Identification of Kinases Responsible for p53-Dependent Autophagy
| Autor: | Mark E. Scott, Matthew G. Kortus, Edward Spooner, Ronan C. O'Hagan, Lisette P. Yco, Peter Fuller, Katie R. Martin, Stephanie L. Celano, Jeffrey P. MacKeigan, Stuart D. Shumway, Abigail R. Solitro, Hakan Gunaydin |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
DNA damage 02 engineering and technology CDC42 Biology Myotonic dystrophy Article 03 medical and health sciences Downregulation and upregulation medicine lcsh:Science Multidisciplinary Functional Aspects of Cell Biology Effector Kinase Autophagy Cancer Cell Biology Biological Sciences 021001 nanoscience & nanotechnology medicine.disease 3. Good health Cell biology 030104 developmental biology lcsh:Q 0210 nano-technology |
| Zdroj: | iScience iScience, Vol 15, Iss, Pp 109-118 (2019) |
| ISSN: | 2589-0042 |
| Popis: | 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. Graphical Abstract Highlights • HDM2 inhibitors stabilize and activate p53 leading to robust autophagy induction • RNAi screen uncovers kinases involved in p53-dependent autophagy • ULK1 and the actin cytoskeleton kinase MRCKα mediate p53-induced autophagy Biological Sciences; Cell Biology; Functional Aspects of Cell Biology |
| Databáze: | OpenAIRE |
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