APC/C and SCF cyclin F Constitute a Reciprocal Feedback Circuit Controlling S-Phase Entry

Choudhury, Rajarshi; Bonacci, Thomas; Arceci, Anthony; Lahiri, Debojyoti; Mills, Christine A.; Kernan, Jennifer L.; Branigan, Timothy; DeCaprio, James A.; Burke, Daniel J.; Emanuele, Michael J.

doi:10.1016/j.celrep.2016.08.058

Cited by 73 publications

(112 citation statements)

References 56 publications

(102 reference statements)

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“…AKT1 and AKT2 were depleted from 293T cells by siRNAs and cells were treated with the protein translation inhibitor cycloheximide (CHX). Semi-quantitative analysis of immunoblots performed on these experiment indicates that in control cells (siFF), the half-life of Cyclin F was approximately 137 minutes, consistent with prior observations (Choudhury et al, 2016; D’Angiolella et al, 2012). Following AKT depletion the half-life of Cyclin F was reduced to ~111 minutes (Figure 2C and 2D).…”

Section: Resultssupporting

confidence: 87%

“…We recently demonstrated that Cyclin F is targeted for degradation during G1 phase by a cell cycle E3 ubiquitin ligase termed the Anaphase Promoting Complex/Cyclosome (APC/C) (Choudhury et al, 2016). Cdh1/Fzr1, the substrate receptor for the APC/C during G1 phase, is critical for mediating Cyclin F degradation.…”

Section: Introductionmentioning

confidence: 99%

“…This direct, reciprocal relationship between the APC/C and SCF(Cyclin F) represents an important negative feedback circuit regulating cell cycle progression. Interestingly, Cyclin F accumulation begins in late G1 when APC/C(Cdh1) is presumably still active (Choudhury et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

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The E3 Ubiquitin Ligase SCF(Cyclin F) Transmits AKT Signaling to the Cell-Cycle Machinery

et al. 2017

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SUMMARY The oncogenic AKT kinase is a key regulator of apoptosis, cell growth and cell cycle progression. Despite its important role in proliferation, it remains largely unknown how AKT is mechanistically linked to cell cycle. We show here that Cyclin F, a substrate receptor F-box protein for the SCF family of E3 ubiquitin ligases, is a bona fide AKT substrate. Cyclin F expression oscillates throughout the cell cycle, a rare feature among the 69 human F-box proteins, and all of its known substrates are involved in proliferation. AKT phosphorylation of Cyclin F enhances its stability and promotes assembly into productive E3 ligase complexes. Importantly, expression of mutant versions of Cyclin F that cannot be phosphorylated by AKT impair cell cycle entry. Our data suggest that Cyclin F transmits mitogen signaling through AKT to the core cell cycle machinery. This discovery has potential implications for proliferative control in malignancies where AKT is activated.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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The E3 Ubiquitin Ligase SCF(Cyclin F) Transmits AKT Signaling to the Cell-Cycle Machinery

et al. 2017

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“…We first investigated known APC/C Cdh1 substrates that may also negatively regulate APC/C Cdh1 to generate dual-negative feedback. The cullin E3 ligases SCF Skp2 and SCF Cyclin F have both been reported to degrade APC/C Cdh1 components 7,8 , and Cyclin A2/CDK2 can mediate APC/C Cdh1 inhibition by phosphorylating Cdh1 9,10 . Knockdown of Cyclin A2, Skp2, or Cyclin F (Extended Data Fig.…”

mentioning

confidence: 99%

EMI1 switches from being a substrate to an inhibitor of APC/CCDH1 to start the cell cycle

Cappell

Mark

Garbett

et al. 2018

Nature

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Mammalian cells integrate mitogen and stress signaling prior to the end of G1 phase to decide whether or not to enter the cell cycle1–4. Before cells can replicate their DNA in S phase, they have to activate cyclin-dependent kinases (CDKs), induce an E2F transcription program, and inactivate an E3 ubiquitin ligase, the anaphase promoting complex/cyclosome (APC/CCdh1). It was recently shown that stress can return cells to quiescence after CDK2 activation and E2F induction but cannot after inactivation of APC/CCdh1, arguing that APC/CCdh1 inactivation is the point-of-no-return for cell cycle entry3. While rapid inactivation of APC/CCdh1 requires early mitotic inhibitor 1 (Emi1)3,5, the molecular mechanism controlling this cell cycle commitment step is unknown. Here we show that cell cycle commitment is mediated by an Emi1-APC/CCdh1 dual-negative feedback switch, in which Emi1 is both a substrate and an inhibitor of APC/CCdh1. The inactivation switch triggers a transition between a state with low Emi1 levels and high APC/CCdh1 activity during G1 to a state with high Emi1 levels and low APC/CCdh1 activity during S and G2. Cell-based analysis, in vitro reconstitution, and modeling data show that the underlying dual-negative feedback is bistable and represents a robust irreversible switch. Together, our study argues that mammalian cells commit to the cell cycle by increasing CDK2 activity and Emi1 mRNA expression to trigger a one-way APC/CCdh1 inactivation switch mediated by Emi1 transitioning from a substrate to an inhibitor of APC/CCdh1.

