The Role of Skp2 in the Prostate Tumorigenesis Following Rb and p53 Loss
Abstract
Genetic inactivation of both major tumor suppressors pRb and p53 irreparably disables most cells antitumor mechanisms. TCGA documents recurrent genetic inactivation of RB1 and TP53. They often co-occur and the co-ococcurrences become more frequent in more advanced cancer, which likely explain why advanced cancer are more likely to resist current anticancer therapies. Here, we found that p53 activates expression of Pirh2 and KPC1, two of the three ubiquitin ligases for p27. Loss of p53 in the absence of Skp2, the third ubiquitin ligase for p27, shrinks the cellular pool of p27 ubiquitin ligases to accumulate p27 protein. In the absence of pRb and p53, p27 was unable to inhibit DNA synthesis in spite of its abundance, but could inhibit division of cells that maintain DNA replication with rereplication. This mechanism blocked pRb/p53 doubly deficient pituitary and prostate tumorigenesis lastingly coexistent with bromodeoxyuridine-labeling neoplastic lesions, revealing an unconventional cancer cell vulnerability when pRb and p53 are inactivated.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2014
- Accession Number
- ADA613301
Entities
People
- Hongling Zhao
Organizations
- Albert Einstein College of Medicine