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.

CCT4 suppression inhibits tumor growth in hepatocellular carcinoma by interacting with Cdc20

“…[ 21 ] Another important complex that controls cell cycle progression is the APC; it degrades specific substrates at M and G1 phases to promote cell-cycle progression. [ 22 ] The substrates specificity of APC/C is controlled by distinct activator subunits, Cdh1 and Cdc20, which bind to APC/C at different cell cycle phases. [ 16 ] During the M phase, improper attachment between kinetochore and microtubule can activate the spindle assembly checkpoint (SAC), which inhibits APC/C activity by forming the MCC composed of Mad2, BubR1, and the APC/C activator Cdc20; the MCC can stably bind to APC/C and inhibit its activity.…”

Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

“…The ubiquitin (Ub) ligase APC/C, which is activated via the co-activator FZR1, interacts with RB during the G1 phase of cell cycle. 62 More notably, APC/C FZR1 complex degrades S-phase kinase associated protein 2 (SKP2), which inhibits p27, natural CDK inhibitors, resulting in decreased CDK2, CDK4 and CDK6. 63 Accordingly, the loss of FZR1 results in uncontrolled cell cycle progression from G1 to S phase.…”

Breast Cancer Resistance to Cyclin-Dependent Kinases 4/6 Inhibitors: Intricacy of the Molecular Mechanisms

“…Similar to Rb1, the ubiquitin ligase anaphase promoting complex/cyclosome (APC/C) play an important role in cell cycle regulation. APC/C and pRb interact via the co-activator of APC/C FZR1 , providing an alternative pathway to regulate transition from G1 to S by pRb through a post-translational mechanism ( 22 ). FZR1 is a candidate CDK4/6-cyclin D substrate and as an important determinant in response to CDK4/6 inhibitors.…”