Casein kinase II activates Bik to induce death of hyperplastic mucous cells in a cell cycle‐dependent manner. Issue 2 (6th November 2021)

• Record Type: Journal Article
• Authors: Mebratu, Yohannes A.; Imani, Jewel; Jones, Jane T.; Tesfaigzi, Yohannes
• Is Part Of: Journal of cellular physiology. Volume 237:Issue 2(2022)
• Page Start: 1561
• Page End: 1572
• Publication Date: 2021-11-06
• Subjects: airway epithelial cells -- apoptosis -- cell cycle -- house dust mite allergen -- hyperplastic mucous cells -- kinase -- phosphorylation -- resolution; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30630
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Extensive inflammation causes epithelial cell hyperplasia in the airways and Bcl‐2‐interacting killer (Bik) reduces epithelial cell and mucous cell hyperplasia without affecting resting cells to restore homeostasis. These observations suggest that Bik induces apoptosis in a cell cycle‐specific manner, but the mechanisms are not understood. Mice were exposed to an allergen for 3, 14, or 30 days and Bik expression was induced in airway epithelia of transgenic mice. Bik reduced epithelial and mucous cell hyperplasia when mice were exposed to an allergen for 3 or 14 days, but not when exposure lasted for 30 days, and Ki67‐positivity was reduced. In culture, Bik expression killed proliferating cells but not quiescent cells. To capture the stage of the cell cycle when Bik induces cell death, airway cells that express fluorescent ubiquitin cell cycle indicators were generated that fluoresce red or green during the G0/G1 and S/G2/M phases of the cells cycle, respectively. Regardless of the cell cycle stage, Bik expression eliminated green‐fluorescent cells. Also, Bik, when tagged with a blue‐fluorescent protein, was only detected in green cells. Bik phosphorylation mutants at threonine 33 or serine 35 demonstrated that phosphorylation activated Bik to induce death even in quiescent cells. Immunoprecipitation and proteomic approaches identified casein kinase IIα to be responsible for phosphorylating and activating Bik to kill cells in S/G2/M. As casein kinase 2 alpha (CKIIα) is expressed only during the G2/M phase, we conclude that Bik activation in airway epithelial cells selectively targets hyperplastic epithelial cells, while leaving resting airway cells unaffected.