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 and Liang Zhu ()
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Zhonglei Lu: The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine
Frederick Bauzon: The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine
Hao Fu: The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine
Jinhua Cui: The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine
Hongling Zhao: The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine
Keiko Nakayama: ART, Tohoku University Graduate School of Medicine
Keiich I. Nakayama: Medical Institute of Bioregulation, Kyushu University
Liang Zhu: The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4463

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