Skp2 Deletion Unmasks a p27 Safeguard that Blocks Tumorigenesis in the Absence of pRb and p53 Tumor Suppressors

Hongling Zhao, Frederick Bauzon, Hao Fu, Zhonglei Lu, Jinhua Cui, Keiko Nakayama, Keiich I. Nakayama, Joseph Locker, Liang Zhu

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

pRb and p53 are two major tumor suppressors. 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.

Original languageEnglish (US)
Pages (from-to)645-659
Number of pages15
JournalCancer Cell
Volume24
Issue number5
DOIs
StatePublished - Nov 11 2013

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Zhao, H., Bauzon, F., Fu, H., Lu, Z., Cui, J., Nakayama, K., Nakayama, K. I., Locker, J., & Zhu, L. (2013). Skp2 Deletion Unmasks a p27 Safeguard that Blocks Tumorigenesis in the Absence of pRb and p53 Tumor Suppressors. Cancer Cell, 24(5), 645-659. https://doi.org/10.1016/j.ccr.2013.09.021