aPKCζ-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1.

Abstract

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.

• Authors: Alejandro M Chibly, Wen Yu Wong, Maricela Pier, Hongqiang Cheng, Yongxin Mu, Ju Chen, Sourav Ghosh, Kirsten H Limesand
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 6347 (04 20 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29679075 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Cell Cycle Proteins
• Phosphoproteins
• YAP-Signaling Proteins
• Yap1 protein, mouse
• Insulin-Like Growth Factor I
• protein kinase C zeta
• Protein Kinase C

Topics

• Adaptor Proteins, Signal Transducing (metabolism, physiology)
• Animals
• Cell Cycle Proteins
• Female
• Head and Neck Neoplasms (radiotherapy)
• Insulin-Like Growth Factor I (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Parotid Gland (radiation effects)
• Phosphoproteins (metabolism, physiology)
• Protein Kinase C (metabolism, physiology)
• Radiotherapy (adverse effects)
• Saliva (radiation effects)
• Salivary Glands (cytology, radiation effects)
• Stem Cells (cytology)
• Xerostomia (therapy)
• YAP-Signaling Proteins