scholarly journals Cell cycle-dependent expression of cIAP2 at G2/M phase contributes to survival during mitotic cell cycle arrest

2006 ◽  
Vol 399 (2) ◽  
pp. 335-342 ◽  
Author(s):  
Hyung-Seung Jin ◽  
Tae H. Lee
Keyword(s):  
Cell Cycle ◽  
Gene Activation ◽  
Mitotic Cell ◽  
Phase Cell ◽  
Cell Cycle Gene ◽  
Dependent Manner ◽  
Specific Expression ◽  
Apoptosis Protein ◽  
M Phase ◽  
Cycle Dependent

cIAP2 (cellular inhibitor of apoptosis protein 2) is induced by NF-κB (nuclear factor κB) when cells need to respond quickly to different apoptotic stimuli. A recent study using cDNA microarray technology has suggested that cIAP2 transcription is regulated in a cell cycle-dependent manner, although the mechanism for such regulation is unknown. In this study, we confirmed the cell cycle-dependent regulation of cIAP2 expression at both the mRNA and protein levels. Additionally, we found that a bipartite CDE (cell cycle-dependent element)/CHR (cell cycle gene homology region) element in the cIAP2 promoter mediates cIAP2 gene activation in G2/M phase. Cell cycle-dependent G2/M-phase-specific cIAP2 expression is enhanced by NF-κB activation, and selective down-regulation of cIAP2 causes cells blocked in mitosis with nocodazole to become susceptible to apoptosis, indicating that the G2/M-phase-specific expression of cIAP2 contributes to the survival of mitotically arrested cells. Our studies describing the NF-κB-independent G2/M-phase-specific expression of cIAP2 will help in further understanding the molecular basis of cIAP2 over-expression in a variety of human cancers.

scholarly journals Coupling Phosphate Homeostasis to Cell Cycle-Specific Transcription: Mitotic Activation of Saccharomyces cerevisiae PHO5 by Mcm1 and Forkhead Proteins

2009 ◽  
Vol 29 (18) ◽  
pp. 4891-4905 ◽  
Author(s):  
Santhi Pondugula ◽  
Daniel W. Neef ◽  
Warren P. Voth ◽  
Russell P. Darst ◽  
Archana Dhasarathy ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Mitotic Cell ◽  
Dependent Manner ◽  
Phosphate Homeostasis ◽  
Periodic Cell ◽  
M Phase ◽  
Cycle Dependent ◽  
Nutrient Homeostasis

ABSTRACT Cells devote considerable resources to nutrient homeostasis, involving nutrient surveillance, acquisition, and storage at physiologically relevant concentrations. Many Saccharomyces cerevisiae transcripts coding for proteins with nutrient uptake functions exhibit peak periodic accumulation during M phase, indicating that an important aspect of nutrient homeostasis involves transcriptional regulation. Inorganic phosphate is a central macronutrient that we have previously shown oscillates inversely with mitotic activation of PHO5. The mechanism of this periodic cell cycle expression remains unknown. To date, only two sequence-specific activators, Pho4 and Pho2, were known to induce PHO5 transcription. We provide here evidence that Mcm1, a MADS-box protein, is essential for PHO5 mitotic activation. In addition, we found that cells simultaneously lacking the forkhead proteins, Fkh1 and Fkh2, exhibited a 2.5-fold decrease in PHO5 expression. The Mcm1-Fkh2 complex, first shown to transactivate genes within the CLB2 cluster that drive G2/M progression, also associated directly at the PHO5 promoter in a cell cycle-dependent manner in chromatin immunoprecipitation assays. Sds3, a component specific to the Rpd3L histone deacetylase complex, was also recruited to PHO5 in G1. These findings provide (i) further mechanistic insight into PHO5 mitotic activation, (ii) demonstrate that Mcm1-Fkh2 can function combinatorially with other activators to yield late M/G1 induction, and (iii) couple the mitotic cell cycle progression machinery to cellular phosphate homeostasis.

