TY - JOUR
T1 - Skp2 Deletion Unmasks a p27 Safeguard that Blocks Tumorigenesis in the Absence of pRb and p53 Tumor Suppressors
AU - Zhao, Hongling
AU - Bauzon, Frederick
AU - Fu, Hao
AU - Lu, Zhonglei
AU - Cui, Jinhua
AU - Nakayama, Keiko
AU - Nakayama, Keiich I.
AU - Locker, Joseph
AU - Zhu, Liang
N1 - Funding Information:
This work was supported by National Institutes of Health grants R01 CA127901 and R01 CA131421 (to L.Z.). The Albert Einstein Comprehensive Cancer Research Center (grant 5P30CA13330) and the Albert Einstein Comprehensive Liver Research Center (grant 5P30DK061153) provided core facility support. We thank Dr. Sarah Schweber of the Oncology Division for suggestions of human breast cancer cell lines and Dr. Jinghang Zhang of the Flow Cytometry Core Facility of the Albert Einstein Cancer Center for assistance in using iCys Research Imaging Cytometer and iCys Cytometric Analysis Software. H.Z. is a recipient of U.S. Department of Defense Prostate Cancer Research Program Postdoctoral Fellowship (PC121837), and L.Z. is a recipient of the Irma T. Hirschl Career Scientist Award.
PY - 2013/11/11
Y1 - 2013/11/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccr.2013.09.021
DO - 10.1016/j.ccr.2013.09.021
M3 - Article
C2 - 24229711
AN - SCOPUS:84887560579
VL - 24
SP - 645
EP - 659
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 5
ER -