GSK3-SCF(FBXW7) targets JunB for degradation in G2 to preserve chromatid cohesion before anaphase.
JunB, an activator protein-1 (AP-1) transcription factor component, acts either as a tumor suppressor or as an oncogene depending on the cell context. In particular, JunB is strongly upregulated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) where it enhances cell proliferation. Although its overexpression is linked to lymphomagenesis, the mechanisms whereby JunB promotes neoplastic growth are still largely obscure. Here, we show that JunB undergoes coordinated phosphorylation-dependent ubiquitylation during the G2 phase of the cell cycle. We characterized a critical consensus phospho-degron that controls JunB turnover and identified GSK3 and SCF(FBXW7) as, respectively, the kinase and the E3 ubiquitin ligase responsible for its degradation in G2. Pharmacological or genetic inactivation of the GSK3-FBXW7-JunB axis induced accumulation of JunB in G2/M and entailed transcriptional repression of the DNA helicase DDX11, leading to premature sister chromatid separation. This abnormal phenotype due to dysregulation of the GSK3β/JunB/DDX11 pathway is phenocopied in ALK-positive ALCL. Thus, our results reveal a novel mechanism by which mitosis progression and chromatid cohesion are regulated through GSK3/SCF(FBXW7)-mediated proteolysis of JunB, and suggest that JunB proteolysis in G2 is an essential step in maintaining genetic fidelity during mitosis.
Cytomics Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
B
B
Pérez-Benavente
J L
JL
García
M S
MS
Rodríguez
A
A
Pineda-Lucena
M
M
Piechaczyk
J
J
Font de Mora
R
R
Farràs
D000705:Anaphase; D000077548:Anaplastic Lymphoma Kinase; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002842:Chromatids / Q000378:metabolism*; D020090:Chromosome Segregation; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D015536:Down-Regulation; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D059565:G2 Phase Cell Cycle Checkpoints; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D021122:Protein Subunits / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C581727:JunB protein, human; D021122:Protein Subunits; D012097:Repressor Proteins; D014157:Transcription Factors; C432966:ITCH protein, human; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D004265:DNA Helicases; C101830:DDX11 protein, human; D053487:DEAD-box RNA Helicases