Posttranscriptional cell cycle–dependent regulation of human FANCC expression

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3970-3977 ◽  
Author(s):  
Michael C. Heinrich ◽  
Kirsten V. Silvey ◽  
Stacie Stone ◽  
Amy J. Zigler ◽  
Diana J. Griffith ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dynamic Control ◽  
Complementation Group ◽  
Molecular Regulation ◽  
Phase Cell ◽  
Physical Interaction ◽  
Dependent Manner ◽  
M Phase ◽  
Intensive Investigation ◽  
Cycle Dependent

The Fanconi Anemia (FA) Group C complementation group gene (FANCC) encodes a protein, FANCC, with a predicted Mr of 63000 daltons. FANCC is found in both the cytoplasmic and the nuclear compartments and interacts with certain other FA complementation group proteins as well as with non-FA proteins. Despite intensive investigation, the biologic roles of FANCC and of the other cloned FA gene products (FANCA and FANCG) remain unknown. As an approach to understanding FANCC function, we have studied the molecular regulation of FANCC expression. We found that although FANCCmRNA levels are constant throughout the cell cycle, FANCC is expressed in a cell cycle-dependent manner, with the lowest levels seen in cells synchronized at the G1/S boundary and the highest levels in the M-phase. Cell cycle–dependent regulation occurred despite deletion of the 5′ and 3′ FANCC untranslated regions, indicating that information in the FANCC coding sequence is sufficient to mediate cell cycle–dependent regulation. Moreover, inhibitors of proteasome function blocked the observed regulation. We conclude that FANCC expression is controlled by posttranscriptional mechanisms that are proteasome dependent. Recent work has demonstrated that the functional activity of FA proteins requires the physical interaction of at least FANCA, FANCC, and FANCG, and possibly of other FA and non-FA proteins. Our observation of dynamic control of FANCC expression by the proteasome has important implications for understanding the molecular regulation of the multiprotein complex.

Posttranscriptional cell cycle–dependent regulation of human FANCC expression

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3970-3977 ◽  
Author(s):  
Michael C. Heinrich ◽  
Kirsten V. Silvey ◽  
Stacie Stone ◽  
Amy J. Zigler ◽  
Diana J. Griffith ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dynamic Control ◽  
Complementation Group ◽  
Molecular Regulation ◽  
Phase Cell ◽  
Physical Interaction ◽  
Dependent Manner ◽  
M Phase ◽  
Intensive Investigation ◽  
Cycle Dependent

Abstract The Fanconi Anemia (FA) Group C complementation group gene (FANCC) encodes a protein, FANCC, with a predicted Mr of 63000 daltons. FANCC is found in both the cytoplasmic and the nuclear compartments and interacts with certain other FA complementation group proteins as well as with non-FA proteins. Despite intensive investigation, the biologic roles of FANCC and of the other cloned FA gene products (FANCA and FANCG) remain unknown. As an approach to understanding FANCC function, we have studied the molecular regulation of FANCC expression. We found that although FANCCmRNA levels are constant throughout the cell cycle, FANCC is expressed in a cell cycle-dependent manner, with the lowest levels seen in cells synchronized at the G1/S boundary and the highest levels in the M-phase. Cell cycle–dependent regulation occurred despite deletion of the 5′ and 3′ FANCC untranslated regions, indicating that information in the FANCC coding sequence is sufficient to mediate cell cycle–dependent regulation. Moreover, inhibitors of proteasome function blocked the observed regulation. We conclude that FANCC expression is controlled by posttranscriptional mechanisms that are proteasome dependent. Recent work has demonstrated that the functional activity of FA proteins requires the physical interaction of at least FANCA, FANCC, and FANCG, and possibly of other FA and non-FA proteins. Our observation of dynamic control of FANCC expression by the proteasome has important implications for understanding the molecular regulation of the multiprotein complex.

scholarly journals Cdc4 phospho-degrons allow differential regulation of Ame1CENP-U protein stability across the cell cycle

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Miriam Böhm ◽  
Kerstin Killinger ◽  
Alexander Dudziak ◽  
Pradeep Pant ◽  
Karolin Jänen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Building Blocks ◽  
Meiotic Spindle ◽  
Dependent Manner ◽  
Physiological Importance ◽  
Kinetochore Assembly ◽  
Ubiquitin Ligase Complex ◽  
M Phase ◽  
Novel Strategy ◽  
Cycle Dependent

Kinetochores are multi-subunit protein assemblies that link chromosomes to microtubules of the mitotic and meiotic spindle. It is still poorly understood how efficient, centromere-dependent kinetochore assembly is accomplished from hundreds of individual protein building blocks in a cell cycle dependent manner. Here, by combining comprehensive phosphorylation analysis of native Ctf19CCAN subunits with biochemical and functional assays in the model system budding yeast, we demonstrate that Cdk1 phosphorylation activates phospho-degrons on the essential subunit Ame1CENP-U which are recognized by the E3 ubiquitin ligase complex SCF-Cdc4. Gradual phosphorylation of degron motifs culminates in M-Phase and targets the protein for degradation. Binding of the Mtw1Mis12 complex shields the proximal phospho-degron, protecting kinetochore-bound Ame1 from the degradation machinery. Artificially increasing degron strength partially suppresses the temperature-sensitivity of a cdc4 mutant, while overexpression of Ame1-Okp1 is toxic in SCF mutants, demonstrating the physiological importance of this mechanism. We propose that phospho-regulated clearance of excess CCAN subunits facilitates efficient centromere-dependent kinetochore assembly. Our results suggest a novel strategy for how phospho-degrons can be used to regulate the assembly of multi-subunit complexes.

