LAUSR

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. Human papilloma virus (HPV) E7 protein destabilizes the retinoblastoma protein (Rb) by inducing its ubiquitination in cervical cancer cells, however proteasomal degradation requires cleavage of Rb after Lys 810 and so far it has been unclear how Rb cleavage contributes to its degradation. Here, the authors combine cell based and in vitro assays and show that calpain cleavage exposes a region in Rb that is recognized by the proteasome, leading to rapid proteolysis of Rb, whereas the proteasome cannot initiate degradation efficiently on full-length Rb.