Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity

Zhonglei Lu, Frederick Bauzon, Hao Fu, Jinhua Cui, Hongling Zhao, Keiko Nakayama, Keiich I. Nakayama, Liang Zhu

Research output: Contribution to journalArticle

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Abstract

One mechanism of tumour suppression by pRb is repressing E2F1. Hence, E2f1 deletion diminishes tumorigenesis following Rb1 loss. However, E2F1 promotes both proliferation and apoptosis. It therefore remains unclear how de-repressed E2F1 promotes tumorigenesis. Another mechanism of pRb function is repressing Skp2 to elevate p27 to arrest proliferation. However, Skp2 deletion induced apoptosis, not proliferation arrest, in Rb1-deficient pituitary tumorigenesis. Here we show that Rb1 deletion induces higher expression of E2F1 target genes in the absence of Skp2. E2F1 binds less cyclin A but more target promoters when Rb1 is deleted with Skp2 knockout or p27T187A knockin, suggesting that stabilized p27 prevents cyclin A from binding and inhibiting E2F1. In Rb1-deficient pituitary tumorigenesis, Skp2 deletion or p27T187A mutation converts E2F1's role from proliferative to apoptotic. These findings delineate a pRb-Skp2-p27-cyclin A-E2F1 pathway that determines whether E2F1 is proliferative or apoptotic in Rb1-deficient tumorigenesis.

Original languageEnglish (US)
Article number3463
JournalNature Communications
Volume5
DOIs
StatePublished - Mar 17 2014

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Cyclin A
deletion
apoptosis
Tumors
Carcinogenesis
tumors
Apoptosis
Neoplasms
mutations
Genes
genes
retarding
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity. / Lu, Zhonglei; Bauzon, Frederick; Fu, Hao; Cui, Jinhua; Zhao, Hongling; Nakayama, Keiko; Nakayama, Keiich I.; Zhu, Liang.

In: Nature Communications, Vol. 5, 3463, 17.03.2014.

Research output: Contribution to journalArticle

Lu, Zhonglei ; Bauzon, Frederick ; Fu, Hao ; Cui, Jinhua ; Zhao, Hongling ; Nakayama, Keiko ; Nakayama, Keiich I. ; Zhu, Liang. / Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity. In: Nature Communications. 2014 ; Vol. 5.
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