scholarly journals Circadian Proteins Cry and Rev-erb Deepen Cellular Quiescence by Down-regulating Cyclin D and Cdk4,6

2021 ◽  
Author(s):  
Xia Wang ◽  
Bi Liu ◽  
Qiong Pan ◽  
Jungeun Sarah Kwon ◽  
Matthew A. Miller ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D ◽  
Bistable Switch ◽  
Quiescent Cells ◽  
Tissue Repair And Regeneration ◽  
Serum Stimulation ◽  
Cellular Quiescence ◽  
Underlying Mechanisms ◽  
Network Switch

The proper balance and transition between cellular quiescence and proliferation are critical to tissue homeostasis, and their deregulations are commonly found in many human diseases, including cancer and aging. Recent studies showed that the reentry of quiescent cells to the cell cycle is subjected to circadian regulation. However, the underlying mechanisms are largely unknown. Here, we report that two circadian proteins, Cryptochrome (Cry) and Rev-erb, deepen cellular quiescence in rat embryonic fibroblasts, resulting in stronger serum stimulation required for cells to exit quiescence and reenter the cell cycle. This finding was opposite from what we expected from the literature. By modeling a library of possible regulatory topologies linking Cry and Rev-erb to a bistable Rb-E2f gene network switch that controls the quiescence-to-proliferation transition and by experimentally testing model predictions, we found Cry and Rev-erb converge to downregulate Cyclin D/Cdk4,6 activity, leading to an ultrasensitive increase of the serum threshold to activate the Rb-E2f bistable switch. Our findings suggest a mechanistic role of circadian proteins in modulating the depth of cellular quiescence, which may have implications in the varying potentials of tissue repair and regeneration at different times of the day.

scholarly journals Cell cycle-independent integration of stress signals promotes Non-G1/G0 quiescence entry

2021 ◽  
Author(s):  
Orlando Argüello-Miranda ◽  
Ashley Marchand ◽  
Taylor Kennedy ◽  
Marielle AX Russo ◽  
Jungsik Noh
Keyword(s):  
Machine Learning ◽  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Transcription Factors ◽  
Kinase Activity ◽  
Nuclear Accumulation ◽  
Quiescent Cells ◽  
Developmental Mechanisms ◽  
Cellular Quiescence ◽  
Stress Signals

AbstractCellular quiescence is a non-proliferative state required for cell survival under stress and during development. In most quiescent cells, proliferation is stopped in a reversible state of low Cdk1 kinase activity; in many organisms, however, quiescent states with high Cdk1 activity can also be established through still uncharacterized stress or developmental mechanisms. Here, we used a microfluidics approach coupled to phenotypic classification by machine learning to identify stress pathways associated with starvation-triggered high-Cdk1 quiescent states in Saccharomyces cerevisiae. We found that low- and high-Cdk1 quiescent states shared a core of stress-associated processes, such as autophagy, protein aggregation, and mitochondrial upregulation, but differed in the nuclear accumulation of the stress transcription factors Xbp1, Gln3, and Sfp1. The decision between low- or high-Cdk1 quiescence was controlled by cell cycle-independent accumulation of Xbp1, which acted as a time-delayed integrator of the duration of stress stimuli. Our results show how cell cycle-independent stress-activated factors promote cellular quiescence outside of G1/G0.

Abstract P119: S100A6 Regulates Endothelial Cell Physiology

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Shumei Ren ◽  
Karsten Peppel ◽  
Patrick Most
Keyword(s):  
Cell Cycle ◽  
Endothelial Cell ◽  
Protein Function ◽  
Cell Cycle Control ◽  
Tube Formation ◽  
Cell Physiology ◽  
Ki 67 ◽  
Proliferation Markers ◽  
Serum Stimulation

