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. 2012;3(3):273-81.
Epub 2012 Sep 25.

Induction of cell senescence by targeting to Cullin-RING Ligases (CRLs) for effective cancer therapy

Yongfu Pan  1 , Hua Xu, Rujiao Liu, Lijun Jia
Affiliations

Induction of cell senescence by targeting to Cullin-RING Ligases (CRLs) for effective cancer therapy

Yongfu Pan et al. Int J Biochem Mol Biol. 2012.

Abstract

Cullin-RING ligases (CRLs) are the biggest family of multiunit ubiquitin E3 ligases, controlling many biological processes by promoting the degradation of a broad spectrum of proteins associated with cell cycle, signal transduction and cell growth. The dysfunction of CRLs causes a lot of diseases including cancer, which meanwhile offers us a promising approach to cancer therapy by targeting to CRLs. Recent studies have demonstrated that genetic or pharmaceutical inactivation of CRLs often leads to cancer cell death by activating multiple cell-killing pathways including senescence, an emerging anticancer mechanism of therapeutic agents. Here, we summarize the induction of cellular senescence and its mechanism of action, triggered by targeting to specific subunits of CRLs via multiple approaches including siRNA silencing, genetic knockout as well as small molecule inhibitor, exhibiting anticancer effect in vitro and in vivo.

Keywords: CRLs; MLN4924; RBX1/ROC1; Skp2; cullin neddylation; senescence.

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Figures

Figure 1
Figure 1
Skematics of protein degradation by ubiquitin proteasome system (UPS). Protein degradation through UPS can be divided into two successive processes, ubiquitylation and degradation. Firstly, protein is ubiquitylated through E1-E2-E3 cascade reaction. Then ubiquitylated proteins are recognized and degraded to small peptides by 26S proteasome.
Figure 2
Figure 2
The schematic structure and functions of Cullin-RING ligase (CRLs). CRLs are composed of core catalytic subunit, cullin and RING-finger protein RBX/ROC, which assemble as a multi-subunit complex by recruiting ubiquitin transfer enzyme E2 to RBX/ROC and substrates to the N-terminal of cullin through the motif recognized by substrate receptor (SR) with/without the assistance of an adaptor protein. The activation of CRLs requires the modification of NEDD8 through neddylation. As a complex, CRLs regulate a set of biological processes including cell cycle, transcription signal transduction and survival.
Figure 3
Figure 3
Targeting to Cullin RING ligases (CRLs) induces cellular senescence. The inactivation of Cullin RING ligases (CRLs) by RNAi, genetic deletion or inhibitors induces the accumulation of substrates, such as p21 and p27, which in turn trigger cell senescence, as well as apoptosis and autophagy. The crosstalk among these three different cell killing pathways remains elusive.
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