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Secreted Wnt6 mediates diabetes-associated centrosome amplification via its receptor FZD4.

He, Qin Ju; Wang, Pu; Liu, Qinqin; Wu, Qigui; Li, Yuan Fei; Wang, Jie; Lee, Shao Chin.
Artigo em Inglês | MEDLINE | ID: mdl-31618077
We have recently published that type 2 diabetes promotes cell centrosome amplification via up-regulation of ROCK1 and 14-3-3σ. The study further investigated the molecular mechanisms underlying the diabetes-associated centrosome amplification. We found that treatment of cells with high glucose, insulin and palmitic acid increased the intracellular and the extracellular protein levels of Wnt6 as well as the cellular level of ß-catenin. The treatment also activated ß-catenin and promoted its nuclear translocation. Treatment of cells with siRNA species for Wnt6, FZD4 or ß-catenin as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture medium could all attenuate the treatment-triggered centrosome amplification. Moreover, we showed that secreted Wnt6-FZD4-ß-catenin was the signaling pathway which was upstream of ROCK1 and 14-3-3σ. We also found that AGEs were also able to increase the cellular and extracellular levels of Wnt6, the cellular protein level of ß-catenin, and centrosome amplification. Treatment of the cells with siRNA species for Wnt6 or FZD4 as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture could all inhibit the AGEs-elicited centrosome amplification. In colon tissues from diabetic mice model, the protein levels of Wnt6 and 14-3-3σ were increased. In conclusion, our results showed that the pathophysiological factors in type 2 diabetes, including AGEs, were able to induce centrosome amplification. It is suggested that secreted Wnt6 binds to FZD4 to activate the canonical Wnt6 signaling pathway which is upstream of ROCK1 and 14-3-3σ, which is the cell signaling pathway underlying the diabetes-associated centrosome amplification.
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