title: SUMO1 modification stabilizes CDK6 protein and drives the cell cycle and glioblastoma progression.
abstract: Ubiquitination governs oscillation of cyclin-dependent kinase (CDK) activity through a periodic degradation of cyclins for orderly cell cycle progression; however, the mechanism that maintains the constant CDK protein levels throughout the cell cycle remains unclear. Here we show that CDK6 is modified by small ubiquitin-like modifier-1 (SUMO1) in glioblastoma, and that CDK6 SUMOylation stabilizes the protein and drives the cell cycle for the cancer development and progression. CDK6 is also a substrate of ubiquitin; however, CDK6 SUMOylation at Lys 216 blocks its ubiquitination at Lys 147 and inhibits the ubiquitin-mediated CDK6 degradation. Throughout the cell cycle, CDK1 phosphorylates the SUMO-specific enzyme, ubiquitin-conjugating enzyme9 (UBC9) that in turn mediates CDK6 SUMOylation during mitosis; CDK6 remains SUMOylated in G1 phase and drives the cell cycle through G1/S transition. Thus, SUMO1-CDK6 conjugation constitutes a mechanism of cell cycle control and inhibition of this SUMOylation pathway may provide a strategy for treatment of glioblastoma.
authors: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4.
authors: Anita C
authors: AC
authors: Bellail
authors: Department of Neurosurgery, Emory University School of Medicine, 1365B Clifton Road, Atlanta, Georgia 30322, USA.
authors: Jeffrey J
authors: JJ
authors: Olson
authors: Department of Pathology, Montreal Neurological Institute & Hospital, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4.
authors: Chunhai
authors: C
authors: Hao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D055550:Protein Stability; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D025842:SUMO-1 Protein; D025801:Ubiquitin; D016203:CDC2 Protein Kinase; D051361:Cyclin-Dependent Kinase 6