Faculty Opinions recommendation of Developmental defects observed in hypomorphic anaphase-promoting complex mutants are linked to cell cycle abnormalities.

2003 ◽  
Author(s):  
Bruce Bowerman
Keyword(s):  
Cell Cycle ◽  
Anaphase Promoting Complex ◽  
Developmental Defects

scholarly journals The Role of Cdh1p in Maintaining Genomic Stability in Budding Yeast

Genetics ◽  
2003 ◽  
Vol 165 (2) ◽  
pp. 489-503 ◽  
Author(s):  
Karen E Ross ◽  
Orna Cohen-Fix
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Chromosome Loss ◽  
Cyclin Dependent Kinase ◽  
Anaphase Promoting Complex ◽  
Growth Defects ◽  
Genes Encoding ◽  
Specificity Factor

Abstract Cdh1p, a substrate specificity factor for the cell cycle-regulated ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C), promotes exit from mitosis by directing the degradation of a number of proteins, including the mitotic cyclins. Here we present evidence that Cdh1p activity at the M/G1 transition is important not only for mitotic exit but also for high-fidelity chromosome segregation in the subsequent cell cycle. CDH1 showed genetic interactions with MAD2 and PDS1, genes encoding components of the mitotic spindle assembly checkpoint that acts at metaphase to prevent premature chromosome segregation. Unlike cdh1Δ and mad2Δ single mutants, the mad2Δ cdh1Δ double mutant grew slowly and exhibited high rates of chromosome and plasmid loss. Simultaneous deletion of PDS1 and CDH1 caused extensive chromosome missegregation and cell death. Our data suggest that at least part of the chromosome loss can be attributed to kinetochore/spindle problems. Our data further suggest that Cdh1p and Sic1p, a Cdc28p/Clb inhibitor, have overlapping as well as nonoverlapping roles in ensuring proper chromosome segregation. The severe growth defects of both mad2Δ cdh1Δ and pds1Δ cdh1Δ strains were rescued by overexpressing Swe1p, a G2/M inhibitor of the cyclin-dependent kinase, Cdc28p/Clb. We propose that the failure to degrade cyclins at the end of mitosis leaves cdh1Δ mutant strains with abnormal Cdc28p/Clb activity that interferes with proper chromosome segregation.

scholarly journals Cell Cycle-Dependent Expression of Mammalian E2-C Regulated by the Anaphase-Promoting Complex/Cyclosome

2000 ◽  
Vol 11 (8) ◽  
pp. 2821-2831 ◽  
Author(s):  
Atsushi Yamanaka ◽  
Shigetsugu Hatakeyama ◽  
Kin-ichiro Kominami ◽  
Masatoshi Kitagawa ◽  
Masaki Matsumoto ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Substrate Specificity ◽  
Critical Role ◽  
Anaphase Promoting Complex ◽  
Polyubiquitin Chain ◽  
M Phase ◽  
Ubiquitin Conjugating Enzyme ◽  
Recognition Motifs ◽  
Cycle Dependent ◽  
Conjugating Enzyme

Progression through mitosis requires the precisely timed ubiquitin-dependent degradation of specific substrates. E2-C is a ubiquitin-conjugating enzyme that plays a critical role with anaphase-promoting complex/cyclosome (APC/C) in progression of and exit from M phase. Here we report that mammalian E2-C is expressed in late G2/M phase and is degraded as cells exit from M phase. The mammalian E2-C shows an autoubiquitinating activity leading to covalent conjugation to itself with several ubiquitins. The ubiquitination of E2-C is strongly enhanced by APC/C, resulting in the formation of a polyubiquitin chain. The polyubiquitination of mammalian E2-C occurs only when cells exit from M phase. Furthermore, mammalian E2-C contains two putative destruction boxes that are believed to act as recognition motifs for APC/C. The mutation of this motif reduced the polyubiquitination of mammalian E2-C, resulting in its stabilization. These results suggest that mammalian E2-C is itself a substrate of the APC/C-dependent proteolysis machinery, and that the periodic expression of mammalian E2-C may be a novel autoregulatory system for the control of the APC/C activity and its substrate specificity.

scholarly journals Adenovirus E4orf4 protein induces PP2A-dependent growth arrest in Saccharomyces cerevisiae and interacts with the anaphase-promoting complex/cyclosome

2001 ◽  
Vol 154 (2) ◽  
pp. 331-344 ◽  
Author(s):  
Daniel Kornitzer ◽  
Rakefet Sharf ◽  
Tamar Kleinberger
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Mammalian Cells ◽  
Growth Arrest ◽  
Anaphase Promoting Complex ◽  
Reading Frame ◽  
Cycle Growth ◽  
M Phase ◽  
Dependent Growth ◽  
Synthetically Lethal

Adenovirus early region 4 open reading frame 4 (E4orf4) protein has been reported to induce p53-independent, protein phosphatase 2A (PP2A)–dependent apoptosis in transformed mammalian cells. In this report, we show that E4orf4 induces an irreversible growth arrest in Saccharomyces cerevisiae at the G2/M phase of the cell cycle. Growth inhibition requires the presence of yeast PP2A-Cdc55, and is accompanied by accumulation of reactive oxygen species. E4orf4 expression is synthetically lethal with mutants defective in mitosis, including Cdc28/Cdk1 and anaphase-promoting complex/cyclosome (APC/C) mutants. Although APC/C activity is inhibited in the presence of E4orf4, Cdc28/Cdk1 is activated and partially counteracts the E4orf4-induced cell cycle arrest. The E4orf4–PP2A complex physically interacts with the APC/C, suggesting that E4orf4 functions by directly targeting PP2A to the APC/C, thereby leading to its inactivation. Finally, we show that E4orf4 can induce G2/M arrest in mammalian cells before apoptosis, indicating that E4orf4-induced events in yeast and mammalian cells are highly conserved.

