreover, sustained EGCG treatment caused apoptotic cell death. In addition to inhibiting EGFR, cell-free studies demonstrated that EGCG directly inhibits ERK1/2 and AKT, suggesting that EGCG acts simultaneously at multiple levels to inhibit EGF-dependent signaling. Importantly, the EGCG inhibition is selective, as EGCG does not effect the EGFR-dependent activation of JNK. These results suggest that EGCG acts to selectively inhibit multiple EGF-dependent kinases to inhibit cell proliferation.