scholarly journals Degradation of FBXO31 by APC/C is regulated by AKT- and ATM-mediated phosphorylation

2018 ◽  
Vol 115 (5) ◽  
pp. 998-1003 ◽  
Author(s):  
Srinadh Choppara ◽  
Sunil K. Malonia ◽  
Ganga Sankaran ◽  
Michael R. Green ◽  
Manas Kumar Santra
Keyword(s):  
Cell Cycle ◽  
Genotoxic Stress ◽  
Anaphase Promoting Complex ◽  
Physiological Regulation ◽  
Cell Cycle Regulatory Proteins ◽  
A Cell ◽  
Low Levels ◽  
Stressed Cells ◽  
F Box Protein ◽  
Prosurvival Kinase

The F-box protein FBXO31 is a tumor suppressor that is encoded in 16q24.3, for which there is loss of heterozygosity in various solid tumors. FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2. FBXO31 levels are normally low but increase substantially following genotoxic stress through a mechanism that remains to be determined. Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle–regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT. Following genotoxic stress, phosphorylation of FBXO31 on serine-278 by another kinase, the DNA damage kinase ATM, results in disruption of its interaction with CDH1 and CDC20, thereby preventing FBXO31 degradation. Collectively, our results reveal how alterations in FBXO31 phosphorylation, mediated by AKT and ATM, underlie physiological regulation of FBXO31 levels in unstressed and genotoxically stressed cells.

scholarly journals Regulation of cell cycle drivers by Cullin-RING ubiquitin ligases

2020 ◽  
Vol 52 (10) ◽  
pp. 1637-1651 ◽  
Author(s):  
Sang-Min Jang ◽  
Christophe E. Redon ◽  
Bhushan L. Thakur ◽  
Meriam K. Bahta ◽  
Mirit I. Aladjem
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Cycle Progression ◽  
Ubiquitin Ligases ◽  
Anaphase Promoting Complex ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Cellular Pathways ◽  
Regulation Of Cell Cycle ◽  
F Box Protein

Abstract The last decade has revealed new roles for Cullin-RING ubiquitin ligases (CRLs) in a myriad of cellular processes, including cell cycle progression. In addition to CRL1, also named SCF (SKP1-Cullin 1-F box protein), which has been known for decades as an important factor in the regulation of the cell cycle, it is now evident that all eight CRL family members are involved in the intricate cellular pathways driving cell cycle progression. In this review, we summarize the structure of CRLs and their functions in driving the cell cycle. We focus on how CRLs target key proteins for degradation or otherwise alter their functions to control the progression over the various cell cycle phases leading to cell division. We also summarize how CRLs and the anaphase-promoting complex/cyclosome (APC/C) ligase complex closely cooperate to govern efficient cell cycle progression.

scholarly journals PARP inhibition during alkylation-induced genotoxic stress signals a cell cycle checkpoint response mediated by ATM

DNA Repair ◽  
2009 ◽  
Vol 8 (11) ◽  
pp. 1264-1272 ◽  
Author(s):  
Michael J. Carrozza ◽  
Donna F. Stefanick ◽  
Julie K. Horton ◽  
Padmini S. Kedar ◽  
Samuel H. Wilson
Keyword(s):  
Cell Cycle ◽  
Genotoxic Stress ◽  
Cell Cycle Checkpoint ◽  
Parp Inhibition ◽  
Checkpoint Response ◽  
Cycle Checkpoint ◽  
A Cell ◽  
Stress Signals

scholarly journals The importance of ubiquitin E3 ligases, SCF and APC/C, in human cancers

2015 ◽  
Vol 88 (1) ◽  
pp. 9-14 ◽  
Author(s):  
Ovidiu Vasile Bochis ◽  
Bogdan Fetica ◽  
Catalin Vlad ◽  
Patriciu Achimas-Cadariu ◽  
Alexandru Irimie
Keyword(s):  
Cell Cycle ◽  
Anaphase Promoting Complex ◽  
E3 Ligases ◽  
Cyclin Dependent Kinases ◽  
Ubiquitin Proteasome Pathway ◽  
Complex Process ◽  
Target Therapies ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
F Box Protein

