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.
Copyright © 2013 Elsevier Inc. All rights reserved.
MeSH terms
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Animals
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Apoptosis
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Carcinogenesis / genetics*
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Carcinogenesis / metabolism
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Cell Line, Tumor
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Cellular Senescence
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Cyclin-Dependent Kinase Inhibitor p27 / physiology*
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DNA Replication
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Gene Deletion
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Humans
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Male
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Transgenic
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Pituitary Neoplasms / genetics
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Pituitary Neoplasms / pathology
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Prostatic Intraepithelial Neoplasia / genetics*
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Prostatic Intraepithelial Neoplasia / pathology
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / pathology
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism*
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S-Phase Kinase-Associated Proteins / genetics*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Ubiquitin-Protein Ligases / metabolism
Substances
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Phosphoproteins
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Retinoblastoma Protein
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S-Phase Kinase-Associated Proteins
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TP53 protein, human
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Tumor Suppressor Protein p53
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Cyclin-Dependent Kinase Inhibitor p27
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Rchy1 protein, mouse
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Ubiquitin-Protein Ligases