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Query: UMLS:C0033036 (
APC
)
10,214
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Human
Aurora-A
is related to a protein kinase originally identified by its close homology to Ipl1p from Saccharomyces cerevisiae and aurora from Drosophila melanogaster, which are key regulators of the structure and function of the mitotic spindle. We previously showed that human
Aurora-A
is turned over through the anaphase promoting complex/cyclosome (
APC
/C)-ubiquitin-proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the
APC
/C. The present study shows that
Aurora-A
degradation is dependent on hCdh1 in vivo, not on hCdc20, and that
Aurora-A
is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity.
...
PMID:Degradation of human Aurora-A protein kinase is mediated by hCdh1. 1202 18
We have demonstrated previously that Xenopus
Aurora-A
is degraded at late mitosis by the
APC
/Fizzy-Related in a D-Box-dependent manner. Here we demonstrate that, although Aurora-B possesses the same D-Box as
Aurora-A
, Aurora-B is not degraded by this ubiquitin ligase. We have constructed a chimera
Aurora-A
/B with the N-terminus of
Aurora-A
and the C-terminus of Aurora-B and we have examined its degradation by
APC
/Fizzy-Related. We demonstrate that the N-terminus of
Aurora-A
confers degradation capacity on the C-terminus of Aurora-B and that this feature is blocked by mutation of the conserved D-Box sequence. We characterize the minimal degradation signal at the N-terminus of
Aurora-A
and demonstrate that its deletion blocks the degradation of this protein by
APC
/Fizzy-Related. Thus, we conclude that two different degradation signals are required for proteolysis of
Aurora-A
. The first one, which we designated D-Box-activating domain, within the N-terminal domain of
Aurora-A
confers the functionality to the second, a silent D-Box, present within the C-terminus of the kinase.
...
PMID:The D-Box-activating domain (DAD) is a new proteolysis signal that stimulates the silent D-Box sequence of Aurora-A. 1244 69
L2DTL is a human ortholog of Drosophila lethal (2) denticleless, l(2)dtl. This study is to elucidate its function and clinicopathological significance in hepatocellular carcinoma (HCC) progression. We used RT-PCR, immunostaining, Western blotting, and centrosome isolation to determine the L2DTL expression and protein localization, and RNAi to analyze its role in tumor cell growth. L2DTL protein located to the nucleus in interphase and centered to centrosomes, with colocalization of gamma-tubulin and
Aurora-A
, throughout the cell cycle, and cofractionated with gamma-tubulin. L2DTL gene expression increased during G1/S phase, and the DNA synthesis in liver regeneration. L2DTL protein decreased in mitosis via degradation by the
APC
/C-Cdh1 complex. L2DTL was downregulated in the induced differentiation of HepG2 and NT2 cells. L2DTL downregulation by RNAi oligos led to reduced cancer cell growth and invasion capability in vitro, in which microarray analysis disclosed dysregulation of genes involved in cell cycle regulation, chromosome segregation, and cell division. L2DTL overexpressed in 59% of 270 resected, unifocal, primary HCCs. L2DTL overexpression correlated with bigger tumor (p=0.000003), high-grade (p=0.00003), and high-stage tumors with portal vein invasion (p=1x10(-8)). L2DTL overexpression was associated with a lower 10-year survival, particularly in the p53-mutated HCCs (p=0.00006). In conclusion, L2DTL encodes a nuclear protein with centrosome targeting in mitosis, and plays important roles in DNA synthesis, cell cycle progression, cytokinesis, proliferation, and differentiation. L2DTL overexpression is associated with enhanced metastatic potential of HCC, and contributes synergistically with p53 mutation, which leads to the loss of p53-governed checkpoints, toward advanced HCC with poor prognosis.
...
