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aPKCζ-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1.
Scientific Reports ( IF 4.6 ) Pub Date : 2018-04-20 , DOI: 10.1038/s41598-018-24678-4
Alejandro M Chibly 1 , Wen Yu Wong 1 , Maricela Pier 2 , Hongqiang Cheng 3 , Yongxin Mu 3 , Ju Chen 3 , Sourav Ghosh 4 , Kirsten H Limesand 1, 2
Affiliation  

Xerostomia and salivary hypofunction often result as a consequence of radiation therapy for head and neck cancers, which are diagnosed in roughly 60,000 individuals every year in the U.S. Due to the lack of effective treatments for radiation-induced salivary hypofunction, stem cell-based therapies have been suggested to regenerate the irradiated salivary glands. Pharmacologically, restoration of salivary gland function has been accomplished in mice by administering IGF-1 shortly after radiation treatment, but it is not known if salivary stem and progenitor cells play a role. We show that radiation inactivates aPKCζ and promotes nuclear redistribution of Yap in a population of label-retaining cells in the acinar compartment of the parotid gland (PG)- which comprises a heterogeneous pool of salivary progenitors. Administration of IGF-1 post-radiation maintains activation of aPKCζ and partially rescues Yap's cellular localization in label retaining cells, while restoring salivary function. Finally, IGF-1 fails to restore saliva production in mice lacking aPKCζ, demonstrating the importance of the kinase as a potential therapeutic target.

中文翻译:

aPKCζ依赖的Yap抑制对于用IGF-1辐射的唾液腺的功能恢复是必要的。

口干症和唾液功能低下通常是由于头颈癌的放射疗法导致的,在美国每年大约有60,000个人被诊断出头颈癌。由于缺乏有效的放射线诱发的唾液功能低下的疗法,基于干细胞的疗法有已建议再生经辐射的唾液腺。在药理上,通过在放射治疗后不久施用IGF-1,已在小鼠中实现了唾液腺功能的恢复,但是尚不清楚唾液干细胞和祖细胞是否发挥作用。我们显示辐射使aPKCζ失活,并促进腮腺(PG)的腺泡区室中的标签保留细胞群体中Yap的核再分布,后者包括唾液祖细胞的异质性池。放射后施用IGF-1可以维持aPKCζ的活化,并部分挽救Yap在标签保留细胞中的细胞定位,同时恢复唾液功能。最后,IGF-1无法在缺乏aPKCζ的小鼠中恢复唾液生成,这表明该激酶作为潜在治疗靶标的重要性。
更新日期:2018-04-20
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