Identification of Kinases Responsible for p53-Dependent Autophagy

Stephanie L Celano; Lisette P Yco; Matthew G Kortus; Abigail R Solitro; Hakan Gunaydin; Mark Scott; Edward Spooner; Ronan C O'Hagan; Peter Fuller; Katie R Martin; Stuart D Shumway; Jeffrey P MacKeigan

doi:10.1016/j.isci.2019.04.023

Identification of Kinases Responsible for p53-Dependent Autophagy

iScience. 2019 May 31:15:109-118. doi: 10.1016/j.isci.2019.04.023. Epub 2019 Apr 23.

Authors

Affiliations

¹ College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Center for Cancer Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
² College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
³ Center for Cancer Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁴ Van Andel Institute Graduate School, Grand Rapids, MI 49503, USA.
⁵ Department of Modeling & Informatics, Merck & Co., Inc., Boston, MA 02115, USA.
⁶ Process Research & Development, Gilead Alberta ULC, Edmonton, AB T6S1A1, Canada.
⁷ Department of Oncology, Merck & Co., Inc., Boston, MA 02115, USA.
⁸ Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA.
⁹ College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Center for Cancer Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Van Andel Institute Graduate School, Grand Rapids, MI 49503, USA. Electronic address: mackeig1@msu.edu.

Abstract

In cancer, autophagy is upregulated to promote cell survival and tumor growth during times of nutrient stress and can confer resistance to drug treatments. Several major signaling networks control autophagy induction, including the p53 tumor suppressor pathway. In response to DNA damage and other cellular stresses, p53 is stabilized and activated, while HDM2 binds to and ubiquitinates p53 for proteasome degradation. Thus blocking the HDM2-p53 interaction is a promising therapeutic strategy in cancer; however, the potential survival advantage conferred by autophagy induction may limit therapeutic efficacy. In this study, we leveraged an HDM2 inhibitor to identify kinases required for p53-dependent autophagy. Interestingly, we discovered that p53-dependent autophagy requires several kinases, including the myotonic dystrophy protein kinase-like alpha (MRCKα). MRCKα is a CDC42 effector reported to activate actin-myosin cytoskeletal reorganization. Overall, this study provides evidence linking MRCKα to autophagy and reveals additional insights into the role of kinases in p53-dependent autophagy.

Keywords: Biological Sciences; Cell Biology; Functional Aspects of Cell Biology.

Grants and funding

R01 CA197398/CA/NCI NIH HHS/United States