     A normal evolution of the cell-cycle phases consists of multiple consecutive events, which makes it a highly complex process. Its preservation is regulated by Cyclin-Cdks (cyclin-dependent kinases) interactions and protein degradation, which is often controlled by the ubiquitin-mediated proteolysis.The goal of this review is to emphasize the most important features of the regulation of the cell-cycle involved in cancerogenesis, by presenting the involvement of E3 ubiquitin ligases SCF (Skp1-Cul1-F-box protein) and APC/C (Anaphase-promoting complex/cyclosome) in human malignancies. Also, we discuss the importance of the ubiquitin proteasome pathway blockade in cancer treatment. We know that a better understanding of the regulatory biology of the cell cycle can lead to the development of new target therapies for cancer.

scholarly journals A Role for Cell Polarity in Lifespan and Mitochondrial Quality Control in the Budding Yeast Saccharomyces cerevisiae

2021 ◽  
Author(s):  
Emily J. Yang ◽  
Wolfgang M Pernice ◽  
Liza A. Pon
Keyword(s):  
Cell Cycle ◽  
Quality Control ◽  
Cell Division ◽  
Yeast Cell ◽  
Cell Polarity ◽  
Yeast Saccharomyces Cerevisiae ◽  
A Cell ◽  
Mitochondrial Distribution ◽  
Mother Cells ◽  
F Box Protein

SummaryBabies are born young, largely independent of the age of their mothers. Mother-daughter age asymmetry in yeast is achieved, in part, by inheritance of higher-functioning mitochondria by daughter cells and retention of some high-functioning mitochondria in mother cells. The mitochondrial F-box protein, Mfb1p, tethers mitochondria at both poles in a cell cycle-regulated manner: it localizes to and anchors mitochondria to the mother cell tip throughout the cell cycle, and to the bud tip prior to cytokinesis. Here, we report that cell polarity and polarized localization of Mfb1p decline with age in S. cerevisiae. Moreover, deletion of BUD1/RSR1, a Ras protein required for cytoskeletal polarization during asymmetric yeast cell division, results in depolarized Mfb1p localization, defects in mitochondrial distribution and quality control, and reduced replicative lifespan. Our results demonstrate a role for the polarity machinery in lifespan through modulating Mfb1 function in asymmetric inheritance of mitochondria during yeast cell division.

A Role for NIPA in DNA Damage Response.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1265-1265
Author(s):  
Christine von Klitzing ◽  
Florian Bassermann ◽  
Stephan W. Morris ◽  
Christian Peschel ◽  
Justus Duyster
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Phosphorylation Site ◽  
Genotoxic Stress ◽  
S Phase ◽  
Damage Response ◽  
A Cell ◽  
Cycle Dependent

Abstract The nuclear interaction partner of ALK (NIPA) is a nuclear protein identified by our group in a screen for NPM-ALK interaction partners. We recently reported that NIPA is an F-box protein that assembles with SKP1, Cul1 and Roc1 to establish a novel SCF-type E3 ubiquitin ligase. The formation of the SCFNIPA complex is regulated by cell cycle-dependent phosphorylation of NIPA that restricts SCFNIPA assembly from G1- to late S-phase, thus allowing its substrates to be active from late S-phase throughout mitosis. Proteins involved in cell cycle regulation frequently play a role in DNA damage checkpoints. We therefore sought to determine whether NIPA has a function in the cellular response to genotoxic stress. For this reason we treated NIH/3T3 cells with various DNA-damaging agents. Surprisingly, we observed phosphorylation of NIPA in response to some of these agents, including UV radiation. This phosphorylation was cell cycle phase independent and thus independent of the physiological cell cycle dependent phosphorylation of NIPA. The relevant phosphorylation site is identical to the respective site in the course of cell cycle-dependent phosphorylation of NIPA. Thus, phosphorylation of NIPA upon genotoxic stress would inactivate the SCFNIPA complex in a cell cycle independent manner. Interestingly, this phosphorylation site lies within a consensus site of the Chk1/Chk2 checkpoint kinases. These kinases are central to DNA damage checkpoint signaling. Chk1 is activated by ATR in response to blocked replication forks as they occur after treatment with UV. We performed experiments using the ATM/ATR inhibitor caffeine and the Chk1 inhibitor SB218078 to investigate a potential role of Chk1 in NIPA phosphorylation. Indeed, we found both inhibitors to prevent UV-induced phosphorylation of NIPA. Current experiments applying Chk1 knock-out cells will unravel the role of Chk1 in NIPA phosphorylation. Additional experiments were performed to investigate a function for NIPA in DNA-damage induced apoptosis. In this regard, we observed overexpression of NIPA WT to induce apoptosis in response to UV, whereas no proapoptotic effect was seen with the phosphorylation deficient NIPA mutant. Therefore, the phosphorylated form of NIPA may be involved in apoptotic signaling pathways. In summary, we present data suggesting a cell cycle independent function for NIPA. This activity is involved in DNA damage response and may be involved in regulating apoptosis upon genotoxic stress.

