Activating transcription factor 6 (ATF6) negatively regulates Polo-like kinase 4 expression via recruiting C/EBP beta to the upstream-promoter during ER stress

摘要

Polo-like kinase 4 (PLK4) is a member of the serine/threonine protein kinase family involved in cell-cycle regulation and cellular response to stresses. However, the alteration of PLK4 in response to endoplasmic reticulum (ER) stress has not been well described. In the present study, we focused on the regulation of PLK4 regulation in response to ER stress. PLK4 expression was dramatically reduced under ER stress induced by brefeldin A (BFA), tunicamycin (TM), or thapsigargin (TG) and down regulation of PLK4 expression was dependent on activating transcription factor 6 (ATF6) and CCAAT/enhancer-binding protein beta (C/EBP beta). Luciferase activity analysis of the truncated PLK4 promoter indicated that region from - 1343 to -1250 of the PLK4 promoter was sensitive to BFA or TG. Additionally, ChIP and ChIP Re-IP assays showed that ATF6 and C/EBP beta were assembled on the same region of Plk4 promoter. Notably, we identified one C/EBP beta responsive element at position -1284, to which ATF6 or C/EBP beta binding was enhanced by BFA or TG under in vitro and in vivo conditions. Finally, overexpression of PLK4 inhibits apoptosis and promotes cell proliferation in response to ER stress. In summary, these results demonstrated that ER stress plays a crucial role in PLK4 expression. ATF6 may upregulate DNA-binding affinities after BFA treatment, via recruiting C/EBP beta to the upstream promoter of PLK4. These findings may contribute to the understanding of the molecular mechanism of PLK4 regulation.