Cell Cycle Regulation in Macrophages and Susceptibility to HIV-1

Macrophages are the first line of defence against invading pathogens. They play a crucial role in immunity but also in regeneration and homeostasis. Their remarkable plasticity in their phenotypes and function provides them with the ability to quickly respond to environmental changes and infection. Recent work shows that macrophages undergo cell cycle transition from a G0/terminally differentiated state to a G1 state. This G0-to-G1 transition presents a window of opportunity for HIV-1 infection. Macrophages are an important target for HIV-1 but express high levels of the deoxynucleotide-triphosphate hydrolase SAMHD1, which restricts viral DNA synthesis by decreasing levels of dNTPs. While the G0 state is non-permissive to HIV-1 infection, a G1 state is very permissive to HIV-1 infection. This is because macrophages in a G1 state switch off the antiviral restriction factor SAMHD1 by phosphorylation, thereby allowing productive HIV-1 infection. Here, we explore the macrophage cell cycle and the interplay between its regulation and permissivity to HIV-1 infection.

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Phosphorylation by Casein Kinase 2 Regulates Nap1 Localization and Function

Molecular and Cellular Biology ◽

10.1128/mcb.01035-07 ◽

2007 ◽

Vol 28 (4) ◽

pp. 1313-1325 ◽

Cited By ~ 26

Author(s):

Meredith E. K. Calvert ◽

Kristin M. Keck ◽

Celeste Ptak ◽

Jeffrey Shabanowitz ◽

Donald F. Hunt ◽

...

Keyword(s):

Cell Cycle ◽

Casein Kinase ◽

Casein Kinase 2 ◽

S Phase ◽

Bud Formation ◽

Evolutionarily Conserved ◽

Assembly Factor ◽

And Function ◽

Cycle Regulation

ABSTRACT In Saccharomyces cerevisiae, the evolutionarily conserved nucleocytoplasmic shuttling protein Nap1 is a cofactor for the import of histones H2A and H2B, a chromatin assembly factor and a mitotic factor involved in regulation of bud formation. To understand the mechanism by which Nap1 function is regulated, Nap1-interacting factors were isolated and identified by mass spectrometry. We identified several kinases among these proteins, including casein kinase 2 (CK2), and a new bud neck-associated protein, Nba1. Consistent with our identification of the Nap1-interacting kinases, we showed that Nap1 is phosphorylated in vivo at 11 sites and that Nap1 is phosphorylated by CK2 at three substrate serines. Phosphorylation of these serines was not necessary for normal bud formation, but mutation of these serines to either alanine or aspartic acid resulted in cell cycle changes, including a prolonged S phase, suggesting that reversible phosphorylation by CK2 is important for cell cycle regulation. Nap1 can shuttle between the nucleus and cytoplasm, and we also showed that CK2 phosphorylation promotes the import of Nap1 into the nucleus. In conclusion, our data show that Nap1 phosphorylation by CK2 appears to regulate Nap1 localization and is required for normal progression through S phase.

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DREAM represses distinct targets by cooperating with different THAP domain proteins

10.1101/2020.08.13.249698 ◽

2020 ◽

Author(s):

Csenge Gal ◽

Francesco Nicola Carelli ◽

Alex Appert ◽

Chiara Cerrato ◽

Ni Huang ◽

...

Keyword(s):

Cell Cycle ◽

Mechanism Of Action ◽

Cell Cycle Regulation ◽

Gene Body ◽

C Elegans ◽

Cellular Quiescence ◽

And Function ◽

Cycle Regulation

ABSTRACTThe DREAM (DP, Retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell cycle and other genes, but its mechanism of action is unclear. Here we demonstrate that two C. elegans THAP domain proteins, LIN-15B and LIN-36, co-localize with DREAM and function by different mechanisms for repression of distinct sets of targets. LIN-36 represses classical cell cycle targets by promoting DREAM binding and gene body enrichment of H2A.Z, and we find that DREAM subunit EFL-1/E2F is specific for LIN-36 targets. In contrast, LIN-15B represses germline specific targets in the soma by facilitating H3K9me2 promoter marking. We further find that LIN-36 and LIN-15B differently regulate DREAM binding. In humans, THAP proteins have been implicated in cell cycle regulation by poorly understood mechanisms. We propose that THAP domain proteins are key mediators of Rb/DREAM function.

