Oncotarget

Research Papers:

STIP is a critical nuclear scaffolding protein linking USP7 to p53-Mdm2 pathway regulation

Mao Ye _, Yani Tang, Shijun Tang, Jing Liu, Kuangpei Wu, Shan Yao, Yang Sun, Lei Zhou, Tanggang Deng, Ying Chen, Chenghan Huang and Weihong Tan

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Oncotarget. 2015; 6:34718-34731. https://doi.org/10.18632/oncotarget.5303

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Abstract

Mao Ye1,*, Yani Tang1,*, Shijun Tang1,*, Jing Liu2, Kuangpei Wu1, Shan Yao1, Yang Sun1, Lei Zhou3, Tanggang Deng1, Ying Chen4, Chenghan Huang4, Weihong Tan1,*

1Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, Hunan 410082, China

2School of Life Sciences, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China

3Department of Molecular Genetics and Microbiology & UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA

4Laboratory of Biochemistry and Molecular Genetics, New York Blood Center, New York, NY10065, USA

*These authors have contributed equally to this work

Correspondence to:

Mao Ye, e-mail: [email protected]

Weihong Tan, e-mail: [email protected]

Jing Liu, e-mail: [email protected]

Keywords: USP7, deubiquitinating enzyme, Mdm2, p53, tenary protein complex

Received: March 13, 2015     Accepted: September 28, 2015     Published: October 10, 2015

ABSTRACT

The ubiquitin-specific protease USP7 stabilizes both Mdm2 and p53 by removing ubiquitins, hence playing an important enzymatic role in the p53-Mdm2 pathway. However, it is poorly understood how USP7 executes its dual-stabilization effect on Mdm2 and p53 in cellular context. Here, we report that STIP is a novel macromolecular scaffold that links USP7 to the p53-Mdm2 pathway. STIP and a fraction of USP7 interact and constitutively colocalize in nucleoplasma. Overexpression of STIP stabilizes Mdm2 and p53, whereas downregulation of STIP decreases Mdm2 and p53 levels. The effect of STIP on Mdm2 and p53 depends on USP7 function as a deubiquitinating enzyme. Furthermore, we demonstrate that STIP mediates the assembly of two separate ternary protein complexes in vivo as STIP-USP7-Mdm2 and STIP-USP7-p53, which facilitates USP7-mediated stabilization of Mdm2 and p53. Collectively, these results pinpoint a new molecular function of STIP and reveal a novel mechanism whereby USP7 executes its dual-stabilization effect on Mdm2 and p53 via STIP scaffolding.


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