Novel functions for the anaphase-promoting complex in neurobiology

Department of Pathology, Harvard Medical School, Boston, MA 02115, United States.
Seminars in Cell and Developmental Biology (Impact Factor: 6.27). 03/2011; 22(6):586-94. DOI: 10.1016/j.semcdb.2011.03.006
Source: PubMed

ABSTRACT In recent years, diverse and unexpected neurobiological functions have been uncovered for the major cell cycle-regulated ubiquitin ligase, the anaphase-promoting complex (APC). Functions of the APC in the nervous system range from orchestrating neuronal morphogenesis and synapse development to the regulation of neuronal differentiation, survival, and metabolism. The APC acts together with the coactivating proteins Cdh1 and Cdc20 in neural cells to target specific substrates for ubiquitination and consequent degradation by the proteasome. As we continue to unravel APC functions and mechanisms in neurobiology, these studies should advance our understanding of the molecular mechanisms of neuronal connectivity, with important implications for the study of brain development and disease.

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    • "A big surprise came several years later, when the anaphase promoting complex (APC), a classical component of the cell cycle [22], was discovered to be both highly expressed in postmitotic neurons and localized to synapses [23–25]. This massive E3 complex, composed of at least 12 subunits, requires binding by Cdh1 or Cdc20 to function, allowing APC activity to be controlled in distinct subcellular compartments by either of these activator proteins [26]. The APC, specifically in conjunction with Cdh1, regulates axon length [25, 27, 28]. "
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    ABSTRACT: The ubiquitin-proteasome system (UPS) is most widely known for its role in intracellular protein degradation; however, in the decades since its discovery, ubiquitination has been associated with the regulation of a wide variety of cellular processes. The addition of ubiquitin tags, either as single moieties or as polyubiquitin chains, has been shown not only to mediate degradation by the proteasome and the lysosome, but also to modulate protein function, localization, and endocytosis. The UPS plays a particularly important role in neurons, where local synthesis and degradation work to balance synaptic protein levels at synapses distant from the cell body. In recent years, the UPS has come under increasing scrutiny in neurons, as elements of the UPS have been found to regulate such diverse neuronal functions as synaptic strength, homeostatic plasticity, axon guidance, and neurite outgrowth. Here we focus on recent advances detailing the roles of the UPS in regulating the morphogenesis of axons, dendrites, and dendritic spines, with an emphasis on E3 ubiquitin ligases and their identified regulatory targets.
    Neural Plasticity 02/2013; 2013(3, article e9842):196848. DOI:10.1155/2013/196848 · 3.58 Impact Factor
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    • "Proper regulation of APC Cdc20 may increase chromosome segregation fidelity, reducing non-disjunction events, and potentially increasing cellular healthspan. Other non-mitotic functions have now been ascribed to the APC, including maintaining neuronal development and genomic stability, as well as regulating chromatin metabolism and enhancing longevity in yeast and higher eukaryotic organisms (Harkness et al., 2002, 2004, 2005; Baker et al., 2004; Arnason et al., 2005; Turnell et al., 2005; Li et al., 2008; Turner et al., 2010; Eguren et al., 2011; Islam et al., 2011; Puram and Bonni, 2011; Postnikoff et al., 2012). As diverse as APC functions seem to be, regulatory mechanisms controlling APC output remain largely unknown. "
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    ABSTRACT: The longevity of an organism depends on the health of its cells. Throughout life cells are exposed to numerous intrinsic and extrinsic stresses, such as free radicals, generated through mitochondrial electron transport, and ultraviolet irradiation. The cell has evolved numerous mechanisms to scavenge free radicals and repair damage induced by these insults. One mechanism employed by the yeast Saccharomyces cerevisiae to combat stress utilizes the Anaphase Promoting Complex (APC), an essential multi-subunit ubiquitin-protein ligase structurally and functionally conserved from yeast to humans that controls progression through mitosis and G1. We have observed that yeast cells expressing compromised APC subunits are sensitive to multiple stresses and have shorter replicative and chronological lifespans. In a pathway that runs parallel to that regulated by the APC, members of the Forkhead box (Fox) transcription factor family also regulate stress responses. The yeast Fox orthologs Fkh1 and Fkh2 appear to drive the transcription of stress response factors and slow early G1 progression, while the APC seems to regulate chromatin structure, chromosome segregation, and resetting of the transcriptome in early G1. In contrast, under non-stress conditions, the Fkhs play a complex role in cell-cycle progression, partially through activation of the APC. Direct and indirect interactions between the APC and the yeast Fkhs appear to be pivotal for lifespan determination. Here we explore the potential for these interactions to be evolutionarily conserved as a mechanism to balance cell-cycle regulation with stress responses.
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