Cell-cycle transitions: a common role for stoichiometric inhibitors

Hopkins, M. J. G.; Tyson, John J.; Novák, Béla

doi:10.1091/mbc.e17-06-0349

Cited by 24 publications

(26 citation statements)

References 53 publications

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“…Thus, it will be important to elucidate the precise mechanisms by which the LIN-41 Deg domains link CDK-1 activity to SCF SEL-10 -mediated degradation. The regulation of the Gl/S phase transition in budding yeast provides a framework for thinking about this issue (Nash et al 2001; Kõvomägi et al 2011; Yang et al 2013; reviewed by Hopkins et al 2017). The cyclin-dependent kinase complex, Cdk1-Clb5/6 promotes the entry into S phase but is inhibited by binding to its inhibitor Sic1 (Nugroho and Mendenhall 1994; Schwob et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Multiple Mechanisms Inactivate the LIN-41 RNA-Binding Protein to Ensure A Robust Oocyte-to-Embryo Transition inCaenorhabditis elegans

Greenstein

Spike

Huelgas-Morales

et al. 2018

Preprint

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In the nematode Caenorhabditis elegans, the conserved LIN-41 RNA-binding protein is a translational repressor that coordinately controls oocyte growth and meiotic maturation. LIN-41 exerts these effects, at least in part, by preventing the premature activation of the cyclin-dependent kinase CDK-1. Here we investigate the mechanism by which LIN-41 is rapidly eliminated upon the onset of meiotic maturation. Elimination of LIN-41 requires the activities of CDK-1 and multiple SCF-type ubiquitin ligase subunits, including the conserved substrate adaptor protein SEL-10/Fbw7/Cdc4, suggesting that LIN-41 is a target of ubiquitin-mediated protein degradation. Within the LIN-41 protein, two non-overlapping regions, Deg-A and Deg-B, are individually necessary for LIN-41 degradation; both contain several potential phosphodegron sequences, and at least one of these sites is required for LIN-41 degradation. Finally, Deg-A and Deg-B are sufficient, in combination, to mediate SEL-10-dependent degradation when transplanted into a different oocyte protein. Although LIN-41 is a potent inhibitor of protein translation and M-phase entry, the failure to eliminate LIN-41 from early embryos does not result in the continued translational repression of LIN-41 oocyte mRNA targets. Based on these observations, we propose a molecular model for the elimination of LIN-41 by SCFSEL-10 and suggest that LIN-41 is inactivated before it is degraded. Furthermore, we provide evidence that another RNA-binding protein, the GLD-1 tumor suppressor, is regulated similarly. Redundant mechanisms to extinguish translational repression by RNA-binding proteins may both control and provide robustness to irreversible developmental transitions, including meiotic maturation and the oocyte-to-embryo transition.

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Section: Discussionmentioning

confidence: 99%

Multiple Mechanisms Inactivate the LIN-41 RNA-Binding Protein to Ensure A Robust Oocyte-to-Embryo Transition inCaenorhabditis elegans

Greenstein

Spike

Huelgas-Morales

et al. 2018

Preprint

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“…Thus, excess expression of the substrate will lead to buildup of the competing complex, and a reduction in enzymatic flux and product. Although substrate competition, in which catalysis of one substrate inhibits an enzyme's ability to catalyze other substrates has been described (33,34), the motif described here is distinct, in that a single substrate is capable of forming alternate forms (oligomeric complexes) that lead to functionally distinct products. This feature alone leads to the striking nonmonotonic dose-response relationship described here.…”

Section: Discussionmentioning

confidence: 89%

Substrate complex competition is a regulatory motif that allows NFκB RelA to license but not amplify NFκB RelB

Mitchell

Hoffmann

2019

Proc. Natl. Acad. Sci. U.S.A.

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Signaling pathways often share molecular components, tying the activity of one pathway to the functioning of another. In the NFκB signaling system, distinct kinases mediate inflammatory and developmental signaling via RelA and RelB, respectively. Although the substrates of the developmental, so-called noncanonical, pathway are induced by inflammatory/canonical signaling, crosstalk is limited. Through dynamical systems modeling, we identified the underlying regulatory mechanism. We found that as the substrate of the noncanonical kinase NIK, the nfkb2 gene product p100, transitions from a monomer to a multimeric complex, it may compete with and inhibit p100 processing to the active p52. Although multimeric complexes of p100 (IκBδ) are known to inhibit preexisting RelA:p50 through sequestration, here we report that p100 complexes can inhibit the enzymatic formation of RelB:p52. We show that the dose-response systems properties of this complex substrate competition motif are poorly accounted for by standard Michaelis-Menten kinetics, but require more detailed mass action formulations. In sum, although tonic inflammatory signaling is required for adequate expression of the noncanonical pathway precursors, the substrate complex competition motif identified here can prevent amplification of the active RelB:p52 dimer in elevated inflammatory conditions to ensure reliable RelB-dependent developmental signaling independent of inflammatory context.NFκB canonical pathway | NFκB noncanonical pathway | inflammation | crosstalk | immune development

