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

2015; Impact Journals LLC; Volume: 6; Issue: 33 Linguagem: Inglês

10.18632/oncotarget.5303

1949-2553

Mao Ye, Ya-Ni Tang, Shi-Jun Tang, Jing Liu, Kuangpei Wu, Shan Yao, Yang Sun, Lei Zhou, Tanggang Deng, Ying Chen, Cheng‐Han Huang, Weihong Tan,

Cancer Research and Treatments

// Mao Ye 1, * , Yani Tang 1, * , Shijun Tang 1, * , Jing Liu 2 , Kuangpei Wu 1 , Shan Yao 1 , Yang Sun 1 , Lei Zhou 3 , Tanggang Deng 1 , Ying Chen 4 , Chenghan Huang 4 , Weihong Tan 1, * 1 Molecular 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 2 School of Life Sciences, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China 3 Department of Molecular Genetics and Microbiology & UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA 4 Laboratory 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: yemaocsu@hotmail.com Weihong Tan, e-mail: tan@chem.ufl.edu Jing Liu, e-mail: jingliucsu@hotmail.com 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.