Elucidation of the in vivo function of the Ras/Rap effector phospholipase Cε

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(1) The skin of phospholipase Cε (PLCε) knockout mice exhibited great reduction in inflammatory responses accompanied by edema and in leukocyte infiltration induced by phorbor ester (TPA) treatment compared to that of wild-type mice. Concomitantly, reduced expression of proinflammatory cytokines such as interleukin-1α was observed in keratinocytes and dermal fibroblasts cultured from PLCε knockout mice upon TPA treatment. We also showed that PLCε is activated downstream of TPA, which is mediated by Rap1 activation via RasGRP3, a direct target of TPA. Furthermore, by employing various inflammation-inducing mouse model systems, such as an ulcerative colitis model using dextran sulfate, a contact dermatitis model using dinitrofluorobenzene as a hapten, and an ultraviolet radiation-induced dermatitis, we observed severe decrease in inflammatory responses. These results imply that PLCε plays a crucial and general role in inflammatory responses through induction of proinflammatory cytokines. … More (2) Great reduction in de novo intestinal tumor formation and subsequent malignant progression of Min mice, which carry a loss-of-function mutation in the anti-oncogene APC, was observed on the PLCε-knockout background compared to wild-type background. Taken together with our previous result showing that PLCε knockout mice are highly resistant to tumor formation and subsequent malignant progression in the two stage skin chemical carcinogenesis model, these results are quite interesting because they suggest a close link between inflammation and cancer promotion.(3) We generated PLCε transgenic mice, which overexpress PLCε specifically in skin keratinocytes, by using the Cre-loxP recombination system. Interestingly, these mice exhibited strong skin inflammation accompanied by prominent hyperkeratosis and elevated angiogenesis. The results described in 1-3 suggest that PLCε may make a good molecular target for the development of cancer-preventing drugs or anti-inflammatory drugs.(4) We analyzed molecular mechanisms whereby PLCε knockout mice exhibit defective semilunar valvulogenesis during embryonic period. We showed that PLCε is regulated by downstream signaling from heparin-binding epidermal growth factor-like growth factor (HB-EGF) receptor and inhibits proliferation of valvular precursor cells through inhibition of Smad1/5/8 phosphorylation induced by the bone morphogenetic protein (BMP) receptor stimulation. Less