APC/C Ubiquitin Ligase: Coupling Cellular Differentiation to G1/G0 Phase in Multicellular Systems

The cell cycle regulator APC/C regulates cell differentiation through cell cycle-independent functions in multicellular organisms. APC/C regulates a range of differentiation processes, from cell fate specification in unspecified progenitor cells to terminal differentiation of specific cell types, via ubiquitin-dependent proteolysis. APC/C influences cell differentiation by exerting at least three types of context-dependent mechanism: (i) regulating the expression levels of cell type-specific transcriptional regulators; (ii) modulating cellular responses to signalling pathways; and (iii) regulating the organisation and functions of centrosomes. APC/C is able to spatiotemporally coordinate these context-dependent differentiation processes with G1/G0 progression in the same cell. The anaphase-promoting complex/cyclosome (APC/C) is an evolutionarily conserved ubiquitin ligase that controls cell cycle progression through spatiotemporally regulated proteolysis. Although recent studies revealed its postmitotic function, our knowledge of the role of APC/C beyond cell cycle regulation in the biology of multicellular organisms is far from complete. Here, I review recent advances in the function of APC/C in animal development, specifically focusing on its emerging role in regulating cell differentiation. I describe how APC/C regulates distinct processes during the course of differentiation by deploying diverse molecular machineries in a variety of developmental contexts. Also, I discuss the significance and clinical relevance of the unique capacity of APC/C and other cell cycle regulators to couple distinct cellular processes with cell proliferation control. The anaphase-promoting complex/cyclosome (APC/C) is an evolutionarily conserved ubiquitin ligase that controls cell cycle progression through spatiotemporally regulated proteolysis. Although recent studies revealed its postmitotic function, our knowledge of the role of APC/C beyond cell cycle regulation in the biology of multicellular organisms is far from complete. Here, I review recent advances in the function of APC/C in animal development, specifically focusing on its emerging role in regulating cell differentiation. I describe how APC/C regulates distinct processes during the course of differentiation by deploying diverse molecular machineries in a variety of developmental contexts. Also, I discuss the significance and clinical relevance of the unique capacity of APC/C and other cell cycle regulators to couple distinct cellular processes with cell proliferation control. ubiquitin ligases are enzymes that catalyse the transfer of ubiquitin molecules onto their substrate proteins. CRLs are a family of multisubunit ubiquitin ligases containing a Cullin-like protein and a RING finger protein as their catalytic centres, which include APC/C, SCF (Skp1-Cullin1-Fbox), VBC (pVHL-Elongin B/C-Cullin2), Cullin3-BTB, and Cullin4 complexes. a family of kinases forming a complex with a regulatory subunit, cyclin, including CDK1-cyclin A/B, CDK2-cyclin A/E, and CDK4/6-cyclin D complexes. Typically, the cellular levels of cyclins oscillate during the cell cycle, reflecting the enzymatic activities of their associated kinases. a medical condition characterised by a reduced brain size, which may be present at birth due to abnormal brain development or can develop after birth due to defective brain growth. coordinated orientation of cells or cellular structures within the plane of an epithelial tissue. Prime examples are the epithelia of the Drosophila eyes and wings, where photoreceptor cell clusters and wing hairs are oriented in certain directions across the tissues, and which have been used as major model systems to study the mechanism regulating PCP. the hypothetical time point in G1 phase where mammalian cells are considered to commit to the next round of the cell cycle. The cell that has passed the R-point will initiate DNA replication without a delay regardless of whether critical amino acids or serums are withdrawn. Currently, the stable activation of the transcriptional activity of E2F is considered the defining event of R-point. the transcriptional repressor important for the regulation of the G1 to S phase transition as well as the exit from G0 phase. pRb directly binds E2F transcription factor to inhibit its transactivation activity. Upon phosphorylation by CDK4-cyclin D, pRb releases E2F, which in turn induces transcription of various cell cycle regulator genes, including cyclin E, to initiate DNA replication. highly regulated molecular cascade that mediates targeted protein degradation in an ATP-dependent manner. In the UPP, three types of enzyme [ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s)] cooperate to covalently link polyubiquitin chains to lysine residues of target proteins. The polyubiquitinated proteins are then recognised by 26S proteasome, a large complex comprising proteases and ATPase and non-ATPase subunits, and are degraded into small peptides. The highest level of regulation and specificity is conferred by E3s, which directly bind both substrates and E2s in specific spatiotemporal windows and catalyse ubiquitin transfer, and deubiquitinating enzymes (DUBs), a large group of proteases that cleave and modify ubiquitin chains.