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“…Since VprBP is not overexpressed at the mRNA level based on transcriptomic analysis, it is presumably due to regulation of either its translation or its degradation. Cross talk between cell cycle E3 ligases is an emerging theme in cell cycle control (63), and perhaps VprBP stability is controlled by a second ubiquitin ligase.…”

Section: Discussionmentioning

confidence: 99%

VprBP/DCAF1 Regulates the Degradation and Nonproteolytic Activation of the Cell Cycle Transcription Factor FoxM1

Wang

Arceci

Bird

et al. 2017

Molecular and Cellular Biology

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The oncogenic transcription factor FoxM1 plays a vital role in cell cycle progression, is activated in numerous human malignancies, and is linked to chromosome instability. We characterize here a cullin 4-based E3 ubiquitin ligase and its substrate receptor, VprBP/DCAF1 (CRL4 VprBP ), which we show regulate FoxM1 ubiquitylation and degradation. Paradoxically, we also found that the substrate receptor VprBP is a potent FoxM1 activator. VprBP depletion reduces expression of FoxM1 target genes and impairs mitotic entry, whereas ectopic VprBP expression strongly activates a FoxM1 transcriptional reporter. VprBP binding to CRL4 is reduced during mitosis, and our data suggest that VprBP activation of FoxM1 is ligase independent. This implies a nonproteolytic activation mechanism that is reminiscent of, yet distinct from, the ubiquitin-dependent transactivation of the oncoprotein Myc by other E3s. Significantly, VprBP protein levels were upregulated in high-grade serous ovarian patient tumors, where the FoxM1 signature is amplified. These data suggest that FoxM1 abundance and activity are controlled by VprBP and highlight the functional repurposing of E3 ligase substrate receptors independent of the ubiquitin system. KEYWORDS cell cycle, cullin ring ligase, FoxM1, transcriptional regulation, ubiquitination C hanges in gene expression combined with targeted protein degradation dynamically shape the protein landscape. Gene expression is coordinated by transcription factors that specify genes for activation and cofactors that modulate transcription factor activity or alter the local chromatin environment. Posttranslational modifications (PTMs) play a crucial role in transcriptional dynamics. Phosphorylation, acetylation, methylation, and ubiquitylation of histone proteins are well studied and contribute significantly to gene expression dynamics (1). Similarly, posttranslational modification of transcription factors plays an important role in regulating genome output.FoxM1 is an oncogenic, cell cycle-regulated transcription factor that was discovered as both a marker and a key mediator of cell proliferation (2-4). Subsequent work clarified the importance of FoxM1 in proliferation through its role in cell cycle progression (reviewed in reference 5). FoxM1 controls the mitotic transcriptional program, and its depletion significantly impairs normal mitotic entry and progression (6-9). In addition, FoxM1 and its transcriptional network have been associated with numerous cancers (5, 10). Notably, FoxM1 is the key regulator of a proliferative gene expression signature found in high-grade serous ovarian cancer (HGSOC), basal-like breast cancers,

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APC/C and SCF cyclin F Constitute a Reciprocal Feedback Circuit Controlling S-Phase Entry

Cited by 73 publications

References 56 publications

The E3 Ubiquitin Ligase SCF(Cyclin F) Transmits AKT Signaling to the Cell-Cycle Machinery

The E3 Ubiquitin Ligase SCF(Cyclin F) Transmits AKT Signaling to the Cell-Cycle Machinery

EMI1 switches from being a substrate to an inhibitor of APC/CCDH1 to start the cell cycle

VprBP/DCAF1 Regulates the Degradation and Nonproteolytic Activation of the Cell Cycle Transcription Factor FoxM1

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