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.
Wang
Hongbo
H
Department of Developmental and Molecular Biology and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.
Bauzon
Frederick
F
Ji
Peng
P
Xu
Xiaoliang
X
Sun
Daqian
D
Locker
Joseph
J
Sellers
Rani S
RS
Nakayama
Keiko
K
Nakayama
Keiich I
KI
Cobrinik
David
D
Zhu
Liang
L
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D013997:Time Factors
D016160:Retinoblastoma Protein; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27