APC/C and retinoblastoma interaction: cross-talk of retinoblastoma protein with the ubiquitin proteasome pathway

Abstract

The ubiquitin (Ub) ligase anaphase promoting complex/cyclosome (APC/C) and the tumour suppressor retinoblastoma protein (pRB) play key roles in cell cycle regulation. APC/C is a critical regulator of mitosis and G1-phase of the cell cycle whereas pRB keeps a check on proliferation by inhibiting transition to the S-phase. APC/C and pRB interact with each other via the co-activator of APC/C, FZR1, providing an alternative pathway of regulation of G1 to S transition by pRB using a post-translational mechanism. Both pRB and FZR1 have complex roles and are implicated not only in regulation of cell proliferation but also in differentiation, quiescence, apoptosis, maintenance of chromosomal integrity and metabolism. Both are also targeted by transforming viruses. We discuss recent advances in our understanding of the involvement of APC/C and pRB in cell cycle based decisions and how these insights will be useful for development of anti-cancer and anti-viral drugs.

Keywords: FZR1; LxCxE; anaphase promoting complex/cyclosome; cell cycle; human papilloma virus; retinoblastoma.

Figure 1. Regulation of cell cycle by the SCF and APC/C E3 ligases

Schematic diagrams of the modular structure of the SCF (A) and APC/C (B) showing the relative positions of various subunits. The stages of the cell cycle where activities of these complexes regulates key events are shown in (C) along with some of the key substrates. The activities of two APC/C assemblies (APC/C^CDC20 and APC/C^FZR1) are regulated in opposite manner by phosphorylation resulting their manifestation at different stages (D). APC/C^CDC20 is activated upon phosphorylation by the mitotic cyclin/CDK complex but its activity is kept in check by the SAC. Once SAC is satisfied, APC/C^CDC20 targets mitotic cyclins resulting in decrease in kinase activity thus inactivating APC/C^CDC20. At the same time, activation of the phosphatase Cdc14 dephosphorylate FZR1 resulting in activation of APC/C^FZR1.

Figure 2. Different mechanisms of G₁-S regulation by pRB

Transcriptional and post-translational regulation of G₁-S transition by pRB-E2F and pRB-APC/C^FZR1 complexes. The phosphorylation status of pRB is indicated by black solid balls, with numbers of balls reflecting hypo- or hyper phosphorylation of pRB (not actual number of phosphorylation sites) (A). Domain organization of pRB showing phosphorylation sites and regions of interactions with various cellular proteins. Numbers show amino acid positions (B).

Figure 3. Domain organization of viral proteins

LxCxE motif is indicated with solid black ball. Numbers indicate amino acids (A). Mechanisms of displacement of E2F from pRB by LxCxE containing viral proteins (B).