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SENP1 deSUMOylates and regulates Pin1 protein activity and cellular function
Chun-Hau Chen1, Che-Chang Chang, Tae Ho Lee
1Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Cancer Research
|May 2, 2013
Summary
Pin1 prolyl isomerase activity and oncogenic function are inhibited by SUMOylation. SENP1 deSUMOylation promotes Pin1 function, increasing its stability and driving tumorigenesis, particularly in breast cancer.
Area of Science:
- Molecular Biology
- Cancer Biology
- Enzymology
Background:
- Pin1 prolyl isomerase regulates phosphorylation signaling and is upregulated in oncogenesis.
- SUMOylation and deSUMOylation are key regulatory mechanisms for protein activity, with SUMO proteases (SENP) involved in cancer.
- The role of SUMOylation in regulating Pin1 function was previously unknown.
Purpose of the Study:
- To investigate the role of SUMOylation in regulating Pin1 function.
- To identify the specific SUMOylation sites on Pin1.
- To determine the impact of SENP1 on Pin1 SUMOylation and its oncogenic activity.
Main Methods:
- Western blotting to detect SUMOylation.
- Co-immunoprecipitation to assess protein interactions.
- Cell transformation assays and centrosome amplification analysis.
- Analysis of human breast cancer specimens.
Main Results:
- Pin1 undergoes SUMOylation on Lys6 and Lys63, inhibiting its activity and oncogenic function.
- SENP1 binds to and deSUMOylates Pin1.
- SENP1 overexpression or disruption of Pin1 SUMOylation enhances Pin1's ability to induce centrosome amplification and cell transformation.
- SENP1 increases Pin1 protein stability, and Pin1 levels correlate positively with SENP1 levels in breast cancer.
Conclusions:
- Pin1 SUMOylation on Lys6/63 is a novel inhibitory mechanism for its activity and function.
- SENP1-mediated deSUMOylation is critical for promoting Pin1 function during tumorigenesis.
- Targeting Pin1 SUMOylation or SENP1 activity may offer therapeutic strategies for breast cancer.
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