Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1

Höckner, Sebastian; Neumann-Arnold, Lea; Seufert, Wolfgang

doi:10.1091/mbc.e15-11-0787

Cited by 24 publications

(15 citation statements)

References 91 publications

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“…It is well established that in normal cells, phosphorylation of CDH1 at the G 1 -S-transition is driven by Cyclin-CDK complexes and is required to dissociate CDH1 from the APC/C and hence reduce ligase activity to allow accumulation of proteins needed for S-phase progression (24,27,(35)(36)(37)(38). APC/C CDH1 activity can also be reduced by CDH1 phosphorylation events that lead to decreased CDH1 stability or drive localization changes of CDH1 between the nucleus and cytoplasm (36,(39)(40)(41). We observed an increase in CDH1 phosphorylation and a concordant decreased binding of CDH1 to the APC/C, but of note, all of our studies were focused on APC/C CDH1 in early G 1 , just after cells have transitioned from mitosis, and not at the G 1 -S-transition where phos-phorylation on CDH1 normally would occur.…”

Section: Discussionmentioning

confidence: 99%

Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CCDH1 Activity and Pharmacologic Inhibition of APC/CCDH1/CDC20 Compromises Viability

Grubb

Zalenski

et al. 2019

Molecular Cancer Research

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Glioblastoma (GBM) is the most common and lethal primary brain tumor and remains incurable. This is in part due to the cellular heterogeneity within these tumors, which includes a subpopulation of treatment-resistant cells called cancer stem-like cells (CSC). We previously identified that the anaphase-promoting complex/cylosome (APC/C), a key cell-cycle regulator and tumor suppressor, had attenuated ligase activity in CSCs. Here, we assessed the mechanism of reduced activity, as well as the efficacy of pharmacologically targeting the APC/C in CSCs. We identified hyperphosphorylation of CDH1, but not pseudosubstrate inhibition by early mitotic inhibitor 1 (EMI1), as a major mechanism driving attenuated APC/C CDH1 activity in the G 1 -phase of the cell cycle in CSCs. Small-molecule inhibition of the APC/C reduced viability of both CSCs and nonstem tumor cells (NSTCs), with the combination of proTAME and apcin having the biggest impact. Combinatorial drug treatment also led to the greatest mitotic arrest and chromosomal abnormalities.Implications: Our findings demonstrate how the activity of the APC/C CDH1 tumor suppressor is reduced in CSCs and also validates small-molecule inhibition of the APC/C as a promising therapeutic target for the treatment of GBM.

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Section: Discussionmentioning

confidence: 99%

Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CCDH1 Activity and Pharmacologic Inhibition of APC/CCDH1/CDC20 Compromises Viability

Grubb

Zalenski

et al. 2019

Molecular Cancer Research

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“…The APC/C E2 enzymes, Ube2S and Ube2C, are unstable proteins and are also APC/C substrates [4,96]. The substrate receptor Cdh1 is subject to CDK dependent phosphorylation, preventing its association with the APC/C and likely affecting its localization [89,[97][98][99][100][101]. Finally, accumulation of Emi1 is controlled by E2F, contributing to APC/C inhibition [16,80,84].…”

Section: Involvement Of Apc/c In G1/smentioning

confidence: 99%

Ubiquitin Signaling in Regulation of the Start of the Cell Cycle

Emanuele¹,

Enrico²

2019

Ubiquitin Proteasome System - Current Insights Into Mechanism Cellular Regulation and Disease

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The small protein ubiquitin plays a vital role in virtually all aspects of cellular life. Among the diverse signaling outcomes associated with ubiquitination, the most well-established is the targeted degradation of substrates via the proteasome. During cell growth and proliferation, ubiquitin plays an outsized role in promoting progression through the cell cycle. In particular, ubiquitin-mediated degradation is critically important at transition points where it provides directionality and irreversibility to the cell cycle, which is essential for maintaining genome integrity. Specifically, the boundary between G1 and S-phase is tightly regulated by the ubiquitin proteasome system. Notably, the G1/S boundary represents a major barrier to cell proliferation and is universally dysfunctional in cancer cells, allowing for the unbridled proliferation observed in malignancy. Numerous E3 ubiquitin ligases, which facilitate the ubiquitination of specific substrates, have been shown to control G1/S. In this chapter, we will discuss components in the ubiquitin proteasome system that are implicated in G1/S control, how these enzymes are interconnected, gaps in our current knowledge, and the potential role of these pathways in the cancer cycle and disease proliferation.