Periodic biosynthesis of the human M-phase promoting factor catalytic subunit p34 during the cell cycle

1990 ◽  
Vol 10 (7) ◽  
pp. 3847-3851
Author(s):  
C H McGowan ◽  
P Russell ◽  
S I Reed
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Hela Cells ◽  
Catalytic Subunit ◽  
Dependent Manner ◽  
Reversible Phosphorylation ◽  
M Phase ◽  
A Cell ◽  
Cycle Dependent

The product of the CDC2Hs gene is the protein kinase subunit of the M-phase promoting factor, which is required for entry into mitosis. The activity of this kinase is regulated in a cell cycle-dependent manner by reversible phosphorylation and through association with other proteins. We report here that in HeLa cells, the abundance of the CDC2Hs mRNA and the rate of synthesis of the encoded protein, p34, vary in a cell cycle-dependent manner.

Cell cycle regulation of the p34cdc2/p33cdk2-activating kinase p40MO15

1994 ◽  
Vol 107 (10) ◽  
pp. 2789-2799 ◽  
Author(s):  
R.Y. Poon ◽  
K. Yamashita ◽  
M. Howell ◽  
M.A. Ershler ◽  
A. Belyavsky ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Phosphorylation Site ◽  
Mitotic Cell ◽  
Phase Cell ◽  
Serum Starvation ◽  
Interphase Cell ◽  
Cell Extracts ◽  
M Phase ◽  
Equivalent Site ◽  
Cycle Regulation

A key component of Cdc2/Cdk2-activating kinase (CAK) is p40MO15, a protein kinase subunit that phosphorylates the T161/T160 residues of p34cdc2/p33cdk2. The level and activity of p40MO15 were essentially constant during cleavage of fertilised Xenopus eggs and in growing mouse 3T3 cells, but serum starvation of these cells reduced both the level and activity of p40MO15. Although the level and activity of endogenous p40MO15 did not vary in the cell cycle, we found that bacterially expressed p40MO15 was activated more rapidly by M-phase cell extracts than by interphase cell extracts. Bacterially expressed p40MO15 was phosphorylated mainly on serine 170 (a p34cdc2 phosphorylation site) by mitotic cell extracts, but mutation of S170 to alanine did not affect the activation of p40MO15, whereas mutation of T176 (the equivalent site to T161/T160 in p34cdc2/p33cdk2) abolished the activation of P40MO15. These studies suggest that the level and activity of p40MO15 is probably not a major determinant of p34cdc2/p33cdk2 activity in the cell cycle, and that the activation of p40MO15 may require phosphorylation on T176.

C-terminal domain phosphorylation of ERK3 controlled by Cdk1 and Cdc14 regulates its stability in mitosis

2010 ◽  
Vol 428 (1) ◽  
pp. 103-111 ◽  
Author(s):  
Pierre-Luc Tanguay ◽  
Geneviève Rodier ◽  
Sylvain Meloche
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Mitotic Cell ◽  
Mitogen Activated Protein Kinase ◽  
Phosphorylation Sites ◽  
Dependent Manner ◽  
Cell Extracts ◽  
Cycle Dependent

ERK3 (extracellular-signal-regulated kinase 3) is an atypical MAPK (mitogen-activated protein kinase) that is suggested to play a role in cell-cycle progression and cellular differentiation. However, it is not known whether the function of ERK3 is regulated during the cell cycle. In the present paper, we report that ERK3 is stoichiometrically hyperphosphorylated during entry into mitosis and is dephosphorylated at the M→G1 transition. The phosphorylation of ERK3 is associated with the accumulation of the protein in mitosis. In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. All four sites are followed by a proline residue. We have shown that purified cyclin B-Cdk1 (cyclindependent kinase 1) phosphorylates these sites in vitro and demonstrate that Cdk1 acts as a major Thr698 kinase in vivo. Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. The results of the present study identify a novel regulatory mechanism of ERK3 that operates in a cell-cycle-dependent manner.