Endothelial cell dysfunction is central to the development of cardiovascular pathologies. While Calcium cycling is of recognized importance to myocyte physiology and cardiac perfomance, the role of Ca2+ signaling in endothelial cell (EC) physiology remains relatively unexplored. In this study we investigated the role of S100A6 (calcyclin), an EF-hand type Ca2+ -binding protein that modulates target protein function dependent upon intracellular Ca2+ signaling. S100A6 displays cytoplasmic distribution in quiescent, confluent HUVEC, but translocates to the nucleus upon serum stimulation. Oxidative stress, induced by incubation of HUVEC with H¬2O2 (150 uM) leads to redistribution of nuclear S100A6 to the cytosol and cell cycle arrest. Knockdown of S100A6 by siRNA transfection reduced S100A6 levels by over 70% and diminished DNA synthesis by more than 75% (±12%, n=9, p<0.01), as well as expression of the proliferation markers PCNA and KI-67 (by more than 70% (±15%, n=9, p<0.01). Reduced S100A6 levels in HUVEC lead to an increase in cellular senescence, as measured by the expression of senescence associated β-galactosidase expression (by more than 6-fold, n=4, p<0.01) and a reduction of EC tube formation on matrigel matrix (by more than 90%, n=3, p<0.01). Reduction of S100A6 increased the expression of the cell cycle control and DNA repair-associated gene BRCA2, but did not change in the expression of BRCA1, cyclins or p53 (by RT-PCR array). We conclude that Ca2+ regulation by S100A6 is essential for multiple aspects of EC physiology.

scholarly journals D-type cyclin-dependent kinase activity in mammalian cells.

1994 ◽  
Vol 14 (3) ◽  
pp. 2066-2076 ◽  
Author(s):  
H Matsushime ◽  
D E Quelle ◽  
S A Shurtleff ◽  
M Shibuya ◽  
C J Sherr ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mammalian Cells ◽  
Kinase Activity ◽  
Cyclin D3 ◽  
Tween 20 ◽  
Cyclin D ◽  
Cyclin Dependent Kinase ◽  
Proliferating Cells ◽  
Quiescent Cells ◽  
Serum Stimulation

D-type cyclin-dependent kinase activities have not so far been detected in mammalian cells. Lysis of rodent fibroblasts, mouse macrophages, or myeloid cells with Tween 20 followed by precipitation with antibodies to cyclins D1, D2, and D3 or to their major catalytic partner, cyclin-dependent kinase 4 (cdk4), yielded kinase activities in immune complexes which readily phosphorylated the retinoblastoma protein (pRb) but not histone H1 or casein. Virtually all cyclin D1-dependent kinase activity in proliferating macrophages and fibroblasts could be attributed to cdk4. When quiescent cells were stimulated by growth factors to enter the cell cycle, cyclin D1-dependent kinase activity was first detected in mid G1, reached a maximum near the G1/S transition, and remained elevated in proliferating cells. The rate of appearance of kinase activity during G1 phase lagged significantly behind cyclin induction and correlated with the more delayed accumulation of cdk4 and formation of cyclin D1-cdk4 complexes. Thus, cyclin D1-associated kinase activity was not detected during the G0-to-G1 transition, which occurs within the first few hours following growth factor stimulation. Rodent fibroblasts engineered to constitutively overexpress either cyclin D1 alone or cyclin D3 together with cdk4 exhibited greatly elevated cyclin D-dependent kinase activity, which remained absent in quiescent cells but rose to supraphysiologic levels as cells progressed through G1. Therefore, despite continued enforced overproduction of cyclins and cdk4, the assembly of cyclin D-cdk4 complexes and the appearance of their kinase activities remained dependent upon serum stimulation, indicating that upstream regulators must govern formation of the active enzymes.

scholarly journals Modelling mammalian cellular quiescence

2014 ◽  
Vol 4 (3) ◽  
pp. 20130074 ◽  
Author(s):  
Guang Yao
Keyword(s):  
Dynamic Control ◽  
Control Mechanisms ◽  
Bistable Switch ◽  
Environmental Signals ◽  
Tissue Repair And Regeneration ◽  
Cycle Arrest ◽  
Permanent Cell ◽  
Cellular Quiescence ◽  
Novel Therapeutic Strategies ◽  
Multicellular Organisms