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“…These phosphorylations regulate both Cdh1 localization and its ability to bind APC/C. These Cdc28 sites can be subdivided into two groups, according to their location and functionality ( Figure 8A) (Hockner et al, 2016): sites 1-3 regulate Cdh1 localization, whereas sites 4-9 mediate its interaction with APC/C. Dephosphorylation of Cdh1 sites 1-3 leads to preferential accumulation of Cdh1in the nucleus.…”

Section: Cdk-mediated Phosphorylation May Regulate Cdh1 Stabilitymentioning

confidence: 99%

“…Cdh1 is inhibited by phosphorylation by cyclin-dependent protein kinases (CDK), polo-like kinase Cdc5, and the meiosis-specific kinase Ime2 Jaquenoud et al, 2002;Zhou et al, 2003;Holt et al, 2007;Crasta et al, 2008). CDK interacts with Cdh1 in a complex, mutually inhibitory manner: Cdh1 inhibits CDK by promoting the ubiquitination and degradation mitotic B-cyclins, whereas CDK-mediated phosphorylation near a nuclear localization signal (NLS) in Cdh1 and near its C-box cause its nuclear export and prevent its interaction with the core APC/C, respectively (Brandeis and Hunt, 1996;Irniger and Nasmyth, 1997;Schwab et al, 1997;Zachariae et al, 1998;Jaspersen et al, 1999;Hockner et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

APC/C^Cdh1-mediated degradation of Cdh1 during meiosis inS. cerevisiae

Ostapenko

Solomon

2018

Preprint

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The Anaphase-Promoting Complex/Cyclosome (APC/C) is a ubiquitin ligase that promotes the ubiquitination and subsequent degradation of numerous cell cycle regulators during mitosis and in G1. Proteins are recruited to the APC/C by activator proteins such as Cdh1.During the cell cycle, Cdh1 is subject to precise regulation so that substrates are not degraded prematurely. We have explored the regulation of Cdh1 during the developmental transition into meiosis and sporulation in the budding yeast S. cerevisiae. Transition to sporulation medium triggers the degradation of Cdh1. Degradation requires that cells be of the a/a mating type and be starved for glucose, but they do not actually need to enter into the meiotic program.Degradation requires an intact SNF1 protein kinase complex (orthologous to the mammalian AMPK nutritional sensor), which is activated by the absence of glucose. Cdh1 degradation is mediated by the APC/C itself in a 'trans' mechanism in which one molecule of Cdh1 recruits a second molecule of Cdh1 to the APC/C for ubiquitination. However, Cdh1-Cdh1 recognition does not depend on the degradation motifs or binding sites involved in the recognition of typical APC/C substrates. We hypothesize that Cdh1 degradation is necessary for the preservation of cell cycle regulators and chromosome cohesion proteins between the reductional and equational meiotic divisions, which occur without the intervening Gap or S phases found in mitotic cell cycles.

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Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1

Cited by 24 publications

References 91 publications

Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CCDH1 Activity and Pharmacologic Inhibition of APC/CCDH1/CDC20 Compromises Viability

Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CCDH1 Activity and Pharmacologic Inhibition of APC/CCDH1/CDC20 Compromises Viability

Ubiquitin Signaling in Regulation of the Start of the Cell Cycle

APC/C^Cdh1-mediated degradation of Cdh1 during meiosis inS. cerevisiae

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Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1

Cited by 24 publications

References 91 publications

Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CCDH1 Activity and Pharmacologic Inhibition of APC/CCDH1/CDC20 Compromises Viability

Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CCDH1 Activity and Pharmacologic Inhibition of APC/CCDH1/CDC20 Compromises Viability

Ubiquitin Signaling in Regulation of the Start of the Cell Cycle

APC/CCdh1-mediated degradation of Cdh1 during meiosis inS. cerevisiae

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APC/C^Cdh1-mediated degradation of Cdh1 during meiosis inS. cerevisiae