scholarly journals The Saccharomyces cerevisiae Anaphase-Promoting Complex Interacts with Multiple Histone-Modifying Enzymes To Regulate Cell Cycle Progression

2010 ◽  
Vol 9 (10) ◽  
pp. 1418-1431 ◽  
Author(s):  
Emma L. Turner ◽  
Mackenzie E. Malo ◽  
Marnie G. Pisclevich ◽  
Megan D. Dash ◽  
Gerald F. Davies ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Chromatin Assembly ◽  
Temperature Sensitive ◽  
Anaphase Promoting Complex ◽  
Cycle Progression ◽  
Ubiquitin Ligase Complex ◽  
Genes Encoding ◽  
Dependent Cell ◽  
Histone Modifying Enzymes

ABSTRACT The anaphase-promoting complex (APC), a large evolutionarily conserved ubiquitin ligase complex, regulates cell cycle progression through mitosis and G1. Here, we present data suggesting that APC-dependent cell cycle progression relies on a specific set of posttranslational histone-modifying enzymes. Multiple APC subunit mutants were impaired in total and modified histone H3 protein content. Acetylated H3K56 (H3K56Ac) levels were as reduced as those of total H3, indicating that loading histones with H3K56Ac is unaffected in APC mutants. However, under restrictive conditions, H3K9Ac and dimethylated H3K79 (H3K79me2) levels were more greatly reduced than those of total H3. In a screen for histone acetyltransferase (HAT) and histone deacetylase (HDAC) mutants that genetically interact with the apc5 CA (chromatin assembly) mutant, we found that deletion of GCN5 or ELP3 severely hampered apc5 CA temperature-sensitive (ts) growth. Further analyses showed that (i) the elp3Δ gcn5Δ double mutant ts defect was epistatic to that observed in apc5 CA cells; (ii) gcn5Δ and elp3Δ mutants accumulate in mitosis; and (iii) turnover of the APC substrate Clb2 is not impaired in elp3Δ gcn5Δ cells. Increased expression of ELP3 and GCN5, as well as genes encoding the HAT Rtt109 and the chromatin assembly factors Msi1 and Asf1, suppressed apc5 CA defects, while increased APC5 expression partially suppressed elp3Δ gcn5Δ growth defects. Finally, we demonstrate that Gcn5 is unstable during G1 and following G1 arrest and is stabilized in APC mutants. We present our working model in which Elp3/Gcn5 and the APC work together to facilitate passage through mitosis and G1. To progress into S, we propose that at least Gcn5 must then be targeted for degradation in an APC-dependent fashion.

scholarly journals Intricate Regulatory Mechanisms of the Anaphase-Promoting Complex/Cyclosome and Its Role in Chromatin Regulation

2021 ◽  
Vol 9 ◽  
Author(s):  
Tatyana Bodrug ◽  
Kaeli A. Welsh ◽  
Megan Hinkle ◽  
Michael J. Emanuele ◽  
Nicholas G. Brown
Keyword(s):  
Cell Cycle ◽  
Signaling Pathways ◽  
Biological Process ◽  
Conformational Dynamics ◽  
Intimate Relationship ◽  
Regulatory Mechanisms ◽  
Cell Cycle Regulators ◽  
Chromatin Regulation ◽  
Anaphase Promoting Complex

The ubiquitin (Ub)-proteasome system is vital to nearly every biological process in eukaryotes. Specifically, the conjugation of Ub to target proteins by Ub ligases, such as the Anaphase-Promoting Complex/Cyclosome (APC/C), is paramount for cell cycle transitions as it leads to the irreversible destruction of cell cycle regulators by the proteasome. Through this activity, the RING Ub ligase APC/C governs mitosis, G1, and numerous aspects of neurobiology. Pioneering cryo-EM, biochemical reconstitution, and cell-based studies have illuminated many aspects of the conformational dynamics of this large, multi-subunit complex and the sophisticated regulation of APC/C function. More recent studies have revealed new mechanisms that selectively dictate APC/C activity and explore additional pathways that are controlled by APC/C-mediated ubiquitination, including an intimate relationship with chromatin regulation. These tasks go beyond the traditional cell cycle role historically ascribed to the APC/C. Here, we review these novel findings, examine the mechanistic implications of APC/C regulation, and discuss the role of the APC/C in previously unappreciated signaling pathways.

Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase

Development ◽  
1995 ◽  
Vol 121 (4) ◽  
pp. 1053-1063 ◽  
Author(s):  
T. Xu ◽  
W. Wang ◽  
S. Zhang ◽  
R.A. Stewart ◽  
W. Yu
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Tumor Suppressors ◽  
Sequence Similarity ◽  
Developmental Defects ◽  
Genetic Mosaics ◽  
Putative Protein ◽  
Powerful Approach ◽  
Mutant Cells ◽  
Putative Protein Kinase

We have identified recessive overproliferation mutations by screening and examining clones of mutant cells in genetic mosaics of the fruitfly Drosophila melanogaster. This type of screen provides a powerful approach for identifying and studying potential tumor suppressors. One of the identified genes, lats, has been cloned and encodes a putative protein kinase that shares high levels of sequence similarity with three proteins in budding yeast and Neurospora that are involved in regulation of the cell cycle and growth. Mutations in lats cause dramatic overproliferation phenotypes and various developmental defects in both mosaic animals and homozygous mutants.

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