1. Yap activation in irradiated parotid salivary glands is regulated by ROCK activity
- Author
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Kirsten H. Limesand, Wen Yu Wong, and Kristy E. Gilman
- Subjects
medicine.medical_treatment ,Cancer Treatment ,Acinar Cells ,Biochemistry ,Salivary Glands ,Mice ,Medicine and Health Sciences ,Morphogenesis ,Parotid Gland ,Insulin-Like Growth Factor I ,Post-Translational Modification ,Phosphorylation ,Cells, Cultured ,Cytoskeleton ,education.field_of_study ,rho-Associated Kinases ,Multidisciplinary ,Stem Cells ,Dipeptides ,Oncology ,Head and Neck Neoplasms ,Medicine ,Anatomy ,Cellular Structures and Organelles ,Research Article ,Clinical Oncology ,Science ,Population ,Immunoblotting ,DNA transcription ,Radiation Therapy ,Molecular Probe Techniques ,Biology ,Dental Caries ,Research and Analysis Methods ,Xerostomia ,Exocrine Glands ,Major Salivary Gland ,medicine ,Genetics ,Animals ,Regeneration ,Progenitor cell ,education ,Protein kinase A ,Radiation Injuries ,Molecular Biology Techniques ,Molecular Biology ,Growth factor ,Regeneration (biology) ,Biology and Life Sciences ,Proteins ,Cell Biology ,Radiation therapy ,Cancer research ,Gene expression ,Clinical Medicine ,Digestive System ,Organism Development ,Developmental Biology - Abstract
Radiotherapy plays a major role in the curative treatment of head and neck cancer, either as a single modality therapy, or in combination with surgery or chemotherapy, or both. Despite advances to limit radiation-induced side-effects, the major salivary glands are often affected. This frequently leads to hyposalivation which causes an increased risk for xerostomia, dental caries, mucositis, and malnutrition culminating in a significant impact on patients’ quality of life. Previous research demonstrated that loss of salivary function is associated with a decrease in polarity regulators and an increase in nuclear Yap localization in a putative stem and progenitor cell (SPC) population. Yap activation has been shown to be essential for regeneration in intestinal injury models; however, the highest levels of nuclear Yap are observed in irradiated salivary SPCs that do not regenerate the gland. Thus, elucidating the inputs that regulate nuclear Yap localization and determining the role that Yap plays within the entire tissue following radiation damage and during regeneration is critical. In this study, we demonstrate that radiation treatment increases nuclear Yap localization in acinar cells and Yap-regulated genes in parotid salivary tissues. Conversely, administration of insulin-like growth factor 1 (IGF1), known to restore salivary function in mouse models, reduces nuclear Yap localization and Yap transcriptional targets to levels similar to untreated tissues. Activation of Rho-associated protein kinase (ROCK) using calpeptin results in increased Yap-regulated genes in primary acinar cells while inhibition of ROCK activity (Y-27632) leads to decreased Yap transcriptional targets. These results suggest that Yap activity is dependent on ROCK activity and provides new mechanistic insights into the regulation of radiation-induced hyposalivation.
- Published
- 2020