scholarly journals Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling

2021 ◽  
Author(s):  
Yinhua Jin ◽  
Teni Anbarchian ◽  
Peng Wu ◽  
Abby Sarkar ◽  
Matt Fish ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Target Gene ◽  
Transcriptional Repressor ◽  
Hepatocyte Proliferation ◽  
Transcriptional Repressors ◽  
New Paradigm ◽  
Cycle Progression ◽  
Block Cell Cycle Progression ◽  
Cell Division Control

Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition. In several tissues including the liver, transcriptional repressors such as E2F7 and E2F8 function as inhibitors of mitosis and promote polyploidy, but how growth factors release these mitotic inhibitors to facilitate cell cycle progression is unknown. We describe here a newly identified mechanism of cell division control in which Wnt/βcatenin signaling in the postnatal liver maintains active hepatocyte proliferation through Tbx3, a Wnt target gene. TBX3 directly represses transcription of E2f7 and E2f8, promoting a low ploidy state and cell cycle progression. This sequential transcriptional repressor cascade, initiated by Wnts, provides a new paradigm for exploring how a commonly active developmental signal impacts cell cycle completion.

scholarly journals Role of Baculovirus IE2 and Its RING Finger in Cell Cycle Arrest

1998 ◽  
Vol 72 (1) ◽  
pp. 684-692 ◽  
Author(s):  
Elena A. Prikhod’ko ◽  
Lois K. Miller
Keyword(s):  
Cell Cycle ◽  
Trichoplusia Ni ◽  
Helicoverpa Zea ◽  
Cell Cycle Progression ◽  
Ring Finger ◽  
Regulatory Activity ◽  
Cycle Progression ◽  
Dna Contents ◽  
Block Cell Cycle Progression ◽  
Ring Finger Motif

ABSTRACT The ie2 gene of Autographa californicanuclear polyhedrosis virus (AcMNPV) is known to transactivate transient expression from viral promoters in a host cell-specific manner. We report that transfection ofSpodoptera frugiperda (SF-21) cells with ie2was sufficient to arrest the cell cycle, resulting in the accumulation of enlarged cells with abnormally high DNA contents. By 72 h posttransfection, more than 50% of ie2-transfected cells had DNA contents greater than 4N. There was no evidence of mitotic spindle formation in these cells, and expression ofie2 appeared to block cell cycle progression in S phase. Several ie2 mutants were analyzed to further define the region of IE2 responsible for arresting the cell cycle. Analysis of these mutants showed that deletion of the RING finger motif eliminated the ability of IE2 to arrest the cell cycle but did not affect its ability to transactivate the ie1 promoter. Moreover, mutation of a single conserved cysteine (C251) of the RING finger motif abolished the ability of IE2 to block cell cycle progression but had no apparent effect on its trans-regulatory activity. In contrast, a mutant of IE2 containing a deletion of residues 94 to 173 was able to block cell division but lacked trans-regulatory activity. Thus, the ability of IE2 to arrest the cell cycle depended on the integrity of the RING finger motif and was distinct from and independent of its ability to trans-activate theie1 promoter. IE2 also arrested the division of cells derived from other insect species, Trichoplusia ni (TN-368 and BTI-TN-5B1-4) and Helicoverpa zea (Hz-AM1).

scholarly journals A negative reciprocal regulatory axis between cyclin D1 and HNF4α modulates cell cycle progression and metabolism in the liver

2020 ◽  
Vol 117 (29) ◽  
pp. 17177-17186 ◽  
Author(s):  
Heng Wu ◽  
Yitzhak Reizel ◽  
Yue J. Wang ◽  
Jessica L. Lapiro ◽  
Betsy T. Kren ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Glycogen Synthesis ◽  
Hepatocyte Proliferation ◽  
In Vivo Model ◽  
Large Network ◽  
Cell Cycle Protein ◽  
Cycle Progression

Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of liver function and a tumor suppressor in hepatocellular carcinoma (HCC). In this study, we explore the reciprocal negative regulation of HNF4α and cyclin D1, a key cell cycle protein in the liver. Transcriptomic analysis of cultured hepatocyte and HCC cells found that cyclin D1 knockdown induced the expression of a large network of HNF4α-regulated genes. Chromatin immunoprecipitation-sequencing (ChIP-seq) demonstrated that cyclin D1 inhibits the binding of HNF4α to thousands of targets in the liver, thereby diminishing the expression of associated genes that regulate diverse metabolic activities. Conversely, acute HNF4α deletion in the liver induces cyclin D1 and hepatocyte cell cycle progression; concurrent cyclin D1 ablation blocked this proliferation, suggesting that HNF4α maintains proliferative quiescence in the liver, at least, in part, via repression of cyclin D1. Acute cyclin D1 deletion in the regenerating liver markedly inhibited hepatocyte proliferation after partial hepatectomy, confirming its pivotal role in cell cycle progression in this in vivo model, and enhanced the expression of HNF4α target proteins. Hepatocyte cyclin D1 gene ablation caused markedly increased postprandial liver glycogen levels (in a HNF4α-dependent fashion), indicating that the cyclin D1-HNF4α axis regulates glucose metabolism in response to feeding. In AML12 hepatocytes, cyclin D1 depletion led to increased glucose uptake, which was negated if HNF4α was depleted simultaneously, and markedly elevated glycogen synthesis. To summarize, mutual repression by cyclin D1 and HNF4α coordinately controls the cell cycle machinery and metabolism in the liver.

scholarly journals Fuyuan Decoction Enhances SOX9 and COL2A1 Expression and Smad2/3 Phosphorylation in IL-1β-Activated Chondrocytes

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Yudi Zhang ◽  
Rongheng Li ◽  
Yu Zhong ◽  
Sihan Zhang ◽  
Lingyun Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Target Gene ◽  
Phase Cell ◽  
Cell Growth Inhibition ◽  
Sox9 Expression ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Col2a1 Expression ◽  
Polymerase Chain

Fuyuan Decoction (FYD), a herbal formula in China, has been widely used for osteoarthritis (OA) treatment. Herein, we determined the effects of FYD on the expression of transcription factor SOX9 and its target gene collagen type II, alpha 1 (COL2A1) as well as the activation of Smad2/3 in interleukin- (IL-) 1β-stimulated SW1353 chondrosarcoma cells. Serum-derived FYD (FYD-CS) was prepared to treat SW1353 cells with or without SB431542, a TGF-β1 receptor inhibitor. Cell cycle progression was tested by flow cytometry. The expression of SOX9 and COL2A1 and the activation of Smad2/3 (p-Smad2/3) were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and/or western blot. The results showed that, after treatment, FYD-CS, while inducing S-phase cell cycle arrest, enhanced cell proliferation and protected the cells against IL-1β- and/or SB431542-induced cell growth inhibition. Furthermore, FYD-CS reversed the decreased expression of COL2A1 and SOX9 induced by IL-1βand SB431542 and blocked the decreased phosphorylation of Smad2/3 induced by IL-1βalone or in combination with SB431542. Our results suggest that FYD promotes COL2A1 and SOX9 expression as well as Smad2/3 activation in IL-1β-induced chondrocytes, thus benefiting cell survival.

scholarly journals P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy

2014 ◽  
Vol 307 (11) ◽  
pp. G1073-G1087 ◽  
Author(s):  
Bryan C. Tackett ◽  
Hongdan Sun ◽  
Yu Mei ◽  
Janielle P. Maynard ◽  
Sayuri Cheruvu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Partial Hepatectomy ◽  
Cell Cycle Progression ◽  
Purinergic Receptors ◽  
Purinergic Receptor ◽  
Receptor Activation ◽  
Hepatocyte Proliferation ◽  
Receptor Subtypes ◽  
Cycle Progression ◽  
The Impact

Extracellular nucleotides via activation of P2 purinergic receptors influence hepatocyte proliferation and liver regeneration in response to 70% partial hepatectomy (PH). Adult hepatocytes express multiple P2Y (G protein-coupled) and P2X (ligand-gated ion channels) purinergic receptor subtypes. However, the identity of key receptor subtype(s) important for efficient hepatocyte proliferation in regenerating livers remains unknown. To evaluate the impact of P2Y2 purinergic receptor-mediated signaling on hepatocyte proliferation in regenerating livers, wild-type (WT) and P2Y2 purinergic receptor knockout (P2Y2−/−) mice were subjected to 70% PH. Liver tissues were analyzed for activation of early events critical for hepatocyte priming and subsequent cell cycle progression. Our findings suggest that early activation of p42/44 ERK MAPK (5 min), early growth response-1 (Egr-1) and activator protein-1 (AP-1) DNA-binding activity (30 min), and subsequent hepatocyte proliferation (24–72 h) in response to 70% PH were impaired in P2Y2−/− mice. Interestingly, early induction of cytokines (TNF-α, IL-6) and cytokine-mediated signaling (NF-κB, STAT-3) were intact in P2Y2−/− remnant livers, uncovering the importance of cytokine-independent and nucleotide-dependent early priming events critical for subsequent hepatocyte proliferation in regenerating livers. Hepatocytes isolated from the WT and P2Y2−/− mice were treated with ATP or ATPγS for 5–120 min and 12–24 h. Extracellular ATP alone, via activation of P2Y2 purinergic receptors, was sufficient to induce ERK phosphorylation, Egr-1 protein expression, and key cyclins and cell cycle progression of hepatocytes in vitro. Collectively, these findings highlight the functional significance of P2Y2 purinergic receptor activation for efficient hepatocyte priming and proliferation in response to PH.

