The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppression

Abstract

Deregulation of the G1/G0 phase of the cell cycle can lead to cancer. During G1, most cells commit alternatively to DNA replication and division, or to cell-cycle exit and differentiation. The anaphase-promoting complex or cyclosome (APC/C) activated by Cdh1 coordinately eliminates positive cell-cycle regulators as well as inhibitors of differentiation, thereby coupling cell-cycle exit and differentiation. Misregulation of Cdh1 thus has the potential to promote both cell-cycle re-entry and either perturbed differentiation or dedifferentiation. In addition, APC/C(Cdh1) is required to maintain genomic stability. As a result, loss of Cdh1 can contribute to tumorigenesis in the form of proliferation of poorly differentiated and genetically unstable cells.

Figure 1. APC/C^Cdh1-dependent control of the cell cycle

a, The anaphase-promoting complex/cyclosome (APC/C) is activated by Cdh1 from the end of mitosis through G1 (APC/C^Cdh1). APC/C^Cdh1 controls G1 to either allow differentiation or to prepare for a new round of cell division. In G2 APC/C^Cdh1 can be activated in response to DNA damage to block mitotic entry and to initiate DNA repair. In mitosis APC/C activated by Cdc20 (APC/C^Cdc20) mediates chromosome separation and initiates mitotic exit. At the end of mitosis APC/C^Cdh1 inactivates APC/C^Cdc20 and modulates anaphase spindle dynamics and cytokinesis. Inactivation of Cdh1 can contribute to tumorigenesis by deregulation of these cell cycle transitions. b, APC/C^Cdh1-dependent degradation of positive cell cycle regulators (such as cyclin-Cdk) and inhibitors of differentiation keeps the balance in G1/G0 between proliferation and differentiation. When APC/C^Cdh1 remains active in G1 cells can exit the cell cycle and differentiate, or Cdh1 is switched off in late G1 and the cell enters a new cell cycle. APC/C^Cdc20 maintains the proliferative state by controlling progression through mitosis before it is inactivated by APC/C^Cdh1.

Figure 1. APC/C^Cdh1-dependent control of the cell cycle

a, The anaphase-promoting complex/cyclosome (APC/C) is activated by Cdh1 from the end of mitosis through G1 (APC/C^Cdh1). APC/C^Cdh1 controls G1 to either allow differentiation or to prepare for a new round of cell division. In G2 APC/C^Cdh1 can be activated in response to DNA damage to block mitotic entry and to initiate DNA repair. In mitosis APC/C activated by Cdc20 (APC/C^Cdc20) mediates chromosome separation and initiates mitotic exit. At the end of mitosis APC/C^Cdh1 inactivates APC/C^Cdc20 and modulates anaphase spindle dynamics and cytokinesis. Inactivation of Cdh1 can contribute to tumorigenesis by deregulation of these cell cycle transitions. b, APC/C^Cdh1-dependent degradation of positive cell cycle regulators (such as cyclin-Cdk) and inhibitors of differentiation keeps the balance in G1/G0 between proliferation and differentiation. When APC/C^Cdh1 remains active in G1 cells can exit the cell cycle and differentiate, or Cdh1 is switched off in late G1 and the cell enters a new cell cycle. APC/C^Cdc20 maintains the proliferative state by controlling progression through mitosis before it is inactivated by APC/C^Cdh1.

Figure 2. Mechanisms of differentiation control by APC/C^Cdh1

In response to TGFβ stimulation Smad3 and Smad2 can recruit APC/C^Cdh1 to ubiquitinate SnoN leading to its degradation and activation of TGF-beta target genes and growth inhibition. Similarly, the retinoblastoma protein (pRB) can recruit APC/C^Cdh1 to target Skp2 resulting in p27 stabilization and cell cycle arrest. APC/C^Cdh1 also targets Id (inhibitor of differentiation/DNA binding) proteins. This leads to activation of basic helix-loop-helix (bHLH) transcription factors and target gene expression mediating differentiation in various cell types.

Figure 3. Dysregulation of APC/C^Cdh1 can cause genomic instability

Inactivation of Cdh1 leads to stabilization and unscheduled expression of several target proteins. This results in deregulation of DNA replication and mitosis leading to chromosomal aberrations. See text for details.