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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The retinoblastoma protein (pRB) negatively regulates the progression from G1 to S phase of the cell cycle, in part, by repressing E2F-dependent transcription. pRB also possesses E2F-independent functions that contribute to cell-cycle control--for example, during pRB-mediated cell-cycle arrest pRB associates with Skp2, the F-box protein of the Skp1-Cullin-F-box protein (SCF) E3 ubiquitin ligase complex, and promotes the stability of the cyclin-dependent kinase-inhibitor p27(Kip1) through an unknown mechanism. Degradation of p27(Kip1) is mediated by ubiquitin-dependent targeting of p27(Kip1) by SCF -Skp2 (ref. 4). Here, we report a novel interaction between pRB and the anaphase-promoting complex/cyclosome (APC/C) that controls p27(Kip1) stability by targeting Skp2 for ubiquitin-mediated degradation. Cdh1, an activator of APC/C, not only interacts with pRB but is also required for a pRB-induced cell-cycle arrest. The results reveal an unexpected physical convergence between the pRB tumour-suppressor protein and E3 ligase complexes, and raise the possibility that pRB may direct APC/C to additional targets during pRB-mediated cell-cycle exit.
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PMID:Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. 1726 77

Progression through meiosis in yeast is governed by the cyclin-dependent kinase Cdk1, in concert with a related kinase called Ime2. It remains unclear how these kinases collaborate to meet the unique demands of meiotic progression. We demonstrate that Ime2 and Cdk1 phosphorylate an overlapping substrate set and that the two kinases overlap functionally as inhibitors of the ubiquitin ligase APC(Cdh1) and replication origin licensing. Surprisingly, Ime2 phosphorylates Cdk1 substrates at distinct phosphorylation sites that are highly resistant to dephosphorylation by the phosphatase Cdc14. We propose that Ime2-dependent phosphorylation of a subset of cell-cycle proteins limits the effects of Cdc14 in meiosis.
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PMID:Evolution of Ime2 phosphorylation sites on Cdk1 substrates provides a mechanism to limit the effects of the phosphatase Cdc14 in meiosis. 1734 56

Mitotic cyclin-dependent kinases (CDKs) control entry into mitosis, but their role during mitotic progression is less well understood. Here we characterize the functions of CDK activity associated with the mitotic cyclins Clb1, Clb2, and Clb3. We show that Clb-CDKs are important for the activation of the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C)-Cdc20 that triggers the metaphase-anaphase transition. Furthermore, we define an essential role for Clb-CDK activity in anaphase spindle elongation. Thus, mitotic CDKs serve not only to initiate M phase, but are also needed continuously throughout mitosis to trigger key mitotic events such as APC/C activation and anaphase spindle elongation.
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PMID:Mitotic CDKs control the metaphase-anaphase transition and trigger spindle elongation. 1851 44

Anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that destabilizes cell cycle proteins, is activated by Cdh1 in post-mitotic neurons, where it regulates axonal growth, synaptic plasticity and survival. The APC/C-Cdh1 substrate, cyclin B1, has been found to accumulate in degenerating brain areas in Alzheimer's disease and stroke. This highlights the importance of elucidating cyclin B1 regulation by APC/C-Cdh1 in neurons under stress conditions relevant to neurological disease. Here, we report that stimulation of N-methyl-D-aspartate receptors (NMDARs) that occurs in neurodegenerative diseases promoted the accumulation of cyclin B1 in the nuclei of cortical neurons; this led the neurons to undergo apoptotic death. Moreover, we found that the Ser-40, Thr-121 and Ser-163 triple phosphorylation of Cdh1 by the cyclin-dependent kinase-5 (Cdk5)-p25 complex was necessary and sufficient for cyclin B1 stabilization and apoptotic death after NMDAR stimulation. These results reveal Cdh1 as a novel Cdk5 substrate that mediates cyclin B1 neuronal accumulation in excitotoxicity.
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PMID:Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity. 1881 92

Genetic and biochemical studies have provided considerable insight into the multiple functions of cyclin-dependent kinase subunit (cks)1 in cell division cycle. In addition to enhanced substrate targeting by specific ubiquitin ligases SCF(skp2) and APC/C, its direct interaction with proteasome components normalizes multiple cell cycle regulators. Importantly, it also acts as a transcriptional regulator. cks1 overexpression reflects poor prognosis in malignancy thus indicating its possible role in tumour diagnosis and management. The present review compiles the multiple functional roles of cks1 in cell division with specific emphasis on its molecular mechanisms. Its docking functions and the possible downstream proteolytic and transcriptional targets are described. The spatial configuration of cks1-cdk2 complex and the structural organization of cks1-p27-skp2 assembly required for p27 ubiquitination are discussed in detail. In addition to enhanced p27 degradation, the possible other mechanisms which underlie its pathological functions in human cancer progression are also discussed. Though there are apparent gaps in information, the turnover mechanism of cks1 is well addressed and presents opportunity to exploit the target for disease management.
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PMID:Loss of cks1 homeostasis deregulates cell division cycle. 1922 69

