title: STIP is a critical nuclear scaffolding protein linking USP7 to p53-Mdm2 pathway regulation.
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.
authors.affiliation: 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.
authors.forename: Mao
authors.initials: M
authors.lastname: Ye
authors.affiliation: 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.
authors.forename: Yani
authors.initials: Y
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Shijun
authors.initials: S
authors.lastname: Tang
authors.affiliation: School of Life Sciences, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Kuangpei
authors.initials: K
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Shan
authors.initials: S
authors.lastname: Yao
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Molecular Genetics and Microbiology & UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Tanggang
authors.initials: T
authors.lastname: Deng
authors.affiliation: Laboratory of Biochemistry and Molecular Genetics, New York Blood Center, New York, NY10065, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Laboratory of Biochemistry and Molecular Genetics, New York Blood Center, New York, NY10065, USA.
authors.forename: Chenghan
authors.initials: C
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Weihong
authors.initials: W
authors.lastname: Tan
mesh_terms: D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D019084:Fluorescent Antibody Technique, Indirect; D055785:Gene Knockdown Techniques; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D018613:Microscopy, Confocal; D010750:Phosphoproteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; C413649:ELP2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
keywords: Mdm2; USP7; deubiquitinating enzyme; p53; tenary protein complex