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Proc Natl Acad Sci U S A. 2018 Aug 7;115(32):E7522-E7531. doi: 10.1073/pnas.1802422115. Epub 2018 Jul 23.

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

Author information

1
Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, 518060 Guangdong, China.
2
Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071 Hubei, China.
3
Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, 518060 Guangdong, China; dcarson@ucsd.edu delu@szu.edu.cn.
4
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.

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/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 activity. TPA further induced the phosphorylation of LRP6 at Thr1479 and Ser1490 and the formation of a CK1ε-LRP6-axin1 complex, leading to an increase in cytosolic β-catenin. Moreover, TPA increased the association of β-catenin with TCF4E in a CK1ε/δ-dependent way, resulting in the activation of Wnt target genes. Consistently, treatment with a selective CK1ε/δ inhibitor SR3029 suppressed TPA-induced skin tumor formation in vivo, probably through blocking Wnt/β-catenin signaling. Taken together, our study has identified a pathway by which TPA activates Wnt/β-catenin signaling.

KEYWORDS:

CK1; LRP6; TPA; Wnt/β-catenin signaling; two-stage skin chemical carcinogenesis

PMID:
30038030
PMCID:
PMC6094128
DOI:
10.1073/pnas.1802422115
[Indexed for MEDLINE]
Free PMC Article

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