Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/ mice

Hongbo Wang, Frederick Bauzon, Peng Ji, Xiaoliang Xu, Daqian Sun, Joseph Locker, Rani S. Sellers, Keiko Nakayama, Keiich I. Nakayama, David Cobrinik, Liang Zhu

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)83-88
Number of pages6
JournalNature Genetics
Volume42
Issue number1
DOIs
StatePublished - Jan 2010

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Melanotrophs
Carcinogenesis
Survival
SKP Cullin F-Box Protein Ligases
Intermediate Pituitary Gland
Apoptosis
Retinoblastoma Genes
Retinoblastoma Protein
Retinoblastoma
Ubiquitination
Essential Genes
Alleles
Phosphorylation

ASJC Scopus subject areas

  • Genetics

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Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/ mice. / Wang, Hongbo; Bauzon, Frederick; Ji, Peng; Xu, Xiaoliang; Sun, Daqian; Locker, Joseph; Sellers, Rani S.; Nakayama, Keiko; Nakayama, Keiich I.; Cobrinik, David; Zhu, Liang.

In: Nature Genetics, Vol. 42, No. 1, 01.2010, p. 83-88.

Research output: Contribution to journalArticle

Wang, H, Bauzon, F, Ji, P, Xu, X, Sun, D, Locker, J, Sellers, RS, Nakayama, K, Nakayama, KI, Cobrinik, D & Zhu, L 2010, 'Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/ mice', Nature Genetics, vol. 42, no. 1, pp. 83-88. https://doi.org/10.1038/ng.498
Wang, Hongbo ; Bauzon, Frederick ; Ji, Peng ; Xu, Xiaoliang ; Sun, Daqian ; Locker, Joseph ; Sellers, Rani S. ; Nakayama, Keiko ; Nakayama, Keiich I. ; Cobrinik, David ; Zhu, Liang. / Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/ mice. In: Nature Genetics. 2010 ; Vol. 42, No. 1. pp. 83-88.
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