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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.

The aptamer TY04 is a single-stranded DNA. However, its biological function has not been elucidated. Here, we found that TY04 specifically bound to multiple myeloma cells MM.1S, and some membrane proteins on the surface of MM.1S cells constituted the target molecules of TY04. TY04 inhibited the growth of multiple myeloma cell lines, induced cell cycle arrest in mitosis, and resulted in a significant accumulation of binucleated cells. Following TY04 treatment, a concomitant increase in CDK1 and cyclin B1 expression occurred. In addition, TY04 treatment also resulted in a significant downregulation of γ-tubulin. Considering the unique advantages of aptamers, TY04 shows great potential as a drug candidate to treat multiple myeloma.

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