Journal Article

MK2 regulates the early stages of skin tumor promotion

Claus Johansen, Christian Vestergaard, Knud Kragballe, George Kollias, Matthias Gaestel and Lars Iversen

in Carcinogenesis

Volume 30, issue 12, pages 2100-2108
Published in print December 2009 | ISSN: 0143-3334
Published online October 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp238
MK2 regulates the early stages of skin tumor promotion

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The association between inflammation and tumorigenesis is well recognized. Mitogen-activated protein kinase-activated protein kinase-2 (MK2) is known to play a pivotal role in inflammatory processes. Here, we studied the effect of MK2-deficiency and tumor necrosis factor (TNF)-α-deficiency on skin tumor development in mice using the two-stage chemical carcinogenesis model. We found that MK2−/− mice developed significantly fewer skin tumors compared with both TNF−/− and wild-type mice when induced by initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). The TPA-induced inflammatory response was reduced in both, TNF−/− mice and MK2−/− mice, but most pronounced in TNF−/− mice, indicating that a reduced inflammatory response was not the only explanation for the inhibited tumorigenesis seen in MK2−/− mice. Interestingly, increased numbers of apoptotic cells were detected in the epidermis of MK2−/− mice compared with TNF−/− and wild-type mice, suggesting an additional role of MK2 in the regulation of apoptosis. This was further supported by: (i) increased levels of the tumor suppressor protein p53 in MK2−/− mice after DMBA/TPA treatment compared with controls, (ii) reduced phosphorylation (activation) of the negative p53 regulator, murine double minute 2 in MK2/ mouse keratinocytes in vitro and (iii) a significant decrease in the DMBA/TPA induced apoptosis in cultured MK2−/− keratinocytes transfected with p53 small interfering RNA. Taken together, these findings demonstrate a dual role of MK2 in the early stages of tumor promotion through regulation of both the inflammatory response and apoptosis of DNA-damaged cells. These results also identify MK2 as a putative target for future skin carcinoma therapy.

Journal Article.  5895 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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