PMID:Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma. 1710 65
Mitotic
Aurora-A
is an oncogene, which undergoes a cell-cycle-dependent regulation of both its synthesis and degradation. Overexpression of
Aurora-A
leads to aneuploidy and cellular transformation in cultured cells. It has been shown that the cell-cycle-dependent turnover of
Aurora-A
is mediated by Cdh1 (CDC20 homologue 1) through the anaphase-promoting complex/cyclosome (
APC
/C)-ubiquitin-proteasome pathway. We have described previously the identification of an
Aurora-A
kinase interacting protein, AURKAIP1 (formerly described as AIP), which is also involved in the destabilization of
Aurora-A
through the proteasome-dependent degradation pathway. In an attempt to investigate the mechanism of AURKAIP1-mediated
Aurora-A
degradation, we report here that AURKAIP1 targets
Aurora-A
for degradation in a proteasome-dependent but Ub (ubiquitin)-independent manner. AURKAIP1 inhibits polyubiquitination of
Aurora-A
. A non-interactive AURKAIP1 mutant that cannot destabilize
Aurora-A
restores ubiquitination of
Aurora-A
. An A-box mutant of
Aurora-A
, which cannot be targeted for proteasome-dependent degradation by Cdh1, can still be degraded by AURKAIP1. Inhibition of cellular ubiquitination either by expression of dominant negative Ub mutants or by studies in ts-20 (temperature sensitive-20) CHO (Chinese-hamster ovary) cell line lacking the E1 Ub activating enzyme at the restrictive temperature, cannot abolish AURKAIP1-mediated degradation of
Aurora-A
. AURKAIP1 specifically decreases the stability of
Aurora-A
in ts-20 CHO cells at the restrictive temperature, while cyclinB1 and p21 are not affected. This demonstrates that there exists an Ub-independent alternative pathway for
Aurora-A
degradation and AURKAIP1 promotes
Aurora-A
degradation through this Ub-independent yet proteasome-dependent pathway.
...
PMID:Aurora-A kinase interacting protein 1 (AURKAIP1) promotes Aurora-A degradation through an alternative ubiquitin-independent pathway. 1712 67
Entry into mitosis is a highly regulated process, promoted by the activated Cyclin B1/Cdk1 complex. Activation of this complex is controlled, in part, by the protein kinase
Aurora-A
, which is a member of a multigenic serine/threonine kinase family. In normal cells,
Aurora-A
activity is regulated, at least in part, by degradation through the
APC
-ubiquitin-proteasome pathway. It has recently been proposed that, in Xenopus,
Aurora-A
degradation can be inhibited by phosphorylation. It would thus be expected that a phosphatase activity would release this blockade at the end of mitosis. Here, we have shown that the protein phosphatase PP2A and
Aurora-A
are colocalized at the cell poles during mitosis in human cells and interact within the same complex. Using the PP2A inhibitor okadaic acid and an RNAi approach, we have shown that this interaction is functional within the cell. PP2A/
Aurora-A
interaction is promoted by an S51D mutation in
Aurora-A
and inhibited by a phosphomimetic peptide centered around
Aurora-A
S51, thereby strongly suggesting that PP2A controls
Aurora-A
degradation by dephosphorylating serine 51 in the A box of the human enzyme.
...
PMID:Functional interaction of Aurora-A and PP2A during mitosis. 1722 85
The mitotic regulator
Aurora-A
is an oncogenic protein that is over-expressed in many types of human tumors. However, the underlying mechanism through which
Aurora-A
promotes tumorigenesis remains unclear. Here, we show that overexpression of
Aurora-A
causes an elevation of Cyclin B1 expression. Cyclin B1 degradation is delayed in
Aurora-A
over-expressing cells, which depends on
Aurora-A
kinase activity. In contrast,
Aurora-A
RNAi enhances Cyclin B1 degradation. Furthermore, we found that
Aurora-A
interacts with Cyclin B1, and that
Aurora-A
overexpression reduces the interaction of Cyclin B1 with
APC
subunits. In human esophageal squamous cell carcinomas (ESCC), overexpression of
Aurora-A
was correlated with deregulated expression of Cyclin B1. Taken together, these findings suggest that overexpression of
Aurora-A
may stabilize Cyclin B1 through inhibiting its degradation. These results provide new insight into the mechanism of how deregulated
Aurora-A
contributes to genomic instability and carcinogenesis.
...
PMID:Aurora-A interacts with Cyclin B1 and enhances its stability. 1902 17
The
Aurora-A
kinase has well-established roles in spindle assembly and function and is frequently overexpressed in tumours. Its abundance is cell cycle regulated, with a peak in G2 and M phases, followed by regulated proteolysis at the end of mitosis. The microtubule-binding protein TPX2 plays a major role in regulating the activity and localisation of
Aurora-A
in mitotic cells. Here, we report a novel regulatory role of TPX2 and show that it protects
Aurora-A
from degradation both in interphase and in mitosis in human cells. Specifically,
Aurora-A
levels decrease in G2 and prometaphase cells silenced for TPX2, whereas degradation of
Aurora-A
is impaired in telophase cells overexpressing the
Aurora-A
-binding region of TPX2. The decrease in
Aurora-A
in TPX2-silenced prometaphases requires proteasome activity and the Cdh1 activator of the
APC
/C ubiquitin ligase. Reintroducing either full-length TPX2, or the
Aurora-A
-binding region of TPX2, but not a truncated TPX2 mutant lacking the
Aurora-A
-interaction domain, restores
Aurora-A
levels in TPX2-silenced prometaphases. The control by TPX2 of
Aurora-A
stability is independent of its ability to activate
Aurora-A
and to localise it to the spindle. These results highlight a novel regulatory level impinging on
Aurora-A
and provide further evidence for the central role of TPX2 in regulation of
Aurora-A
.
