APC/C<sup>Cdh1</sup>controls the proteasome-mediated degradation of E2F3 during cell cycle exit

Ping, Zhen; Lim, Ratna; Bashir, Tarig; Pagano, Michele; Guardavaccaro, Daniele

doi:10.4161/cc.20402

Cited by 26 publications

(18 citation statements)

References 22 publications

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“…Indeed, our results indicate that Fzr regulates the expression of adult progenitor markers and the expression stg independently. Interestingly, CDH1, the mammalian fzr homolog, can downregulate particular transcription factors (Li et al, 2008;Ping et al, 2012;Stegmü ller et al, 2006). This is particularly relevant not only for the control of developmental processes but also regarding the link between polyploidy and cancer.…”

Section: Discussionmentioning

confidence: 97%

Specification of Differentiated Adult Progenitors via Inhibition of Endocycle Entry in the Drosophila Trachea

et al. 2014

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A population of Drosophila adult tracheal progenitor cells arises from differentiated cells of the larval main trachea that retain the ability to reenter the cell cycle and give rise to the multiple adult tracheal cell types. These progenitors are unique to the second tracheal metamere as homologous cells from other segments, express fizzy-related (fzr), the Drosophila homolog of CDH1 protein of the APC complex, and enter endocycle and do not contribute to adult trachea. Here, we examine the mechanisms for their quiescence and show that they reenter the cell cycle by expression of string/cdc25 through ecdysone. Furthermore, we show that preventing endocycle entry is both necessary and sufficient for these tracheal cells to exhibit markers of adult progenitors, thus modifying their genetic program. Finally, we show that Hox-mediated regulation of fzr expression is responsible for progenitor identity and thus specifies a group of differentiated cells with facultative stem cell features.

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Section: Discussionmentioning

confidence: 97%

Specification of Differentiated Adult Progenitors via Inhibition of Endocycle Entry in the Drosophila Trachea

et al. 2014

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“…In contrast, E2F7/8 do not interact with DP, and thus cannot be protected against degradation in this manner [5][6][7]40]. Also, the substrate binding by CDC20 and CDH1 appeared to occur via noncanonical recognition motifs in E2F1, and E2F3, because the mutation of putative D-boxes in E2F1 and E2F3 did not affect their Michiel Boekhout et al Feedback between atypical E2Fs and APC/C Cdh1 EMBO reports degradation [26,39]. This indicates that their degradation follows different kinetics than the degradation of E2F7/8.…”

Section: Embo Reportsmentioning

confidence: 99%

Feedback regulation between atypical E2Fs and APC / C ^C ^dh1 coordinates cell cycle progression

et al. 2016

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E2F transcription factors control the oscillating expression pattern of multiple target genes during the cell cycle. Activator E2Fs, E2F1-3, induce an upswing of E2F targets, which is essential for the G1-to-S phase transition, whereas atypical E2Fs, E2F7 and E2F8, mediate a downswing of the same targets during late S, G2, and M phases. Expression of atypical E2Fs is induced by E2F1-3, but it is unknown how atypical E2Fs are inactivated in a timely manner. Here, we demonstrate that E2F7 and E2F8 are substrates of the anaphase-promoting complex/cyclosome (APC/C). Removal of CDH1, or mutating the CDH1-interacting KEN boxes, stabilized E2F7/8 from anaphase onwards and during G1. Expressing KEN mutant E2F7 during G1 impairs S phase entry and eventually results in cell death. Furthermore, we show that E2F8, but not E2F7, interacts also with APC/C Cdc20 . Importantly, atypical E2Fs can activate APC/C Cdh1 by repressing its inhibitors cyclin A, cyclin E, and Emi1. In conclusion, we discovered a feedback loop between atypical E2Fs and APC/C Cdh1 , which ensures balanced expression of cell cycle genes and normal cell cycle progression.

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“…Furthermore, the identification of Mcl-1 [123] as a Cdc20 substrate as well as G9a and GLP [113] as Cdh1 substrates expands APC/C functionality into regulating cellular apoptosis and senescence. In addition, APC/C also participates in other cell cycle-independent functions including regulating cellular metabolism [112], cell mobility [140] and gene transcription [104, 105, 128] through degradation of specific substrates. However, further biochemical and mouse modeling studies are required to validate a physiological role and pinpoint the underlying molecular mechanisms for APC/C Cdh1 in these cellular processes.…”

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/C^Cdh1controls the proteasome-mediated degradation of E2F3 during cell cycle exit

Cited by 26 publications

References 22 publications

Specification of Differentiated Adult Progenitors via Inhibition of Endocycle Entry in the Drosophila Trachea

Specification of Differentiated Adult Progenitors via Inhibition of Endocycle Entry in the Drosophila Trachea

Feedback regulation between atypical E2Fs and APC / C ^C ^dh1 coordinates cell cycle progression

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

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APC/CCdh1controls the proteasome-mediated degradation of E2F3 during cell cycle exit

Cited by 26 publications

References 22 publications

Specification of Differentiated Adult Progenitors via Inhibition of Endocycle Entry in the Drosophila Trachea

Specification of Differentiated Adult Progenitors via Inhibition of Endocycle Entry in the Drosophila Trachea

Feedback regulation between atypical E2Fs and APC / C C dh1 coordinates cell cycle progression

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

Contact Info

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APC/C^Cdh1controls the proteasome-mediated degradation of E2F3 during cell cycle exit

Feedback regulation between atypical E2Fs and APC / C ^C ^dh1 coordinates cell cycle progression