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Involvement of the p38 mitogen-activated protein kinase alpha, beta, and gamma isoforms in myogenic differentiation.

ABSTRACT: We and others previously showed that p38 mitogen-activated protein kinase is indispensable for myogenic differentiation. However, it is less clear which of the four p38 isoforms in the mouse genome participates in this process. Using C2C12 myogenic cells as a model, we showed here that p38alpha, beta, and gamma are expressed with distinct expression patterns during differentiation. Knockdown of any of them by small interfering RNA inhibits myogenic differentiation, which suggests that the functions of the three p38 isoforms are not completely redundant. To further elucidate the unique role of each p38 isoform in myogenic differentiation, we individually knocked down one p38 isoform at a time in C2C12 cells, and we compared the whole-genome gene expression profiles by microarrays. We found that some genes are coregulated by all three p38 isoforms, whereas others are uniquely regulated by one particular p38 isoform. Furthermore, several novel p38 target genes (i.e., E2F2, cyclin D3, and WISP1) are found to be required for myogenin expression, which provides a molecular basis to explain why different p38 isoforms are required for myogenic differentiation.

SUBMITTER: Wang H

PROVIDER: S-EPMC2291428 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Involvement of the p38 mitogen-activated protein kinase alpha, beta, and gamma isoforms in myogenic differentiation.

Wang Haixia H Xu Qing Q Xiao Fang F Jiang Yong Y Wu Zhenguo Z Wu Zhenguo Z

Molecular biology of the cell 20080206 4

We and others previously showed that p38 mitogen-activated protein kinase is indispensable for myogenic differentiation. However, it is less clear which of the four p38 isoforms in the mouse genome participates in this process. Using C2C12 myogenic cells as a model, we showed here that p38alpha, beta, and gamma are expressed with distinct expression patterns during differentiation. Knockdown of any of them by small interfering RNA inhibits myogenic differentiation, which suggests that the functi ...[more]

PMID: 18256287

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Project description:Skin cancer is one of the most common cancers worldwide. Melanoma accounts for ~5% of skin cancers but causes the large majority of skin cancer?related deaths. Recent discoveries have shown that the mitogen?activated protein kinase (MAPK) signaling pathway is critical for melanoma development and progression. Many oncogenic pathways that cause melanoma tumorigenesis have been identified, most of which are due to RAF/MEK/ERK (MAPK) pathway activation. However, the precise role of p38 remains unclear. Using specific short hairpin (sh) RNA to silence p38? and p38?, the present findings demonstrated that p38? was a crucial factor in regulating cell migration in the A375 melanoma cell line. Silencing p38? downregulated the expression of epithelial?mesenchymal transition markers, such as matrix metallopeptidase (MMP) 2, MMP9, twist family bHLH transcription factor 1, snail family transcriptional repressor 1 and vimentin, while mesenchymal?epithelial transition markers, such as E?cadherin, were upregulated. Of note, the results also demonstrated that p38? silencing impaired vascular endothelial growth factor expression, which regulates tumor angiogenesis. Furthermore, p38? knockdown inhibited cell proliferation in melanoma cells. In addition, silencing p38? induced senescence?like features, but not cell cycle arrest. Expression of the senescence markers p16, p21, p53 and ??galactosidase was upregulated, and an increase in the number of senescence?associated ??galactosidase?positive cells was observed in a p38? knockdown stable clone. However, no significant difference was found between control and p38? stable knockdown cells. Taken together, the present results suggested that p38? knockdown impaired migration and proliferation, and increased senescence, in A375 melanoma cells. However, p38? may not be involved in melanoma tumorigenesis. Therefore, targeting p38? may be a valuable approach towards inhibiting tumor growth and metastasis in patients with melanoma.

Dataset Information

Involvement of the p38 mitogen-activated protein kinase alpha, beta, and gamma isoforms in myogenic differentiation.

Publications

Involvement of the p38 mitogen-activated protein kinase alpha, beta, and gamma isoforms in myogenic differentiation.

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