p38δ mitogen-activated protein kinase regulates skin homeostasis and tumorigenesis

Efimova, Tatiana

doi:10.4161/cc.9.3.10541

Cited by 14 publications

(14 citation statements)

References 85 publications

(165 reference statements)

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“…In addition, this NSAID has also been found to induce apoptosis thus providing a basis for the decrease in tumor volume. These effects appear to be regulated through diminution of the MAPK cascade, which has been implicated in the regulation of apoptosis as well as inflammation (18-20). Consistently, exisulind-induced apoptosis in human colon cancer cells has been shown to involve the inhibition of ERK1/2 (21, 22).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Donor Exisulind Is an Effective Inhibitor of Murine Photocarcinogenesis^†

Singh

Chaudhary

Kapur

et al. 2012

Photochem & Photobiology

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NO-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) have been shown to have anti-inflammatory, anti-proliferative and apoptosis-inducing effects in tumor cells. Here we have investigated the effects of NO-exisulind on the growth of UVB-induced skin tumor development in a murine model. We found that the topical treatment with NO-exisulind significantly reduced UVB-induced tumors in SKH-1 hairless mice. The tumors/tumor bearing mouse, the number of tumors/mouse and tumor volume/mouse decreased significantly (p<0.05) as compared to vehicle-treated and UVB-irradiated positive controls. Consistently, NO-exisulind-treated animals showed reduced expression of proliferation markers such as PCNA and cyclin D1. These mice also manifested increased expression of pro-apoptotic Bax and decreased expression of anti-apoptotic Bcl2 with an increase in the number of TUNEL-positive cells in tumors. We also investigated whether NO-exisulind-treated tumors are less invasive and progress less efficiently from benign to malignant carcinomas. For this, tumors were stained for various epithelial-mesenchymal transition (EMT) markers. NO-exisulind decreased the expression of mesenchymal markers such as Fibronectin, N-cadherin, SNAI, Slug and Twist and enhanced the epithelial marker E-cadherin. Similarly, UVB-induced phosphorylation of Erk1/2 and p38 was decreased in NO-exisulind-treated animals. These data suggest that NO-exisulind reduces tumor growth and inhibits tumor progression by blocking proliferation, inducing apoptosis and reducing EMT.

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Section: Discussionmentioning

confidence: 99%

Nitric Oxide Donor Exisulind Is an Effective Inhibitor of Murine Photocarcinogenesis^†

Singh

Chaudhary

Kapur

et al. 2012

Photochem & Photobiology

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“…It is known that p38 is one of the critical components within the downstream signaling pathways of different tyrosine kinase receptors, which are associated with skin development and disorders, including FGFR, EGFR, and IGF1 receptor (IGF1R) (70). Also, p38 signaling is involved in skin homeostasis or epidermal differentiation (71) and plays an important role in osteoblast differentiation (72,73). Activation of the p38 pathway has been associated with craniosynostosis in Apert syndrome mice with the FGFR2 P253R mutation (49).…”

Section: Discussionmentioning

confidence: 99%

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

Wang¹,

Zhou²,

Oberoi³

et al. 2012

J. Clin. Invest.

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Beare-Stevenson cutis gyrata syndrome (BSS) is a human genetic disorder characterized by skin and skull abnormalities. BSS is caused by mutations in the FGF receptor 2 (FGFR2), but the molecular mechanisms that induce skin and skull abnormalities are unclear. We developed a mouse model of BSS harboring a FGFR2 Y394C mutation and identified p38 MAPK as an important signaling pathway mediating these abnormalities. Fgfr2 +/Y394C mice exhibited epidermal hyperplasia and premature closure of cranial sutures (craniosynostosis) due to abnormal cell proliferation and differentiation. We found ligand-independent phosphorylation of FGFR2 and activation of p38 signaling in mutant skin and calvarial tissues. Treating Fgfr2 +/Y394C mice with a p38 kinase inhibitor attenuated skin abnormalities by reversing cell proliferation and differentiation to near normal levels. This study reveals the pleiotropic effects of the FGFR2 Y394C mutation evidenced by cutis gyrata, acanthosis nigricans, and craniosynostosis and provides a useful model for investigating the molecular mechanisms of skin and skull development. The demonstration of a pathogenic role for p38 activation may lead to the development of therapeutic strategies for BSS and related conditions, such as acanthosis nigricans or craniosynostosis.

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“…37,38 Of note, there are four p38 MAPKs, p38α, p38β, p38γ and p38δ, displaying distinct and/or functions. [39][40][41][42][43] Interestingly, the MAPKs are involved in a negative feedback loop, shown to regulate the process of tolerization by blocking LPS-induced MAPK and NFκB signaling cascades in monocytes. 27 Akt1-deficient macrophages demonstrate enhanced responsiveness to endotoxins, and Akt1-deficient mice do not exhibit LPS tolerance in vivo.…”

Section: The Inflammatory Response To Tissue Damagementioning

confidence: 99%

MKP-1 coordinates ordered macrophage-phenotype transitions essential for stem cell-dependent tissue repair

Perdiguero

Kharraz²,

Serrano³

et al. 2012

Cell Cycle

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p38δ mitogen-activated protein kinase regulates skin homeostasis and tumorigenesis

Cited by 14 publications

References 85 publications

Nitric Oxide Donor Exisulind Is an Effective Inhibitor of Murine Photocarcinogenesis^†

Nitric Oxide Donor Exisulind Is an Effective Inhibitor of Murine Photocarcinogenesis^†

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

MKP-1 coordinates ordered macrophage-phenotype transitions essential for stem cell-dependent tissue repair

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p38δ mitogen-activated protein kinase regulates skin homeostasis and tumorigenesis

Cited by 14 publications

References 85 publications

Nitric Oxide Donor Exisulind Is an Effective Inhibitor of Murine Photocarcinogenesis†

Nitric Oxide Donor Exisulind Is an Effective Inhibitor of Murine Photocarcinogenesis†

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

MKP-1 coordinates ordered macrophage-phenotype transitions essential for stem cell-dependent tissue repair

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Nitric Oxide Donor Exisulind Is an Effective Inhibitor of Murine Photocarcinogenesis^†

Nitric Oxide Donor Exisulind Is an Effective Inhibitor of Murine Photocarcinogenesis^†