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Tumor promoter TPA activates Wnt/?-catenin signaling in a casein kinase 1-dependent manner.

ABSTRACT: The tumor promoter 12-O-tetra-decanoylphorbol-13-acetate (TPA) has been defined by its ability to promote tumorigenesis on carcinogen-initiated mouse skin. Activation of Wnt/?-catenin signaling has a decisive role in mouse skin carcinogenesis, but it remains unclear how TPA activates Wnt/?-catenin signaling in mouse skin carcinogenesis. Here, we found that TPA could enhance Wnt/?-catenin signaling in a casein kinase 1 (CK1) ?/?-dependent manner. TPA stabilized CK1? and enhanced its kinase activity. TPA further induced the phosphorylation of LRP6 at Thr1479 and Ser1490 and the formation of a CK1?-LRP6-axin1 complex, leading to an increase in cytosolic ?-catenin. Moreover, TPA increased the association of ?-catenin with TCF4E in a CK1?/?-dependent way, resulting in the activation of Wnt target genes. Consistently, treatment with a selective CK1?/? inhibitor SR3029 suppressed TPA-induced skin tumor formation in vivo, probably through blocking Wnt/?-catenin signaling. Taken together, our study has identified a pathway by which TPA activates Wnt/?-catenin signaling.

SUBMITTER: Su Z

PROVIDER: S-EPMC6094128 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Tumor promoter TPA activates Wnt/β-catenin signaling in a casein kinase 1-dependent manner.

Su Zijie Z Song Jiaxing J Wang Zhongyuan Z Zhou Liang L Xia Yuqing Y Yu Shubin S Sun Qi Q Liu Shan-Shan SS Zhao Liang L Li Shiyue S Wei Lei L Carson Dennis A DA Lu Desheng D

Proceedings of the National Academy of Sciences of the United States of America 20180723 32

The tumor promoter 12-<i>O</i>-tetra-decanoylphorbol-13-acetate (TPA) has been defined by its ability to promote tumorigenesis on carcinogen-initiated mouse skin. Activation of Wnt/β-catenin signaling has a decisive role in mouse skin carcinogenesis, but it remains unclear how TPA activates Wnt/β-catenin signaling in mouse skin carcinogenesis. Here, we found that TPA could enhance Wnt/β-catenin signaling in a casein kinase 1 (CK1) ε/δ-dependent manner. TPA stabilized CK1ε and enhanced its kinase ...[more]

PMID: 30038030

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Project description:In vertebrates, the conserved Wnt signalling cascade promotes the stabilization and nuclear accumulation of beta-catenin, which then associates with the lymphoid enhancer factor/T cell factor proteins (LEF/TCFs) to activate target genes. Wnt/beta -catenin signalling is essential for T cell development and differentiation. Here we show that special AT-rich binding protein 1 (SATB1), the T lineage-enriched chromatin organizer and global regulator, interacts with beta-catenin and recruits it to SATB1's genomic binding sites. Gene expression profiling revealed that the genes repressed by SATB1 are upregulated upon Wnt signalling. Competition between SATB1 and TCF affects the transcription of TCF-regulated genes upon beta-catenin signalling. GATA-3 is a T helper type 2 (T(H)2) specific transcription factor that regulates production of T(H)2 cytokines and functions as T(H)2 lineage determinant. SATB1 positively regulated GATA-3 and siRNA-mediated knockdown of SATB1 downregulated GATA-3 expression in differentiating human CD4(+) T cells, suggesting that SATB1 influences T(H)2 lineage commitment by reprogramming gene expression. In the presence of Dickkopf 1 (Dkk1), an inhibitor of Wnt signalling, GATA-3 is downregulated and the expression of signature T(H)2 cytokines such as IL-4, IL-10, and IL-13 is reduced, indicating that Wnt signalling is essential for T(H)2 differentiation. Knockdown of beta-catenin also produced similar results, confirming the role of Wnt/beta-catenin signalling in T(H)2 differentiation. Furthermore, chromatin immunoprecipitation analysis revealed that SATB1 recruits beta-catenin and p300 acetyltransferase on GATA-3 promoter in differentiating T(H)2 cells in a Wnt-dependent manner. SATB1 coordinates T(H)2 lineage commitment by reprogramming gene expression. The SATB1:beta-catenin complex activates a number of SATB1 regulated genes, and hence this study has potential to find novel Wnt responsive genes. These results demonstrate that SATB1 orchestrates T(H)2 lineage commitment by mediating Wnt/beta-catenin signalling. This report identifies a new global transcription factor involved in beta-catenin signalling that may play a major role in dictating the functional outcomes of this signalling pathway during development, differentiation, and tumorigenesis.

Dataset Information

Tumor promoter TPA activates Wnt/?-catenin signaling in a casein kinase 1-dependent manner.

Publications

Tumor promoter TPA activates Wnt/β-catenin signaling in a casein kinase 1-dependent manner.

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