Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester.

Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. Research Abstract Details 

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Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. Abstract Text:

Shuzo Ikuta,Hironori Edamatsu,Mingzhen Li,Lizhi Hu,Tohru Kataoka,Shuzo Ikuta,Hironori Edamatsu,Mingzhen Li,Lizhi Hu,Tohru Kataoka,

In two-stage skin chemical carcinogenesis, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) acts as a promoter essential for clonal expansion of the initiated cells carrying the activated ras oncogenes. Although protein kinase C (PKC) isozymes are the main targets of TPA, their role in tumor promotion remains controversial. We previously reported that mice lacking a Ras/Rap effector phospholipase C epsilon (PLC epsilon(-/-) mice) exhibited marked resistance to tumor formation in the two-stage skin carcinogenesis. PLC epsilon(-/-) mice also failed to exhibit basal layer cell proliferation and epidermal hyperplasia induced by TPA, suggesting a role of PLC epsilon in tumor promotion. Here, we show that PLC epsilon(-/-) mice exhibit resistance to TPA-induced skin inflammation as assessed by reduction in edema, granulocyte infiltration, and expression of a proinflammatory cytokine, interleukin-1 alpha (IL-1 alpha). On the other hand, the proliferative potentials of keratinocytes or dermal fibroblasts in culture remain unaffected by the PLC epsilon background, suggesting that the PLC epsilon's role in tumor promotion may be ascribed to augmentation of inflammatory responses. In dermal fibroblast primary culture, TPA can induce activation of the PLC epsilon lipase activity, which leads to the induction of IL-1 alpha expression. Experiments using small interfering RNA-mediated knockdown indicate that this activation is mediated by Rap1, which is activated by a TPA-responsive guanine nucleotide exchange factor RasGRP3. Moreover, TPA-induced activation of Rap1 and PLC epsilon is inhibited by a PKC inhibitor GF109203X, indicating a crucial role of PKC in signaling from TPA to PLC epsilon. These results imply that two TPA targets, RasGRP3 and PKC, are involved in TPA-induced inflammation through PLC epsilon activation, leading to tumor promotion.

Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. Publishing Authors By Initials

S Ikuta,H Edamatsu,M Li,L Hu,T Kataoka,S Ikuta,H Edamatsu,M Li,L Hu,T Kataoka,

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Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cancer research

VOLUME: 68

Page Numbers: 64-72

Journal Abbreviation: Cancer Res.

ISSN: 1538-7445

DAY: 1

MONTH: Jan

YEAR: 2008

Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. Information

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LANGUAGE: eng

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AFFILIATION: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.

Country: United States

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MEDLINETA: Cancer Res

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