title: Regulation of TGF-β signaling, exit from the cell cycle, and cellular migration through cullin cross-regulation: SCF-FBXO11 turns off CRL4-Cdt2.
abstract: Deregulation of the cell cycle and genome instability are common features of cancer cells and various mechanisms exist to preserve the integrity of the genome and guard against cancer. The cullin 4-RING ubiquitin ligase (CRL4) with the substrate receptor Cdt2 (CRL4 (Cdt2)) promotes cell cycle progression and prevents genome instability through ubiquitylation and degradation of Cdt1, p21, and Set8 during S phase of the cell cycle and following DNA damage. Two recently published studies report the ubiquitin-dependent degradation of Cdt2 via the cullin 1-RING ubiquitin ligase (CRL1) in association with the substrate specificity factor and tumor suppressor FBXO11 (CRL1 (FBXO11)). The newly identified pathway restrains the activity of CRL4 (Cdt2) on p21 and Set8 and regulates cellular response to TGF-β, exit from the cell cycle and cellular migration. Here, we show that the CRL1 (FBXO11) also promotes the degradation of Cdt2 during an unperturbed cell cycle to promote efficient progression through S and G 2/M phases of the cell cycle. We discuss how this new method of regulating the abundance of Cdt2 participates in various cellular activities.
authors.affiliation: Department of Radiation Oncology; School of Medicine, University of Virginia, Charlottesville, VA, USA. tabbas@virginia.edu
authors.forename: Tarek
authors.initials: T
authors.lastname: Abbas
authors.forename: Mignon
authors.initials: M
authors.lastname: Keaton
authors.forename: Anindya
authors.initials: A
authors.lastname: Dutta
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D042822:Genomic Instability; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; C429530:DTL protein, human; D044783:F-Box Proteins; D009687:Nuclear Proteins; D016212:Transforming Growth Factor beta; C457579:FBXO11 protein, human; D011484:Protein-Arginine N-Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; C584471:CULL-RING ligase, human; D044767:Ubiquitin-Protein Ligases; D020741:rho GTP-Binding Proteins
keywords: Cdt2; FBXO11; Set8; cullin; ubiquitylation
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