...
PMID:Control of Aurora-A stability through interaction with TPX2. 2114 53
Aurora-A
, a centrosomal
serine-threonine kinase
, orchestrates several key aspects of cell division. However, the regulatory pathways for the protein stability and kinase activity of
Aurora-A
are still not completely understood. In this study, PUM2, an RNA-binding protein, is identified as a novel substrate and interacting protein of
Aurora-A
. Overexpression of the PUM2 mutant which fails to interact with
Aurora-A
, and depletion of PUM2 result in a decrease in the amount of
Aurora-A
. PUM2 physically binds to the D-box of
Aurora-A
, which is recognized by
APC
/C(Cdh1). Overexpression of PUM2 prevents ubiquitination and enhances the protein stability of
Aurora-A
, suggesting that PUM2 protects
Aurora-A
from
APC
/C(Cdh1)-mediated degradation. Moreover, association of PUM2 with
Aurora-A
not only makes
Aurora-A
more stable but also enhances the kinase activity of
Aurora-A
. Our study suggests that PUM2 plays two different but important roles during cell cycle progression. In interphase, PUM2 localizes in cytoplasm and plays as translational repressor through its RNA binding domain. However, in mitosis, PUM2 physically associates with
Aurora-A
to ensure enough active
Aurora-A
at centrosomes for mitotic entry. This is the first time to reveal the moonlight role of PUM2 in mitosis.
...
PMID:A translational regulator, PUM2, promotes both protein stability and kinase activity of Aurora-A. 2158 36
Members of sirtuin family regulate multiple critical biological processes, yet their role in carcinogenesis remains controversial. To investigate the physiological functions of SIRT2 in development and tumorigenesis, we disrupted Sirt2 in mice. We demonstrated that SIRT2 regulates the anaphase-promoting complex/cyclosome activity through deacetylation of its coactivators,
APC
(CDH1) and CDC20. SIRT2 deficiency caused increased levels of mitotic regulators, including
Aurora-A
and -B that direct centrosome amplification, aneuploidy, and mitotic cell death. Sirt2-deficient mice develop gender-specific tumorigenesis, with females primarily developing mammary tumors, and males developing more hepatocellular carcinoma (HCC). Human breast cancers and HCC samples exhibited reduced SIRT2 levels compared with normal tissues. These data demonstrate that SIRT2 is a tumor suppressor through its role in regulating mitosis and genome integrity.
...
PMID:SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. 2201 74
Aurora A kinase (AURKA) is overexpressed in 96% of human cancers and is considered an independent marker of poor prognosis. While the majority of tumors have elevated levels of
AURKA protein
, few have AURKA gene amplification, implying that posttranscriptional mechanisms regulating
AURKA protein
levels are significant. Here, we show that NEDD9, a known activator of AURKA, is directly involved in AURKA stability. Analysis of a comprehensive breast cancer tissue microarray revealed a tight correlation between the expression of both proteins, significantly corresponding with increased prognostic value. A decrease in AURKA, concomitant with increased ubiquitination and proteasome-dependent degradation, occurs due to depletion or knockout of NEDD9. Reexpression of wild-type NEDD9 was sufficient to rescue the observed phenomenon. Binding of NEDD9 to AURKA is critical for AURKA stabilization, as mutation of S296E was sufficient to disrupt binding and led to reduced
AURKA protein
levels. NEDD9 confers AURKA stability by limiting the binding of the cdh1-substrate recognition subunit of
APC
/C ubiquitin ligase to AURKA. Depletion of NEDD9 in tumor cells increases sensitivity to AURKA inhibitors. Combination therapy with NEDD9 short hairpin RNAs and AURKA inhibitors impairs tumor growth and distant metastasis in mice harboring xenografts of breast tumors. Collectively, our findings provide rationale for the use of AURKA inhibitors in treatment of metastatic tumors and predict the sensitivity of the patients to AURKA inhibitors based on NEDD9 expression.
...
PMID:NEDD9 depletion destabilizes Aurora A kinase and heightens the efficacy of Aurora A inhibitors: implications for treatment of metastatic solid tumors. 2353 42
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