Distinct outcomes from targeted perturbations of the multi-subunit SCFSkp2 E3 ubiquitin ligase in blocking Trp53/Rb1-null prostate tumorigenesis

• DOI: 10.1038/s42003-025-07662-3
• Publication Date: 2025-02-22T08:08:52Z
• Authors: Yingjiao Xue; Liang Zhu; Saumen Karan; Joseph D. Locker; Craig Branch; Jinghang Zhang; Bang Hoang; Juan Pablo Maianti; Hongling Zhao; Edward L. Schwartz
• Keywords: Blocking (statistics); Null (SQL)

Identifying effective therapies targeting multi-protein complexes that lack catalytic sites or cofactor pockets remains a long-standing challenge. The proto-oncogene, ubiquitin E3 ligase SCFSkp2, is one such target. SCFSkp2 promotes the proteasomal degradation of cyclin-dependent kinase inhibitor p27, which controls cell cycle progression. Targeted knockout Rb1/Trp53 causes metastatic prostate cancer in mice; additional Skp2 completely blocks tumorigenesis. We compared gene-edited mice carried two different single amino acid changes complex, structurally predicted to inhibit p27. Mutation accessory protein Cks1 (Cks1N45R) blocked Rb1/Trp53-driven tumorigenesis, phenocopying knockout, whereas mutation directly stabilizing p27 (p27T187A) did not. This was consistent with structural models binding both and p27T187A SCFSkp2/Cks1/Cdk2/CyclinA/p27 their subsequent ubiquitination degradation, albeit at rates. Two modes, differ dependence on phosphorylated T187, are by model. Studies confirmed role mediating tumorigenesis mutant tumors revealed mutually destabilizing feedback loop. integration gene editing, drug-surrogate mutations, mouse tumor offers blueprint for studying other multi-subunit biomedical targets. drug surrogate genetically engineered CDKI