Cellular quiescence is a reversible non-proliferating state. The reactivation of ‘sleep-like’ quiescent cells (e.g. fibroblasts, lymphocytes and stem cells) into proliferation is crucial for tissue repair and regeneration and a key to the growth, development and health of higher multicellular organisms, such as mammals. Quiescence has been a primarily phenotypic description (i.e. non-permanent cell cycle arrest) and poorly studied. However, contrary to the earlier thinking that quiescence is simply a passive and dormant state lacking proliferating activities, recent studies have revealed that cellular quiescence is actively maintained in the cell and that it corresponds to a collection of heterogeneous states. Recent modelling and experimental work have suggested that an Rb-E2F bistable switch plays a pivotal role in controlling the quiescence–proliferation balance and the heterogeneous quiescent states. Other quiescence regulatory activities may crosstalk with and impinge upon the Rb-E2F bistable switch, forming a gene network that controls the cells’ quiescent states and their dynamic transitions to proliferation in response to noisy environmental signals. Elucidating the dynamic control mechanisms underlying quiescence may lead to novel therapeutic strategies that re-establish normal quiescent states, in a variety of hyper- and hypo-proliferative diseases, including cancer and ageing.

scholarly journals Fos Family Members Induce Cell Cycle Entry by Activating Cyclin D1

1998 ◽  
Vol 18 (9) ◽  
pp. 5609-5619 ◽  
Author(s):  
Jennifer R. Brown ◽  
Elizabeth Nigh ◽  
Richard J. Lee ◽  
Hong Ye ◽  
Margaret A. Thompson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cellular Targets ◽  
Definitive Evidence ◽  
Quiescent Cells ◽  
Cell Cycle Reentry ◽  
Serum Stimulation ◽  
Cell Cycle Entry

ABSTRACT Expression of the fos family of transcription factors is stimulated by growth factors that induce quiescent cells to reenter the cell cycle, but the cellular targets of the Fos family that regulate cell cycle reentry have not been identified. To address this issue, mice that lack two members of the fos family, c-fos and fosB, were derived. ThefosB −/− c-fos −/−mice are similar in phenotype to c-fos −/−mice but are 30% smaller. This decrease in size is consistent with an abnormality in cell proliferation. Fibroblasts derived fromfosB −/− c-fos −/−mice were found to have a defect in proliferation that results at least in part from a failure to induce cyclin D1 following serum-stimulated cell cycle reentry. Although definitive evidence that c-Fos and FosB directly induce cyclin D1 transcription will require further analysis, these findings raise the possibility that c-Fos and FosB are either direct or indirect transcriptional regulators of the cyclin D1 gene and may function as a critical link between serum stimulation and cell cycle progression.

scholarly journals Involvement of the STAT5-cyclin D/CDK4-pRb pathway in β-cell proliferation stimulated by prolactin during pregnancy

2019 ◽  
Vol 316 (1) ◽  
pp. E135-E144 ◽  
Author(s):  
Xin Zhao ◽  
Yili Xu ◽  
Ya Wu ◽  
Hui Zhang ◽  
Houxia Shi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Cell Mass ◽  
Cyclin D ◽  
Β Cell ◽  
Cycle Progression ◽  
Rb Phosphorylation ◽  
Insulinoma Cells