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Cell cycle regulation of VCIP135 deubiquitinase activity and function in p97/p47-mediated Golgi reassembly

Molecular Biology of the Cell ◽

10.1091/mbc.e15-01-0041 ◽

2015 ◽

Vol 26 (12) ◽

pp. 2242-2251 ◽

Cited By ~ 17

Author(s):

Xiaoyan Zhang ◽

Yanzhuang Wang

Keyword(s):

Cell Cycle ◽

Membrane Fusion ◽

Mammalian Cells ◽

Membrane Dynamics ◽

Deubiquitinating Enzyme ◽

Golgi Membrane ◽

Interacting Protein ◽

Daughter Cells ◽

And Function ◽

Cycle Regulation

In mammalian cells, the inheritance of the Golgi apparatus into the daughter cells during each cycle of cell division is mediated by a disassembly and reassembly process, and this process is precisely controlled by phosphorylation and ubiquitination. VCIP135 (valosin-containing protein p97/p47 complex–interacting protein, p135), a deubiquitinating enzyme required for p97/p47-mediated postmitotic Golgi membrane fusion, is phosphorylated at multiple sites during mitosis. However, whether phosphorylation directly regulates VCIP135 deubiquitinase activity and Golgi membrane fusion in the cell cycle remains unknown. We show that, in early mitosis, phosphorylation of VCIP135 by Cdk1 at a single residue, S130, is sufficient to inactivate the enzyme and inhibit p97/p47-mediated Golgi membrane fusion. At the end of mitosis, VCIP135 S130 is dephosphorylated, which is accompanied by the recovery of its deubiquitinase activity and Golgi reassembly. Our results demonstrate that phosphorylation and ubiquitination are coordinated via VCIP135 to control Golgi membrane dynamics in the cell cycle.

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The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression

International Journal of Molecular Sciences ◽

10.3390/ijms22115754 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5754

Author(s):

Tingting Zou ◽

Zhenghong Lin

Keyword(s):

Cell Cycle ◽

Cancer Progression ◽

Ubiquitin Proteasome System ◽

High Accumulation ◽

Cancer Occurrence ◽

Ubiquitin Proteasome ◽

Cell Cycle Transition ◽

Cycle Regulation ◽

Cellular Components ◽

Ubiquitination Machinery

The cell cycle is a collection of events by which cellular components such as genetic materials and cytoplasmic components are accurately divided into two daughter cells. The cell-cycle transition is primarily driven by the activation of cyclin-dependent kinases (CDKs), the activities of which are regulated by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors (CKIs). Thus, the ubiquitin-proteasome system (UPS) plays a pivotal role in the regulation of the cell-cycle process via recognition, interaction, and ubiquitination or deubiquitination of key proteins. The illegitimate degradation of tumor suppressor proteins and oncoproteins or, inversely, abnormally high accumulation results in cell proliferation deregulation, genomic instability, and cancer occurrence. In this review, we demonstrate the diversity and complexity of the UPS machinery regulation of the cell cycle. A profound understanding of the ubiquitination machinery will provide new insights into the regulation of the cell-cycle transition, cancer treatment, and the development of anti-cancer drugs.

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Dual control exerted by dopamine in blood-progenitor cell cycle regulation in Drosophila

10.1101/2021.03.29.437463 ◽

2021 ◽

Author(s):

Tina Mukherjee ◽

Ankita Kapoor ◽

A Padmavathi

Keyword(s):

Cell Cycle ◽

Progenitor Cells ◽

Progenitor Cell ◽

Cell Cycle Progression ◽

Lymph Gland ◽

Cycle Progression ◽

Myeloid Progenitor ◽

G2 Phase ◽

And Function ◽

Cycle Regulation

In Drosophila, definitive hematopoiesis occurs in a specialized organ termed "lymph gland", where multi-potent stem-like blood progenitor cells reside and their homeostasis is central to growth of this organ. Recent findings have implicated a reliance on neurotransmitters in progenitor development and function however, our understanding of these molecules is still limited. Here, we extend our analysis and show that blood-progenitors are self-sufficient in synthesizing dopamine, a well-established neurotransmitter and have modules for its sensing through receptor and uptake via, transporter. Modulating their expression in progenitor cells affects lymph gland growth. Progenitor cell cycle analysis revealed an unexpected requirement for intracellular dopamine in progression of early progenitors from S to G2 phase of the cell cycle, while activation of dopamine-receptor later in development regulated the progression from G2 to entry into mitosis. The dual capacity in which dopamine operates, both intra-cellularly and extra-cellularly, controls lymph gland growth. These data highlight a novel and non-canonical use of dopamine as a proliferative cue by the myeloid-progenitor system and reveals a functional requirement for intracellular dopamine in cell-cycle progression.

