Proteasome-dependent degradation of transcription factor activating enhancer-binding protein 4 (TFAP4) controls mitotic division.
TFAP4, a basic helix-loop-helix transcription factor that regulates the expression of a multitude of genes involved in the regulation of cellular proliferation, stemness, and epithelial-mesenchymal transition, is up-regulated in colorectal cancer and a number of other human malignancies. We have found that, during the G2 phase of the cell division cycle, TFAP4 is targeted for proteasome-dependent degradation by the SCF(βTrCP) ubiquitin ligase. This event requires phosphorylation of TFAP4 on a conserved degron. Expression of a stable TFAP4 mutant unable to interact with βTrCP results in a number of mitotic defects, including chromosome missegregation and multipolar spindles, which eventually lead to the activation of the DNA damage response. Our findings reveal that βTrCP-dependent degradation of TFAP4 is required for the fidelity of mitotic division.
From the Hubrecht Institute-KNAW and University Medical Center Utrecht.
Sara
S
D'Annibale
Jihoon
J
Kim
Roberto
R
Magliozzi
Teck Yew
TY
Low
Shabaz
S
Mohammed
Albert J R
AJ
Heck
Daniele
D
Guardavaccaro
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D016195:G2 Phase; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D014157:Transcription Factors; C055473:enhancer-binding protein AP-4; D044843:SKP Cullin F-Box Protein Ligases; D046988:Proteasome Endopeptidase Complex
BetaTrCP; Cell Cycle; E3 Ubiquitin Ligase; Mitosis; Protein Degradation; TFAP4; Ubiquitin