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SRC-3 coactivator functional lifetime is regulated by a phospho-dependent ubiquitin time clock
Ray-Chang Wu1, Qin Feng, David M Lonard
1Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Cell
|June 19, 2007
Summary
Regulated ubiquitination of SRC-3 (Steroid Receptor Coactivator-3) controls its activation and degradation. This phosphorylation-dependent process acts as a "transcriptional time clock," balancing coactivator function and preventing oncogenesis.
Area of Science:
- Molecular Biology
- Biochemistry
- Cancer Research
Background:
- SRC-3 (Steroid Receptor Coactivator-3)/AIB1 is a crucial growth coactivator implicated in oncogenesis when overactivated.
- Tight regulation of SRC-3 activity is essential for normal cellular function and preventing uncontrolled growth.
Purpose of the Study:
- To elucidate the regulatory mechanisms governing SRC-3 coactivator activation and transcriptional specificity.
- To investigate the role of phosphorylation-dependent ubiquitination in controlling SRC-3 function and stability.
Main Methods:
- Identification of a critical "actron/degron" element within SRC-3.
- Characterization of GSK3 as the responsible kinase and SCF(Fbw7alpha) as the E3 ubiquitin ligase.
- Analysis of SRC-3 ubiquitination patterns (multi-/mono-ubiquitination vs. polyubiquitination) and their functional consequences.
Main Results:
- Discovered a phosphorylation-dependent ubiquitination pathway regulating SRC-3.
- Identified GSK3 and SCF(Fbw7alpha) in this regulatory cascade.
- Demonstrated that SCF(Fbw7alpha) mediates both non-proteolytic activation and proteasomal degradation of SRC-3.
- Observed a biphasic ubiquitination process transitioning from activation to degradation, acting as a "transcriptional time clock."
Conclusions:
- Coordinated phosphorylation and ubiquitination tightly regulate SRC-3 activity and lifespan.
- SRC-3 ubiquitination is a biphasic event controlling coactivator activation and degradation.
- This regulatory mechanism ensures precise control over transcriptional coactivation and prevents oncogenic overactivation.
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