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TAMI-50. PATHWAYS ACTIVATION IN GL261 MICE GLIOMA CELLS BY HIV-1 GLYCOPROTEIN GP120

Neuro-Oncology ◽

10.1093/neuonc/noab196.833 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi208-vi208

Author(s):

Gabriel Valentín Guillama ◽

Lilia Kucheryavykh

Keyword(s):

Cell Cycle ◽

Western Blot ◽

Cell Cycle Regulation ◽

Glycogen Synthase ◽

Glioma Cells ◽

Treatment Resistance ◽

Signaling Mechanism ◽

Knock Out ◽

Cycle Regulation ◽

Hiv 1

Abstract Patients infected with human immunodeficiency virus type 1 (HIV-1) are more prone to developing cancers, including glioblastomas (GBMs). The median survival for GBM patients with HIV is significantly shorter than for HIV-negative GBM patients, even though they receive the same treatments. This difference indicates that HIV infection is associated with more aggressive tumor behavior and with treatment resistance. Earlier we demonstrated that gp120, a main glycoprotein in the HIV shell, stimulates glycolysis and protein synthesis in glioma cells. The purpose of this study was to evaluate the underlying gp120 dependent signaling mechanism in glioma cell. Mouse glioma cells GL-261 were continuously cultured for 7 days in medium with and without soluble gp120 Bal III (100ng/ml) and collected for Western blot and Cell cycle assays. Western blot analysis presented an increase in phosphorylation of Proline-rich tyrosine kinase (Pyk2(Y402)), p38(YT100/Y182) and p70s6(T421/S424), the key proteins of the Pyk2 pathway, along with the increased levels of Akt(S473) and Glycogen Synthase Kinase 3b (GSK3b (S9)) phosphorylation. Flow cytometry analysis of Cell Cycle revealed an increase of G2/M phase in cells cultured in gp120 Bal III when compared to control cells. Furthermore, GL-261 cells with knock-out of Pyk2 via CRISPR Cas 9 gene editing showed no significant change in cell cycle regulation when cultured with gp120 Bal III.Overall, these results demonstrate that gp120 triggers activation of Pyk2/MAPK and Akt/GSK3b pathways and alter cell cycle regulation in GBM. This research was made possible by NIH grant number 1SC1GM122691.

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Cyclin F Disruption Compromises Placental Development and Affects Normal Cell Cycle Execution

Molecular and Cellular Biology ◽

10.1128/mcb.24.6.2487-2498.2004 ◽

2004 ◽

Vol 24 (6) ◽

pp. 2487-2498 ◽

Cited By ~ 50

Author(s):

Michael T. Tetzlaff ◽

Chang Bai ◽

Milton Finegold ◽

John Wilson ◽

J. Wade Harper ◽

...

Keyword(s):

Cell Cycle ◽

Population Doubling ◽

Population Doubling Time ◽

Placental Development ◽

Cell Cycle Reentry ◽

High Conservation ◽

And Function ◽

Cyclin F ◽

Cycle Regulation

ABSTRACT Human cyclin F was originally isolated as a cDNA capable of suppressing the temperature sensitivity of a Saccharomyces cerevisiae cdc4-1 mutant. Its tightly regulated expression and high conservation in the evolutionary progression from amphibians to mammals suggest that it coordinates the timing of a critical cell cycle event. The fact that it contains an F box and can form an SCF (Skp1-Cul1/Cdc53-F-box) complex in vivo further suggests that it may also function in proteolysis. To investigate the role of cyclin F in vivo, we generated mice deficient for cyclin F and conditionally deficient mice as well as mouse embryonic fibroblasts (MEFs) conditionally deficient for cyclin F. Heterozygous animals are normal and fertile, but CycF−/− animals, with a myriad of developmental anomalies due in large part to failures in yolk sac and chorioallantoic placentation, die around embryonic day 10.5. Tissue-specific deletion of cyclin F revealed that it was not required for the development and function of a number of different embryonic and adult tissues. In contrast, MEFs lacking cyclin F, while viable, do exhibit cell cycle defects, including reduced population-doubling time and a delay in cell cycle reentry from quiescence, indicating that cyclin F plays a role in cell cycle regulation.