During pregnancy, maternal pancreatic β-cells undergo a compensatory expansion in response to the state of insulin resistance, where prolactin (PRL) plays a major role. Retinoblastoma protein (Rb) has been shown to critically regulate islet proliferation and function. The aim of the study was to explore the role of Rb in β-cell mass expansion during pregnancy. Expression of pocket protein family and E2Fs were examined in mouse islets during pregnancy and in insulinoma cells (INS-1) stimulated by PRL. PRL-stimulated INS-1 cells were used to explore the signaling pathway that regulates Rb downstream of the PRL receptor. Pancreas-specific Rb-knockout (Rb-KO) mice were assessed to evaluate the in vivo function of Rb in β-cell proliferation during pregnancy. During pregnancy, expression of Rb, phospho-Rb (p-Rb), p107, and E2F1 increased, while p130 decreased in maternal islets. With PRL stimulation, induction of Rb expression occurred mainly in the nucleus, while p-Rb was predominantly in the cytoplasm. Inhibition of STAT5 significantly restrained the expression of CDK4, Rb, p-Rb, and E2F1 in PRL-stimulated INS-1 cells with attenuation in cell cycle progression. Reduction of Rb phosphorylation by CDK4 inhibition blocked PRL-mediated proliferation of INS-1 cells. On the other hand, knockdown of Rb using siRNA led to an induction in E2F1 leading to cell cycle progression from G1 to S and G2/M phase, similar to the effects of PRL-mediated induction of p-Rb that led to cell proliferation. With Rb knockdown, PRL did not lead to further increase in cell cycle progression. Similarly, while Rb-KO pregnant mice displayed better glucose tolerance and higher insulin secretion, they had similar β-cell mass and proliferation to wild-type pregnant controls, supporting the essential role of Rb suppression in augmenting β-cell proliferation during pregnancy. Rb-E2F1 regulation plays a pivotal role in PRL-stimulated β-cell proliferation. PRL promotes Rb phosphorylation and E2F1 upregulation via STAT5-cyclin D/CDK4 pathway during pregnancy.

scholarly journals The Microbiome and Its Implications in Cancer Immunotherapy

Molecules ◽  
2021 ◽  
Vol 26 (1) ◽  
pp. 206
Author(s):  
Hani Choudhry
Keyword(s):  
Cell Cycle ◽  
Cancer Immunotherapy ◽  
Cancer Progression ◽  
Physiological Responses ◽  
Cell Cycle Checkpoints ◽  
Diagnostic Tools ◽  
Different Types ◽  
Underlying Mechanisms ◽  
Therapy Strategies

Cancer is responsible for ~18 million deaths globally each year, representing a major cause of death. Several types of therapy strategies such as radiotherapy, chemotherapy and more recently immunotherapy, have been implemented in treating various types of cancer. Microbes have recently been found to be both directly and indirectly involved in cancer progression and regulation, and studies have provided novel and clear insights into the microbiome-mediated emergence of cancers. Scientists around the globe are striving hard to identify and characterize these microbes and the underlying mechanisms by which they promote or suppress various kinds of cancer. Microbes may influence immunotherapy by blocking various cell cycle checkpoints and the production of certain metabolites. Hence, there is an urgent need to better understand the role of these microbes in the promotion and suppression of cancer. The identification of microbes may help in the development of future diagnostic tools to cure cancers possibly associated with the microbiome. This review mainly focuses on various microbes and their association with different types of cancer, responses to immunotherapeutic modulation, physiological responses, and prebiotic and postbiotic effects.

MiR-1180 promotes cardiomyocyte cell cycle re-entry after injury through the NKIRAS2–NFκB pathway

2020 ◽  
Vol 98 (4) ◽  
pp. 449-457
Author(s):  
Yuhui Ding ◽  
Liyuan Bi ◽  
Jun Wang
Keyword(s):  
Cell Cycle ◽  
Myocardial Injury ◽  
Cell Activity ◽  
Cardiac Repair ◽  
Impaired Health ◽  
Underlying Mechanisms ◽  
Nfκb Pathway ◽  
Over Time

Heart failure (HF) is associated with a considerable number of symptoms and significantly impaired health for humans, including reduced quality of life and physical functioning. Previous studies have indicated that miRNAs have important roles in regulating the development of HF. MiR-1180 is involved in the proliferation, migration, invasiveness, and chemoresistance of cancer cells; however, the underlying mechanisms and role of miR-1180 in the functioning of cardiomyocytes remains unclear. In this study, we found that miR-1180 promotes cell activity and cell cycle processes by driving energy generation through NKIRAS2, which declines over time during development. The expression of miR-1180 is down-regulated in cells subjected to hypoxia–reoxygenation, and use of an miR-1180 mimic significantly reduced myocardial injury and cell apoptosis. In addition, miR-1180 regulates the NFκB pathway through NKIRAS2 in cardiomyocytes. These findings suggest that miR-1180 maybe a novel therapeutic target for use in getting cardiomyocytes to re-enter the cell cycle as well as for cardiac repair following myocardial injury.

