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
Affiliations
Stephanie L. Celano
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
Lisette P. Yco
College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
Matthew G. Kortus
Center for Cancer Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA
Abigail R. Solitro
Van Andel Institute Graduate School, Grand Rapids, MI 49503, USA
Hakan Gunaydin
Department of Modeling & Informatics, Merck & Co., Inc., Boston, MA 02115, USA
Mark Scott
Process Research & Development, Gilead Alberta ULC, Edmonton, AB T6S1A1, Canada
Edward Spooner
Department of Oncology, Merck & Co., Inc., Boston, MA 02115, USA
Ronan C. O'Hagan
Department of Oncology, Merck & Co., Inc., Boston, MA 02115, USA
Peter Fuller
Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA
Katie R. Martin
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
Stuart D. Shumway
Department of Oncology, Merck & Co., Inc., Boston, MA 02115, USA
Jeffrey P. MacKeigan
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; Corresponding author
Summary: 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. : Biological Sciences; Cell Biology; Functional Aspects of Cell Biology Subject Areas: Biological Sciences, Cell Biology, Functional Aspects of Cell Biology
