Abstract
RBX1 (also known as ROC1) is a RING subunit of SCF (Skp1, Cullins, F-box proteins) E3 ubiquitin ligases, required for SCF to direct a timely degradation of diverse substrates, thereby regulating numerous cellular processes under both physiological and pathological conditions. Previous studies have shown that RBX1 is essential for growth in yeast, Caenorhabditis elegans and Drosophila. The role of RBX1 in mouse development and in regulation of cancer cell survival was unknown. Our recent work demonstrated that RBX1 is an essential gene for mouse embryogenesis, and targeted disruption of RBX1 causes embryonic lethality at E7.5 due to hypoproliferation as a result of p27 accumulation. We also showed that RBX1 is overexpressed in a number of human cancers, and siRNA silencing of RBX1 caused cancer cell death as a result of sequential induction of G2-M arrest, senescence and apoptosis. These findings reveal a physiological role of RBX1 during mouse development and a pathological role for the survival of human cancer cells. Differential outcomes between normal (growth arrest) and cancer cells (cell death) upon RBX1 disruption/silencing suggest RBX1 as a valid anticancer target.Comments on:Tan M, Davis SW, Saunders TL, Zhu Y, Sun Y. RBX1/ROC1 disruption results in early embryonic lethality due to proliferation failure, partially rescued by simultaneous loss of p27. Proc Natl Acad Sci USA. 2009; 106:6203–6208Jia L, Soengas MS, Sun Y. ROC1/RBX1 E3 ubiquitin ligase silencing suppresses tumor cell growth via sequential induction of G2-M arrest, apoptosis, and senescence. Cancer Res. 2009; 69:4974–82
Highlights
SCF (Skp1, Cullins, F-box proteins) E3 ubiquitin ligases, consist of Skp1, Cullins, F-box proteins, and the RING domain containing protein RBX1/ROC1 or its family member RBX2/ROC2/SAG
RBX1 in development RBX1-cullin complexes control the proteolysis of numerous substrates related to cell cycle progression, cell growth and cell death, suggesting that RBX1 may play an important role in development
In Caenorhabditis elegans, RBX1 is crucial for cell cycle progression and chromosome metabolism, as evidenced by severe defects in meiosis, mitotic chromosomal condensation and segregation, and cytokinesis upon siRNA knockdown [9]
Summary
SCF (Skp, Cullins, F-box proteins) E3 ubiquitin ligases, consist of Skp, Cullins, F-box proteins, and the RING domain containing protein RBX1/ROC1 or its family member RBX2/ROC2/SAG. RBX1 binds to the C-terminus of cullin-1 via its N-terminus and to an E2 ubiquitin conjugating enzyme via its C-terminal RING domain. RBX1/ Cullin-1 complex catalyzes the ubiquitin transfer from E2 to the substrates which are recognized by different F-box proteins, linked to the N-terminus of cullin-1 via an adaptor protein, Skp1 [3] (Fig 1). By binding to and interaction with different cullins and cullin-associated proteins, RBX1, as an active RING component of the largest family of E3 ubiquitin ligases, plays an essential role in regulation of diverse biological processes by promoting the degradation of different protein substrates. RBX1, on the other hand, binds to Cullin-1 using its N-terminus and an E2 ubiquitin conjugating enzyme using its C-terminal RING domain. RBX1cullin-1 catalyzes the ubiquitin transfer from E2 to protein substrates
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