scholarly journals Building a pseudo-atomic model of the anaphase-promoting complex

2013 ◽  
Vol 69 (11) ◽  
pp. 2236-2243 ◽  
Author(s):  
Kiran Kulkarni ◽  
Ziguo Zhang ◽  
Leifu Chang ◽  
Jing Yang ◽  
Paula C. A. da Fonseca ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Homology Modelling ◽  
Active Form ◽  
Protein Crystallography ◽  
Hybrid Approach ◽  
Atomic Model ◽  
Anaphase Promoting Complex ◽  
Atomic Models ◽  
Entire Complex ◽  
Cell Cycle Regulatory Proteins

The anaphase-promoting complex (APC/C) is a large E3 ubiquitin ligase that regulates progression through specific stages of the cell cycle by coordinating the ubiquitin-dependent degradation of cell-cycle regulatory proteins. Depending on the species, the active form of the APC/C consists of 14–15 different proteins that assemble into a 20-subunit complex with a mass of approximately 1.3 MDa. A hybrid approach of single-particle electron microscopy and protein crystallography of individual APC/C subunits has been applied to generate pseudo-atomic models of various functional states of the complex. Three approaches for assigning regions of the EM-derived APC/C density map to specific APC/C subunits are described. This information was used to dock atomic models of APC/C subunits, determined either by protein crystallography or homology modelling, to specific regions of the APC/C EM map, allowing the generation of a pseudo-atomic model corresponding to 80% of the entire complex.

scholarly journals Regulation of the Anaphase-promoting Complex/Cyclosome bybimA APC3 and Proteolysis of NIMA

1998 ◽  
Vol 9 (11) ◽  
pp. 3019-3030 ◽  
Author(s):  
Xiang S. Ye ◽  
Russell R. Fincher ◽  
Alice Tang ◽  
Aysha H. Osmani ◽  
Stephen A. Osmani
Keyword(s):  
Cell Cycle ◽  
Kinase Activity ◽  
Nuclear Division ◽  
Temperature Sensitive ◽  
Dependent Manner ◽  
Anaphase Promoting Complex ◽  
A Cell ◽  
Protein Instability ◽  
Clock Mechanism ◽  
Very High

Surprisingly, although highly temperature-sensitive, thebimA1 APC3 anaphase-promoting complex/cyclosome (APC/C) mutation does not cause arrest of mitotic exit. Instead, rapid inactivation ofbimA1 APC3 is shown to promote repeating oscillations of chromosome condensation and decondensation, activation and inactivation of NIMA and p34cdc2 kinases, and accumulation and degradation of NIMA, which all coordinately cycle multiple times without causing nuclear division. ThesebimA1 APC3-induced cell cycle oscillations require active NIMA, because a nimA5 +bimA1 APC3 double mutant arrests in a mitotic state with very high p34cdc2 H1 kinase activity. NIMA protein instability during S phase and G2 was also found to be controlled by the APC/C. The bimA1 APC3mutation therefore first inactivates the APC/C but then allows its activation in a cyclic manner; these cycles depend on NIMA. We hypothesize that bimA APC3 could be part of a cell cycle clock mechanism that is reset after inactivation ofbimA1 APC3. ThebimA1 APC3 mutation may also make the APC/C resistant to activation by mitotic substrates of the APC/C, such as cyclin B, Polo, and NIMA, causing mitotic delay. Once these regulators accumulate, they activate the APC/C, and cells exit from mitosis, which then allows this cycle to repeat. The data indicate thatbimA APC3 regulates the APC/C in a NIMA-dependent manner.

