Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 15, Pages 6203-6208Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0812425106
Keywords
SCF E3 ubiquitin ligase; protein degradation; growth suppression
Categories
Funding
- National Cancer Institute [CA111554, CA116982, CA118762]
- University of Michigan Cancer Center
- National Institutes of Health [CA46592]
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RBX1 (RING box protein-1) or ROC1 (regulator of cullins-1) is the RING component of SCF (Skp1, Cullins, F-box proteins) E3 ubiquitin ligases, which regulate diverse cellular processes by targeting various substrates for degradation. However, the in vivo physiological function of RBX1 remains uncharacterized. Here, we show that a gene trap disruption of mouse Rbx1 causes embryonic lethality at embryonic day (E)7.5, mainly due to a failure in proliferation; p27, a cyclin dependent kinase inhibitor, normally undetectable in the early embryos, accumulates at high levels in the absence of Rbx1. Although mice heterozygous for the Rbx1 gene trap appear viable and fertile without obvious abnormalities, the Rbx1(+/Gt) MEFs do show retarded growth with G1 arrest and p27 accumulation. Simultaneous loss of p27 extended the life span of Rbx1(Gt/Gt) embryos from E6.5 to E9.5, indicating that p27-mediated cell cycle inhibition contributes to the early embryonic lethality in the Rbx1-deficient embryos. Our study demonstrates that the in vivo physiological function of RBX1 is to ensure cell proliferation by preventing p27 accumulation during the early stage of embryonic development.
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