Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Centrosome duplication involves the formation of a single procentriole next to each centriole, once per cell cycle. The mechanisms governing procentriole formation and those restricting its occurrence to one event per centriole are poorly understood. Here, we show that HsSAS-6 is necessary for procentriole formation and that it localizes asymmetrically next to the centriole at the onset of procentriole formation. HsSAS-6 levels oscillate during the cell cycle, with the protein being degraded in mitosis and starting to accumulate again at the end of the following G1. Our findings indicate that APC(Cdh1) targets HsSAS-6 for degradation by the 26S proteasome. Importantly, we demonstrate that increased HsSAS-6 levels promote formation of more than one procentriole per centriole. Therefore, regulated HsSAS-6 levels normally ensure that each centriole seeds the formation of a single procentriole per cell cycle, thus playing a fundamental role in driving the centrosome duplication cycle and ensuring genome integrity.
 ...
PMID:Regulated HsSAS-6 levels ensure formation of a single procentriole per centriole during the centrosome duplication cycle. 1768 Nov 32

Deregulated centrosome duplication can result in genetic instability and contribute to tumorigenesis. Here, we show that centrosome duplication is regulated by the activity of an E3-ubiquitin ligase that employs the F-box protein FBXW5 (ref. 3) as its targeting subunit. Depletion of endogenous FBXW5 or overexpression of an F-box-deleted mutant version results in centrosome overduplication and formation of multipolar spindles. We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6. FBXW5 is a cell-cycle-regulated protein with expression levels peaking at the G1/S transition. We show that FBXW5 levels are controlled by the anaphase-promoting (APC/C) complex, which targets FBXW5 for degradation during mitosis and G1, thereby helping to reset the centrosome duplication machinery. In summary, we show that a cell-cycle-regulated SCF complex is regulated by the kinase PLK4, and that this in turn restricts centrosome re-duplication through degradation of the centriolar protein HsSAS-6.
 ...
PMID:The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication. 2180 43

Regulatory mechanisms to prevent centriole overduplication during the cell cycle are not completely understood. In this issue, FBXW5 is shown to control the degradation of the centriole assembly factor HsSAS-6. Moreover, the study proposes that FBXW5 is a substrate of both PLK4 and APC/C, two established regulators of centriole duplication.
 ...
PMID:FBXW5 controls centrosome number. 2172 16

Control of centriole number is crucial for genome stability and ciliogenesis. Here, we characterize the role of human STIL, a protein that displays distant sequence similarity to the centriole duplication factors Ana2 in Drosophila and SAS-5 in Caenorhabditis elegans. Using RNA interference, we show that STIL is required for centriole duplication in human cells. Conversely, overexpression of STIL triggers the near-simultaneous formation of multiple daughter centrioles surrounding each mother, which is highly reminiscent of the phenotype produced by overexpression of the polo-like kinase PLK4 or the spindle assembly abnormal protein 6 homolog (SAS-6). We further show, by fluorescence and immunoelectron microscopy, that STIL is recruited to nascent daughter centrioles at the onset of centriole duplication and degraded, in an APC/C(Cdc20-Cdh1)-dependent manner, upon passage through mitosis. We did not detect a stable complex between STIL and SAS-6, but the two proteins resemble each other with regard to both localization and cell cycle control of expression. Thus, STIL cooperates with SAS-6 and PLK4 in the control of centriole number and represents a key centriole duplication factor in human cells.
 ...
PMID:Cell-cycle-regulated expression of STIL controls centriole number in human cells. 2234 98

In animal cells, centriole number is strictly controlled in order to guarantee faithful cell division and genetic stability, but the mechanism by which the accuracy of centrosome duplication is maintained is not fully understood. Here, we show that CCDC84 constrains centriole number by modulating APC/CCdh1-mediated HsSAS-6 degradation. More importantly, CCDC84 acetylation oscillates throughout the cell cycle, and the acetylation state of CCDC84 at lysine 31 is regulated by the deacetylase SIRT1 and the acetyltransferase NAT10. Deacetylated CCDC84 is responsible for its centrosome targeting, and acetylated CCDC84 promotes HsSAS-6 ubiquitination by enhancing the binding affinity of HsSAS-6 for Cdh1. Our findings shed new light on the function of (de)acetylation in centriole number regulation as well as refine the established centrosome duplication model.
 ...
PMID:CCDC84 Acetylation Oscillation Regulates Centrosome Duplication by Modulating HsSAS-6 Degradation. 3172 19