scholarly journals Sirtuin 5 is Regulated by the SCF-Cyclin F Ubiquitin Ligase and is Involved in Cell Cycle Control

2020 ◽  
Author(s):  
Christine A. Mills ◽  
Xianxi Wang ◽  
Dhaval P. Bhatt ◽  
Paul A. Grimsrud ◽  
Jacob Peter Matson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Genetically Modify ◽  
Ubiquitin Proteasome System ◽  
Subsequent Increase ◽  
Cycle Progression ◽  
A Cell ◽  
F Box Protein ◽  
Cyclin F

The ubiquitin-proteasome system is essential for cell cycle progression. Cyclin F is a cell cycle regulated substrate adapter F-box protein for the SKP1/CUL1/F-box (SCF) family of E3 ubiquitin ligases. Despite its importance in cell cycle progression, identifying SCFCyclin F substrates has remained challenging. Since Cyclin F overexpression rescues a yeast mutant in the cdc4 gene, we considered the possibility that other genes that genetically modify cdc4 mutant lethality could also encode Cyclin F substrates. We identified the mitochondrial and cytosolic deacylating enzyme Sirtuin 5 (SIRT5) as a novel Cyclin F substrate. SIRT5 has been implicated in metabolic processes, but its connection to the cell cycle is not known. We show that Cyclin F interacts with, and controls the ubiquitination, abundance, and stability of SIRT5. We show SIRT5 knockout results in a diminished G1 population, and subsequent increase in both S and G2/M. Global proteomic analyses reveal CDK signaling changes congruent with the cell cycle changes in SIRT5 knockout cells. Together these data demonstrate that SIRT5 is regulated by Cyclin F and suggest a connection between SIRT5, cell cycle regulation, and metabolism.

scholarly journals Acm1 Is a Negative Regulator of the Cdh1-Dependent Anaphase-Promoting Complex/Cyclosome in Budding Yeast

2006 ◽  
Vol 26 (24) ◽  
pp. 9162-9176 ◽  
Author(s):  
Juan S. Martinez ◽  
Dah-Eun Jeong ◽  
Eunyoung Choi ◽  
Brian M. Billings ◽  
Mark C. Hall
Keyword(s):  
Cell Cycle ◽  
Budding Yeast ◽  
Mitotic Exit ◽  
Negative Regulator ◽  
Phosphorylation Sites ◽  
Anaphase Promoting Complex ◽  
Uncharacterized Protein ◽  
Delay Effects ◽  
A Cell ◽  
Lines Of Evidence

ABSTRACT Cdh1 is a coactivator of the anaphase-promoting complex/cyclosome (APC/C) and contributes to mitotic exit and G1 maintenance by facilitating the polyubiquitination and subsequent proteolysis of specific substrates. Here, we report that budding yeast Cdh1 is a component of a cell cycle-regulated complex that includes the 14-3-3 homologs Bmh1 and Bmh2 and a previously uncharacterized protein, which we name Acm1 (APC/C Cdh1 modulator 1). Association of Cdh1 with Bmh1 and Bmh2 requires Acm1, and the Acm1 protein is cell cycle regulated, appearing late in G1 and disappearing in late M. In acm1Δ strains, Cdh1 localization to the bud neck and association with two substrates, Clb2 and Hsl1, were strongly enhanced. Several lines of evidence suggest that Acm1 can suppress APC/CCdh1-mediated proteolysis of mitotic cyclins. First, overexpression of Acm1 fully restored viability to cells expressing toxic levels of Cdh1 or a constitutively active Cdh1 mutant lacking inhibitory phosphorylation sites. Second, overexpression of Acm1 was toxic in sic1Δ cells. Third, ACM1 deletion exacerbated a low-penetrance elongated-bud phenotype caused by modest overexpression of Cdh1. This bud elongation was independent of the morphogenesis checkpoint, and the combination of acm1Δ and hsl1Δ resulted in a dramatic enhancement of bud elongation and G2/M delay. Effects on bud elongation were attenuated when Cdh1 was replaced with a mutant lacking the C-terminal IR dipeptide, suggesting that APC/C-dependent proteolysis is required for this phenotype. We propose that Acm1 and Bmh1/Bmh2 constitute a specialized inhibitor of APC/CCdh1.

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