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“…The cell cycle assay is a rapid and accurate method used to study cell proliferation. The cell cycle is the basic process of cell life that contains four phases: The G 0 /G 1 phase (dNA synthesis prophase), S phase (dNA synthesis phase), G 2 phase (dNA synthesis anaphase) and M phase (dNA division phase) (14,27). The cell is prepared for dNA replication in the G 1 phase, and then chromosomes are replicated during the S phase.…”

Section: Discussionmentioning

confidence: 99%

“…Following this checkpoint, cells become independent of growth factors and commit to cell division. S phase cells participate in cell division, thereby representing the number of cells involved in the division (14,27). In fact, changes in the ratios of G 0 /G 1 to S+G 2 /M cells can reflect cell proliferation and cell cycle status (14).…”

Section: Discussionmentioning

confidence: 99%

eRF3b-37 inhibits the TGF-β1-induced activation of hepatic stellate cells by regulating cell proliferation, G0/G1 arrest, apoptosis and migration

et al. 2018

Int J Mol Med

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The therapeutic management of liver fibrosis remains an unresolved clinical problem. The activation of hepatic stellate cells (HScs) serves a pivotal role in the formation of liver fibrosis. In our previous study, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALdI-TOF MS) was employed to identify potential serum markers for liver cirrhosis, such as eukaryotic peptide chain releasing factor 3b polypeptide (eRF3b-37), which was initially confirmed by our group to serve a protective role in liver tissues in a c-c motif chemokine ligand 4-induced liver cirrhosis mouse model. Therefore, eRF3b-37 was hypothesized to affect the activation state of HScs, which was determined by the expression of pro-fibrogenic associated factors in HSCs. In the present study, peptide synthesis technology was employed to elucidate the role of eRF3b-37 in the expression of pro-fibrogenic factors induced by transforming growth factor-β1 (TGF-β1) in LX-2 cells that were treated with either control, TGF-β1 and TGF-β1+eRF3b-37. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide and flow cytometric assays, and fluorescent microscope examinations were performed to evaluate the effects of eRF3b-37 on proliferation viability, G 0 /G 1 arrest, apoptosis and cell migration. The results of the present study indicated that eRF3b-37 inhibited the activation of HScs. The increased mRNA and protein expression of the pro-fibrogenic factors collagen I, connective tissue growth factor and α-smooth muscle actin (SMA) stimulated by TGF-β1 were reduced by eRF3b-37 via the following mechanisms: i) Inhibiting LX-2 cell proliferation, leading to G 0 /G 1 cell cycle arrest and inhibition of dNA synthesis by downregulating the mRNA expressions of cyclin d1 and cyclin dependent kinase-4, and upregulating the levels of P21; ii) increasing cell apoptosis by upregulating the mRNA level of B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) and Fas, and downregulating the expression of Bcl-2; and iii) reducing cell migration by downregulating the mRNA and protein expression of α-SMA. In addition, eRF3b-37 is thought to serve a role in HScs by inhibiting TGF-β signaling. Therefore, eRF3b-37 may be a novel therapeutic agent for targeting HScs for hepatic fibrosis.

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Cell-cycle transitions: a common role for stoichiometric inhibitors

Cited by 24 publications

References 53 publications

Multiple Mechanisms Inactivate the LIN-41 RNA-Binding Protein to Ensure A Robust Oocyte-to-Embryo Transition inCaenorhabditis elegans

Multiple Mechanisms Inactivate the LIN-41 RNA-Binding Protein to Ensure A Robust Oocyte-to-Embryo Transition inCaenorhabditis elegans

Substrate complex competition is a regulatory motif that allows NFκB RelA to license but not amplify NFκB RelB

eRF3b-37 inhibits the TGF-β1-induced activation of hepatic stellate cells by regulating cell proliferation, G0/G1 arrest, apoptosis and migration

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