pevonedistat and Uterine-Cervical-Neoplasms

Retinoblastoma protein (Rb) is a tumor suppressor that binds and represses E2F transcription factors. In cervical cancer cells, human papilloma virus (HPV) protein E7 binds to Rb, releasing it from E2F to promote cell cycle progression, and inducing ubiquitination of Rb. E7-mediated proteasomal degradation of Rb requires action by another protease, calpain, which cleaves Rb after Lys 810. However, it is not clear why cleavage is required for Rb degradation. Here, we report that the proteasome cannot initiate degradation efficiently on full-length Rb. Calpain cleavage exposes a region that is recognized by the proteasome, leading to rapid proteolysis of Rb. These findings identify a mechanism for regulating protein stability by controlling initiation and provide a better understanding of the molecular mechanism underlying transformation by HPV.

Topics: Acrylates; Calpain; Cell Cycle; Cell Transformation, Neoplastic; Cyclopentanes; E2F Transcription Factors; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; Human papillomavirus 16; Humans; NEDD8 Protein; Oligopeptides; Papillomavirus E7 Proteins; Proteasome Endopeptidase Complex; Protein Stability; Pyrimidines; Recombinant Proteins; Retinoblastoma Binding Proteins; Ubiquitin-Protein Ligases; Ubiquitination; Uterine Cervical Neoplasms