The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner

2000 ◽  
Vol 113 (23) ◽  
pp. 4363-4371 ◽  
Author(s):  
J. Zhao ◽  
T. Tenev ◽  
L.M. Martins ◽  
J. Downward ◽  
N.R. Lemoine
Keyword(s):  
Cell Cycle ◽  
Proteasome Inhibitors ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Apoptosis Protein ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway ◽  
Cycle Dependent

Survivin, a human inhibitor of apoptosis protein (IAP), plays an important role in both cell cycle regulation and inhibition of apoptosis. Survivin is expressed in cells during the G(2)/M phase of the cell cycle, followed by rapid decline of both mRNA and protein levels at the G(1) phase. It has been suggested that cell cycle-dependent expression of survivin is regulated at the transcriptional level. In this study we demonstrate involvement of the ubiquitin-proteasome pathway in post-translational regulation of survivin. Survivin is a short-lived protein with a half-life of about 30 minutes and proteasome inhibitors greatly stabilise survivin in vivo. Expression of the survivin gene under the control of the CMV promoter cannot block cell cycle-dependent degradation of the protein. Proteasome inhibitors can block survivin degradation during the G(1) phase and polyubiquitinated derivatives can be detected in vivo. Mutation of critical amino acid residues within the baculovirus IAP repeat (BIR) domain or truncation of the N terminus or the C terminus sensitises survivin to proteasome degradation. Together, these results indicate that the ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner and structural changes greatly destabilise the survivin protein.

scholarly journals Periodic biosynthesis of the human M-phase promoting factor catalytic subunit p34 during the cell cycle.

1990 ◽  
Vol 10 (7) ◽  
pp. 3847-3851 ◽  
Author(s):  
C H McGowan ◽  
P Russell ◽  
S I Reed
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Hela Cells ◽  
Catalytic Subunit ◽  
Dependent Manner ◽  
Reversible Phosphorylation ◽  
M Phase ◽  
A Cell ◽  
Cycle Dependent

The product of the CDC2Hs gene is the protein kinase subunit of the M-phase promoting factor, which is required for entry into mitosis. The activity of this kinase is regulated in a cell cycle-dependent manner by reversible phosphorylation and through association with other proteins. We report here that in HeLa cells, the abundance of the CDC2Hs mRNA and the rate of synthesis of the encoded protein, p34, vary in a cell cycle-dependent manner.

scholarly journals Chromatin Loading of E2F-MLL Complex by Cancer-Associated Coregulator ANCCA via Reading a Specific Histone Mark

2010 ◽  
Vol 30 (22) ◽  
pp. 5260-5272 ◽  
Author(s):  
Alexey S. Revenko ◽  
Ekaterina V. Kalashnikova ◽  
Abigael T. Gemo ◽  
June X. Zou ◽  
Hong-Wu Chen
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Gene Activation ◽  
Cell Cycle Gene ◽  
Cancer Cell Proliferation ◽  
Aaa Atpase ◽  
H3k4me3 Mark ◽  
Cycle Dependent

ABSTRACT Histone modifications are regarded as the carrier of epigenetic memory through cell divisions. How the marks facilitate cell cycle-dependent gene expression is poorly understood. The evolutionarily conserved AAA ATPase ANCCA (AAA nuclear coregulator cancer-associated protein)/ATAD2 was identified as a direct target of oncogene AIB1/ACTR/SRC-3 and a transcriptional coregulator for estrogen and androgen receptors and is strongly implicated in tumorigenesis. We report here that ANCCA directly interacts with E2F1 to E2F3 and that its N terminus interacts with both the N and C termini of E2F1. ANCCA preferentially associates via its bromodomain with H3 acetylated at lysine 14 (H3K14ac) and is required for key cell cycle gene expression and cancer cell proliferation. ANCCA associates with chromosomes at late mitosis, and its occupancy at E2F targets peaks at the G1-to-S transition. Strikingly, ANCCA is required for recruitment of specific E2Fs to their targets and chromatin assembly of the host cell factor 1 (HCF-1)-MLL histone methyltransferase complex. ANCCA depletion results in a marked decrease of the gene activation-linked H3K4me3 mark. Bromodomain mutations disable ANCCA function as an E2F coactivator and its ability to promote cancer cell proliferation, while ANCCA overexpression in tumors correlates with tumor growth. Together, these results suggest that ANCCA acts as a pioneer factor in E2F-dependent gene activation and that a novel mechanism involving ANCCA bromodomain may contribute to cancer cell proliferation.

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