Existence of different Fos/Jun complexes during the G0-to-G1 transition and during exponential growth in mouse fibroblasts: differential role of Fos proteins

1992 ◽  
Vol 12 (11) ◽  
pp. 5015-5023
Author(s):  
K Kovary ◽  
R Bravo
Keyword(s):  
Exponential Growth ◽  
S Phase ◽  
3T3 Cells ◽  
Mouse Fibroblasts ◽  
Quiescent Cells ◽  
Serum Stimulation ◽  
Fos Protein ◽  
Swiss 3T3 ◽  
Stimulation Of

We have determined the different Fos/Jun complexes present in Swiss 3T3 cells either following serum stimulation of quiescent cells or during exponential growth by immunoprecipitation analyses. We have shown that while c-Fos is the major Fos protein associated with the Jun proteins (c-Jun, JunB, and JunD) soon after serum stimulation, at later times Fra-1 and Fra-2 are the predominant Fos proteins associated with the different Jun proteins. During exponential growth, the synthesis of Fra-1 and Fra-2 is maintained at a significant level, in contrast to c-Fos and FosB, which are expressed at very low or undetectable levels. Consequently, Fra-1 and Fra-2 are the main Fos proteins complexed with the Jun proteins in asynchronously growing cells. To determine whether the Fos proteins are differentially required during the G0-to-G1 transition and exponential growth for the entrance into S phase, we microinjected affinity-purified antibodies directed against c-Fos, FosB, Fra-1, and Fra-2. We have found that while the activities of c-Fos and FosB are required mostly during the G0-to-G1 transition, Fra-1 and Fra-2 are involved both in the G0-to-G1 transition and in asynchronous growth.

scholarly journals Cellular ras activity is required for passage through multiple points of the G0/G1 phase in BALB/c 3T3 cells.

1994 ◽  
Vol 14 (8) ◽  
pp. 5441-5449 ◽  
Author(s):  
S Dobrowolski ◽  
M Harter ◽  
D W Stacey
Keyword(s):  
Cell Cycle ◽  
G1 Phase ◽  
C Cells ◽  
Inhibitory Effects ◽  
Multiple Points ◽  
Oncogenic Ras ◽  
Quiescent Cells ◽  
Serum Stimulation ◽  
G1 Cells ◽  
Cell Cycle Inhibitors

Microinjection experiments demonstrated a requirement for cellular ras activity late in G1. In this study, we used two separate methods to identify an additional requirement for cellular ras activity early in the G0/G1 phase of the cell cycle. Quiescent BALB/c cells were injected with anti-ras antibody prior to stimulation with serum. The cells would therefore be inhibited in progression through the cell cycle at the earliest point requiring ras function. Alternatively, cells were inhibited in late G1 as in previous studies by injecting anti-ras several hours after serum addition to quiescent cells. The injected cultures were then treated with chemical cell cycle inhibitors known to function in mid-G1. Cells injected with anti-ras prior to serum stimulation were retained at a point of ras requirement prior to the execution point of the chemical inhibitor, while cells injected 3 to 5 h after serum stimulation were retained at a point of ras requirement downstream of the execution point of the chemical inhibitor. To confirm these results, quiescent BALB/c cells were injected with anti-ras antibody prior to or several hours following serum addition. In this case, however, second injections of oncogenic ras or adenoviral E1A protein were performed to overcome the inhibitory effects of the anti-ras antibody. Cells injected prior to serum addition were clearly inhibited at an early point of Ras requirement since they required 5 or 6 h longer to enter S phase than cells injected with anti-ras antibody after serum addition.

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