Distinct outcomes from targeted perturbations of the multi-subunit SCF^Skp2 E3 ubiquitin ligase in blocking Trp53/Rb1-null prostate tumorigenesis.

ABSTRACT: 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 SCF^Skp2, is one such target. SCF^Skp2 promotes the proteasomal degradation of the cyclin-dependent kinase inhibitor p27, which controls cell cycle progression. Targeted knockout of Rb1/Trp53 causes metastatic prostate cancer in mice; additional knockout of Skp2 completely blocks tumorigenesis. We compared gene-edited mice that carried two different single amino acid changes in the SCF^Skp2 complex, structurally predicted to inhibit the degradation of p27. Mutation of the SCF^Skp2 accessory protein Cks1 (Cks1^N45R) completely blocked Rb1/Trp53-driven prosta

SUBMITTER: Xue Y 

PROVIDER: S-EPMC11846996 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature