APC/CCdh1-dependent degradation of Cdc20 requires a phosphorylation on CRY-box by Polo-like kinase-1 during somatic cell cycle

Hyun, Sun-Yi; Sarantuya, Badmaarag; Lee, Hee-Jae; Jang, Young-Joo

doi:10.1016/j.bbrc.2013.04.073

Cited by 15 publications

(22 citation statements)

References 29 publications

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“…Consistently, depletion of Cullin 3 prolonged the half-life of Cdc20 (Figure2D and 2E), whereas ectopic expression of Cullin 3 shortened the half-life of Cdc20 in cells (Figure2F and 2G). These results together demonstrate that in addition to the reported APC Cdh1 E3 ligase [8, 42], Cullin 3-based E3 ligase also play a critical role in governing Cdc20 protein stability in cells.…”

Section: Resultssupporting

confidence: 64%

“…Previous studies have reported that Cdc20 was degraded by APC Cdh1 in early G1 phase, which is required of Plk1-dependent phosphorylation of Cdc20 [8, 42]. Our results presented here indicated that the Cullin 3 SPOP regulation of Cdc20 appears to function independently of APC Cdh1 .…”

Section: Discussionsupporting

confidence: 66%

“…Our results presented here indicated that the Cullin 3 SPOP regulation of Cdc20 appears to function independently of APC Cdh1 . Of particular interest in light of these results presented here as well as results from previous studies [8, 42], it remains elusive how these two E3 ligases, Cullin 3 SPOP and APC Cdh1 are controlling Cdc20 degradation. It is plausible that each E3 ligase is working in different cell cycle phase, or in a temporal or spatial specificity to provide a timely control of the Cdc20 stability.…”

Section: Discussionsupporting

confidence: 55%

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Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation

Dai

Gan

et al. 2017

Cancer Letters

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Recent studies revealed that mutations in SPOP (Speckle-type POZ protein) occur in up to 15% of patients with prostate cancer. However, the physiological role of SPOP in regulating prostate tumorigenesis remains elusive. Here, we identified the Cdc20 oncoprotein as a novel ubiquitin substrate of SPOP. As such, pharmacological inhibition of Cullin-based E3 ligases by MLN4924 could stabilize endogenous Cdc20 in cells. Furthermore, we found that Cullin 3, and, to a less extent, Cullin 1, specifically interacted with Cdc20. Depletion of Cullin 3, but not Cullin 1, could upregulate the abudance of Cdc20 largely via prolonging Cdc20 half-life. Moreover, SPOP, the adaptor protein of Cullin 3 family E3 ligase, specifically interacted with Cdc20, and promoted the poly-ubiquitinaton and subsequent degradation of Cdc20 in a degron-dependent manner. Importantly, prostate cancer-derived SPOP mutants failed to interact with Cdc20 to promote its degradation. As a result, SPOP-deficient prostate cancer cells with elevated Cdc20 expression became resistant to a pharmacological Cdc20 inhibitor. Therefore, our results revealed a novel role of SPOP in tumorigenesis in part by promoting the degradation of the Cdc20 oncoprotein.

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Section: Resultssupporting

confidence: 64%

Section: Discussionsupporting

confidence: 66%

Section: Discussionsupporting

confidence: 55%

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Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation

Dai

Gan

et al. 2017

Cancer Letters

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“…Substantial amounts of the complex are still present in anaphase cells when the SAC is supposed to be turned off. This probably should not be too surprising since the MAD2 level remains constant throughout the cell cycle and CDC20 is only degraded by the APC/C Cdh1 in late mitosis and G1303132 with substantial amounts of CDC20 still detectable in anaphase B HeLa cells (Fig. 2a).…”

Section: Resultsmentioning

confidence: 89%

The kinetochore-dependent and -independent formation of the CDC20-MAD2 complex and its functions in HeLa cells

Dang

Wood

et al. 2017

Sci Rep

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The mitotic checkpoint complex (MCC) is formed from two sub-complexes of CDC20-MAD2 and BUBR1-BUB3, and current models suggest that it is generated exclusively by the kinetochores after nuclear envelope breakdown (NEBD). However, neither sub-complex has been visualised in vivo, and when and where they are formed during the cell cycle and their response to different SAC conditions remains elusive. Using single cell analysis in HeLa cells, we show that the CDC20-MAD2 complex is cell cycle regulated with a "Bell" shaped profile and peaks at prometaphase. Its formation begins in early prophase before NEBD when the SAC has not been activated. The complex prevents the premature degradation of cyclin B1. Tpr, a component of the NPCs (nuclear pore complexes), facilitates the formation of this prophase form of the CDC20-MAD2 complex but is inactive later in mitosis. Thus, we demonstrate that the CDC20-MAD2 complex could also be formed independently of the SAC. Moreover, in prolonged arrest caused by nocodazole treatment, the overall levels of the CDC20-MAD2 complex are gradually, but significantly, reduced and this is associated with lower levels of cyclin B1, which brings a new insight into the mechanism of mitotic "slippage" of the arrested cells.The spindle assembly checkpoint (SAC) monitors the faithful segregation of the sister chromatids in mitosis by detecting kinetochore attachment 1,2 . It is believed that there is a diffusible "anaphase wait" signal which is initiated by unattached kinetochores and that even a single kinetochore will generate a sufficiently large signal to delay the metaphase/anaphase transition 3,4 . This signal functions by inhibiting the anaphase promoting complex or cyclosome (APC/C), an E3 ubiquitin ligase, which marks key mitotic regulators, such as cyclin B1 (CCNB1) and securin, for destruction and so prevents the premature onset of anaphase 1,5 .It was previously thought that the SAC signal was controlled in an "on" and "off " manner, and that it was activated after nuclear envelope breakdown (NEBD) in late prophase or early prometaphase in response to unattached kinetochores, and was then rapidly turned off at the metaphase/anaphase transition 1,2 . The MCC (mitotic checkpoint complex), containing the four proteins BUBR1, BUB3, CDC20 and MAD2, has been widely referred to as the predominant inhibitor of the APC/C at the molecular level, and is probably formed from two sub-complexes, CDC20-MAD2 and BUB3-BUBR1 1,2 . This kinetochore-dependant "on" and "off " mechanism has been challenged by the suggestion that the SAC signal is controlled like a "rheostat switch", where its strength depends on the amount of MAD2 recruited to the kinetochores and on the amount of MCC formed which are determined indirectly either by depletion of MAD2 or inhibition of MPS1 6 . However, despite the MCC playing a central role in SAC function, exactly how the MCC assembly is regulated in terms of the strength of the SAC in normal mitotic progression has yet to be revealed.The primary target of the SAC is CDC20/...

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“…For instance, activation of APC/C Cdh1 promotes the degradation of Cdc20 [88, 89], Plk1[137], Aurora A [76], Aurora B [77, 78] and Tpx2 [77], which ensures a low kinase activity environment to pave the road for mitotic exit. Interestingly, it was recently reported that the APC/C regulates spindle formation through promoting the degradation of four spindle-binding proteins Bard1, Hmmr, HURP and NuSAP [82].…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of Anaphase Promoting Complex/Cyclosome (APC/C) E3 ubiquitin ligases in tumorigenesis

Zhang

Wan

Dai

et al. 2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The Anaphase Promoting Complex/Cyclosome (APC/C) is a multi-subunit E3 ubiquitin ligase that primarily governs cell cycle progression. APC/C is composed of at least 14 core subunits and recruits its substrates for ubiquitination via one of the two adaptor proteins, Cdc20 or Cdh1, in M or M/early G1 phase, respectively. Furthermore, recent studies have shed light on crucial functions for APC/C in maintaining genomic integrity, neuronal differentiation, cellular metabolism and tumorigenesis. To gain better insight into the in vivo physiological functions of APC/C in regulating various cellular processes, particularly development and tumorigenesis, a number of mouse models of APC/C core subunits, coactivators or inhibitors have been established and characterized. However, due to their essential role in cell cycle regulation, most of the germline knockout mice targeting the APC/C pathway are embryonic lethal, indicating the need for generating conditional knockout mouse models to assess the role in tumorigenesis for each APC/C signaling component in specific tissues. In this review, we will first provide a brief introduction of the ubiquitin-proteasome system (UPS) and the biochemical activities and cellular functions of the APC/C E3 ligase. We will then focus primarily on characterizing genetic mouse models used to understand the physiological roles of each APC/C signaling component in embryogenesis, cell proliferation, development and carcinogenesis. Finally, we discuss future research directions to further elucidate the physiological contributions of APC/C components during tumorigenesis and validate their potentials as a novel class of anti-cancer targets.

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APC/CCdh1-dependent degradation of Cdc20 requires a phosphorylation on CRY-box by Polo-like kinase-1 during somatic cell cycle

Cited by 15 publications

References 29 publications

Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation

Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation

The kinetochore-dependent and -independent formation of the CDC20-MAD2 complex and its functions in HeLa cells

Functional characterization of Anaphase Promoting Complex/Cyclosome (APC/C) E3 ubiquitin ligases in tumorigenesis

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