SRC-3 coactivator functional lifetime is regulated by a phospho-dependent ubiquitin time clock.
SRC-3/AIB1 is an important growth coactivator whose activity should be tightly regulated since excess activation results in oncogenesis. Herein, we provide evidence that coordinated phosphorylation-dependent ubiquitination regulates SRC-3 coactivator activation and transcriptional specificity. We discovered a critical "actron/degron" element in SRC-3 that is required for this phosphorylation-dependent ubiquitination event and identified GSK3 and SCF(Fbw7alpha) as the respective responsible kinase and E3 ubiquitin ligase. Interestingly, despite that SCF(Fbw7alpha) enhances ubiquitination and promotes eventual transcription-coupled degradation of SRC-3 in a phosphorylation- and Fbw7alpha dosage-dependent manner, our results also uncovered a nonproteolytic "activation" code for SRC-3 ubiquitination induced by Fbw7alpha. We propose that ubiquitination of SRC-3 is a phospho-mediated biphasic event and that a transition from multi-(mono)ubiquitination (SRC-3 activation) to long-chain polyubiquitination (SRC-3 degradation) is processive during the transcriptional coactivation of select transcription factors and can serve as a "transcriptional time clock" to control both the activation and the functional lifetime of coactivators.
Wu
Ray-Chang
RC
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Feng
Qin
Q
Lonard
David M
DM
O'Malley
Bert W
BW
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005786:Gene Expression Regulation; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D056921:Nuclear Receptor Coactivator 3; D010766:Phosphorylation; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000737:chemistry*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D015534:Trans-Activators; D025801:Ubiquitin; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; D044767:Ubiquitin-Protein Ligases