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DNA Damage-Induced Cell Cycle Regulation and Function of Novel Chk2 Phosphoresidues

Molecular and Cellular Biology ◽

10.1128/mcb.00534-06 ◽

2006 ◽

Vol 26 (21) ◽

pp. 7832-7845 ◽

Cited By ~ 33

Author(s):

Giacomo Buscemi ◽

Luigi Carlessi ◽

Laura Zannini ◽

Sofia Lisanti ◽

Enrico Fontanella ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Ataxia Telangiectasia ◽

Dna Double Strand Breaks ◽

Independent Manner ◽

Strand Breaks ◽

Cycle Arrest ◽

And Function ◽

Cycle Regulation

ABSTRACT Chk2 kinase is activated by DNA damage to regulate cell cycle arrest, DNA repair, and apoptosis. Phosphorylation of Chk2 in vivo by ataxia telangiectasia-mutated (ATM) on threonine 68 (T68) initiates a phosphorylation cascade that promotes the full activity of Chk2. We identified three serine residues (S19, S33, and S35) on Chk2 that became phosphorylated in vivo rapidly and exclusively in response to ionizing radiation (IR)-induced DNA double-strand breaks in an ATM- and Nbs1-dependent but ataxia telangiectasia- and Rad3-related-independent manner. Phosphorylation of these residues, restricted to the G1 phase of the cell cycle, was induced by a higher dose of IR (>1 Gy) than that required for phosphorylation of T68 (0.25 Gy) and declined by 45 to 90 min, concomitant with a rise in Chk2 autophosphorylation. Compared to the wild-type form, Chk2 with alanine substitutions at S19, S33, and S35 (Chk2S3A) showed impaired dimerization, defective auto- and trans-phosphorylation activities, and reduced ability to promote degradation of Hdmx, a phosphorylation target of Chk2 and regulator of p53 activity. Besides, Chk2S3A failed to inhibit cell growth and, in response to IR, to arrest G1/S progression. These findings underscore the critical roles of S19, S33, and S35 and argue that these phosphoresidues may serve to fine-tune the ATM-dependent response of Chk2 to increasing amounts of DNA damage.

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Cell cycle regulation of membrane glucocorticoid receptor in CCRF-CEM human ALL cells: correlation to apoptosis.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.3.e571 ◽

1997 ◽

Vol 273 (3) ◽

pp. E571 ◽

Cited By ~ 11

Author(s):

F N Sackey ◽

C S Watson ◽

B Gametchu

Keyword(s):

Cell Cycle ◽

Glucocorticoid Receptor ◽

Fluorescent Microscopy ◽

Leukemic Cell ◽

Leukemic Cell Line ◽

Trypan Blue Exclusion ◽

Second Growth ◽

Human Leukemic Cell Line ◽

And Function ◽

Cycle Regulation

The human leukemic cell line (CCRF-CEM) and a subline enriched for the plasma membrane-resident glucocorticoid receptor (mGR) were studied for the influence of the cell cycle on the expression and function of mGR. Three synchronization procedures (double thymidine, colcemid, and combined thymidine-colcemid blocks) were used. Fluorescent microscopy and flow cytometry simultaneously assessed antibody-tagged mGR and DNA. In addition, mGR was quantitated and characterized by immunoprecipitation and immunoblotting. Apoptosis was assayed by DNA fragmentation (TUNEL assay) and by cell survival (trypan blue exclusion). All synchronization procedures demonstrated that progression from DNA replication (S) to the second growth phase and mitosis (G2/M) leads to cells having the highest levels of mGR expression and being highly glucocorticoid sensitive in the apoptosis assays: 32 and 80% sensitivity of wild type and mGR-enriched cells, respectively, compared with 12 and 30% sensitivity in asynchronous cells. Therefore, mGR expression appears to be cell cycle regulated, with its highest expression at late S-G2/M, when the cells are most sensitive to the lymphocytolytic effects of glucocorticoids.

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