The ubiquitin ligase Cdh1-anaphase promoting complex (Cdh1-APC) plays a key role in the control of axonal morphogenesis in the mammalian brain, but the mechanisms that regulate neuronal Cdh1-APC function remain incompletely understood. Here, we have characterized the effect of phosphorylation of Cdh1 at cyclin-dependent kinase (Cdk) sites on Cdh1-APC function in neurons. We replaced nine conserved sites of Cdk-induced Cdh1 phosphorylation with alanine (9A) or aspartate (9D) to mimic hypo- or hyper-phosphorylation, respectively. We found that the 9A mutation triggered the proteasome-dependent degradation of Cdh1, and conversely the 9D mutation stabilized Cdh1 in neuronal cells. However, the phosphomimic 9D Cdh1 protein failed to associate with the APC core protein Cdc27. In addition, whereas wild-type and 9A Cdh1 predominantly localized to the nucleus, the 9D Cdh1 protein accumulated in the cytoplasm in neurons. Importantly, in contrast to wild-type and 9A Cdh1, the 9D Cdh1 mutant failed to inhibit axon growth in primary cerebellar granule neurons. Collectively, our results suggest that phosphorylation of neuronal Cdh1 at Cdk sites triggers the stabilization of an inactive form of Cdh1 that accumulates in the cytoplasm, leading to the inhibition of Cdh1-APC function in the control of axon growth. Thus, phosphorylation of Cdh1 may represent a critical mechanism regulating Cdh1-APC function in the nervous system.
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PMID:Regulation of Cdh1-APC function in axon growth by Cdh1 phosphorylation. 1933 26

HTLV-1 Tax can induce senescence by up-regulating the levels of cyclin-dependent kinase inhibitors p21(CIP1/WAF1) and p27(KIP1). Tax increases p27(KIP1) protein stability by activating the anaphase promoting complex/cyclosome (APC/C) precociously, causing degradation of Skp2 and inactivation of SCF(Skp2), the E3 ligase that targets p27(KIP1). The rate of p21(CIP1/WAF1) protein turnover, however, is unaffected by Tax. Rather, the mRNA of p21(CIP1/WAF1) is greatly up-regulated. Here we show that Tax increases p21 mRNA expression by transcriptional activation and mRNA stabilization. Transcriptional activation of p21(CIP1/WAF1) by Tax occurs in a p53-independent manner and requires two tumor growth factor-beta-inducible Sp1 binding sites in the -84 to -60 region of the p21(CIP1/WAF1) promoter. Tax binds Sp1 directly, and the CBP/p300-binding activity of Tax is required for p21(CIP1/WAF1) trans-activation. Tax also increases the stability of p21(CIP1/WAF1) transcript. Several Tax mutants trans-activated the p21 promoter, but were attenuated in stabilizing p21(CIP1/WAF1) mRNA, and were less proficient in increasing p21(CIP1/WAF1) expression. The possible involvement of Tax-mediated APC/C activation in p21(CIP1/WAF1) mRNA stabilization is discussed.
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PMID:Induction of p21(CIP1/WAF1) expression by human T-lymphotropic virus type 1 Tax requires transcriptional activation and mRNA stabilization. 1935 50

One of the predominant cell-cycle programs found in mature tissues is endoreplication, also known as endoreduplication, that leads to cellular polyploidy. A key question for the understanding of endoreplication cycles is how oscillating levels of cyclin-dependent kinase activity are generated that control repeated rounds of DNA replication. The APC/C performs a pivotal function in the mitotic cell cycle by promoting anaphase and paving the road for a new round of DNA replication. However, using marker lines and plants in which APC/C components are knocked down, we show here that outgrowing and endoreplicating Arabidopsis leaf hairs display no or very little APC/C activity. Instead we find that RBX1-containing Cullin-RING E3 ubiquitin-Ligases (CRLs) are of central importance for the progression through endoreplication cycles; in particular, we have identified CULLIN4 as a major regulator of endoreplication in Arabidopsis trichomes. We have incorporated our findings into a bio-mathematical simulation presenting a robust two-step model of endoreplication control with one type of cyclin-dependent kinase inhibitor function for entry and a CRL-dependent oscillation of cyclin-dependent kinase activity via degradation of a second type of CDK inhibitor during endoreplication cycles.
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PMID:Cullin 4-ring finger-ligase plays a key role in the control of endoreplication cycles in Arabidopsis trichomes. 2069 6

The anaphase-promoting complex/cyclosome (APC/C) is the ubiquitin ligase essential to mitosis, which ensures that specific proteins are degraded at specific times to control the order of mitotic events. The APC/C coactivator, Cdc20, is targeted by the spindle assembly checkpoint (SAC) to restrict APC/C activity until metaphase, yet early substrates, such as cyclin A, are degraded in the presence of the active checkpoint. Cdc20 and the cyclin-dependent kinase cofactor, Cks, are required for cyclin A destruction, but how they enable checkpoint-resistant destruction has not been elucidated. In this study, we answer this problem: we show that the N terminus of cyclin A binds directly to Cdc20 and with sufficient affinity that it can outcompete the SAC proteins. Subsequently, the Cks protein is necessary and sufficient to promote cyclin A degradation in the presence of an active checkpoint by binding cyclin A-Cdc20 to the APC/C.
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PMID:How cyclin A destruction escapes the spindle assembly checkpoint. 2073 51

Ubiquitin-mediated proteolysis is one of the key mechanisms underlying cell cycle control in all eukaryotes. This is achieved by the action of ubiquitin ligases (E3s), which remove both negative and positive regulators of the cell cycle. Though our current understanding of the plant cell cycle has improved a lot these recent years, the identity of the E3s regulating it and their mode of action is still in its infancy. Nevertheless, recent research in Arabidopsis revealed some novel findings in this area. Thus the anaphase promoting complex/cyclosome (APC/C) not only controls mitotic events, but is also important in post-mitotic cells for normal plant development and cell differentiation. Moreover conserved and novel E3s were identified that target cyclin-dependent kinase inhibitors at different plant developmental stages. Finally, environmental constrains and stress hormones negatively impact on the cell cycle by processes that also include E3s.
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PMID:Selective proteolysis sets the tempo of the cell cycle. 2081 Mar 5


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