Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/− mice
Copyright policy )Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/− mice
Heterozygosity of the retinoblastoma gene Rb1 elicits tumorigenesis in susceptible tissues following spontaneous loss of the remaining functional allele. Inactivation of previously studied retinoblastoma protein (pRb) targets partially inhibited tumorigenesis in Rb1(+/-) mice. Here we report that inactivation of pRb target Skp2 (refs. 7,8) completely prevents spontaneous tumorigenesis in Rb1(+/-) mice. Targeted Rb1 deletion in melanotrophs ablates the entire pituitary intermediate lobe when Skp2 is inactivated. Skp2 inactivation does not inhibit aberrant proliferation of Rb1-deleted melanotrophs but induces their apoptotic death. Eliminating p27 phosphorylation on T187 in p27T187A knock-in mice reproduces the effects of Skp2 knockout, identifying p27 ubiquitination by SCF(Skp2) ubiquitin ligase as the underlying mechanism for Skp2's essential tumorigenic role in this setting. RB1-deficient human retinoblastoma cells also undergo apoptosis after Skp2 knockdown; and ectopic expression of p27, especially the p27T187A mutant, induces apoptosis. These results reveal that Skp2 becomes an essential survival gene when susceptible cells incur Rb1 deficiency.
- Tohoku University Japan
- Kyushu University Japan
- Cornell University United States
- Memorial Sloan Kettering Cancer Center United States
- Massachusetts Institute of Technology United States
Male, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Blotting, Western, Apoptosis, Mice, Inbred Strains, Neoplasms, Experimental, Retinoblastoma Protein, Mice, Inbred C57BL, Mice, Cell Line, Tumor, Pituitary Gland, Mutation, Animals, Humans, Female, RNA Interference, S-Phase Kinase-Associated Proteins, Cyclin-Dependent Kinase Inhibitor p27, Cell Proliferation
Male, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Blotting, Western, Apoptosis, Mice, Inbred Strains, Neoplasms, Experimental, Retinoblastoma Protein, Mice, Inbred C57BL, Mice, Cell Line, Tumor, Pituitary Gland, Mutation, Animals, Humans, Female, RNA Interference, S-Phase Kinase-Associated Proteins, Cyclin-Dependent Kinase Inhibitor p27, Cell Proliferation
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