Proteasomes are a target of the anti-tumour drug vinblastine

2001 ◽  
Vol 356 (3) ◽  
pp. 835-841 ◽  
Author(s):  
Marco PICCININI ◽  
Ornella TAZARTES ◽  
Caterina MEZZATESTA ◽  
Emanuela RICOTTI ◽  
Stefano BEDINO ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Proteasome Inhibitors ◽  
Drug Dose ◽  
26S Proteasome ◽  
Cell Physiology ◽  
Cycle Progression ◽  
Hl60 Cells ◽  
Block Cell Cycle Progression

Proteasomes, the proteolytic machinery of the ubiquitin/ATP-dependent pathway, have a relevant role in many processes crucial for cell physiology and cell cycle progression. Proteasome inhibitors are used to block cell cycle progression and to induce apoptosis in certain cell lines. Here we examine whether proteasomal function is affected by the anti-tumour drug vinblastine, whose cytostatic action relies mainly on the disruption of mitotic spindle dynamics. The effects of vinblastine on the peptidase activities of human 20S and 26S proteasomes and on the proteolytic activity of 26S proteasome were assessed in the presence of specific fluorogenic peptides and 125I-lysozyme–ubiquitin conjugates respectively. The assays of ubiquitin–protein conjugates and of inhibitory κBα (IκBα), which are characteristic intracellular proteasome substrates, by Western blotting on lysates from HL60 cells incubated with or without vinblastine, illustrated the effects of vinblastine on proteasomes in vivo. We also evaluated the effects of vinblastine on the signal-induced degradation of IκBα. Vinblastine at 3–110μM reversibly inhibited the chymotrypsin-like activity of the 20 S proteasome and the trypsin-like and peptidyl-glutamyl-peptide hydrolysing activities of both proteasomes, but only at 110μM vinblastine was the chymotrypsin-like activity of the 26S proteasome inhibited; furthermore, at 25–200μM the drug inhibited the degradation of ubiquitinated lysozyme. In HL60 cells exposed for 6h to 0.5–10μM vinblastine, the drug-dose-related accumulation of polyubiquitinated proteins, as well as that of a high-molecular-mass form of IκBα, occurred. Moreover, vinblastine impaired the signal-induced degradation of IκBα. Cell viability throughout the test was approx. 95%. Proteasomes can be considered to be a new and additional vinblastine target.

scholarly journals Helicobacter pylori interferes with an embryonic stem cell micro RNA cluster to block cell cycle progression

Silence ◽  
2011 ◽  
Vol 2 (1) ◽  
pp. 7 ◽  
Author(s):  
Cédric Belair ◽  
Jessica Baud ◽  
Sandrine Chabas ◽  
Cynthia M Sharma ◽  
Jörg Vogel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Helicobacter Pylori ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Cell Cycle Progression ◽  
Embryonic Stem ◽  
Micro Rna ◽  
Cycle Progression ◽  
Block Cell Cycle Progression

scholarly journals CDK1 phosphorylates ULK1-ATG13 complex to regulate mitotic autophagy and Taxol chemosensitivity

2019 ◽  
Author(s):  
Zhiyuan Li ◽  
Xiaofei Tian ◽  
Xinmiao Ji ◽  
Dongmei Wang ◽  
Xin Zhang
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Site Directed Mutagenesis ◽  
Regulation Mechanism ◽  
Cancer Cell Proliferation ◽  
Double Knockout ◽  
Cycle Progression ◽  
Mutual Regulation ◽  
Block Cell Cycle Progression ◽  
And Function

AbstractULK1-ATG13 is the most upstream autophagy initiation complex that is phosphorylated by mTORC1 and AMPK to induce autophagy in asynchronous conditions. However, the phospho-regulation and function of ULK1-ATG13 in mitosis and cell cycle remains unknown. Here we show that ULK1-ATG13 complex is differentially regulated throughout the cell cycle. Notably, in mitosis, both ULK1 and ATG13 are highly phosphorylated by CDK1/cyclin B, the key cell cycle machinery. Combining mass spectrometry and site-directed mutagenesis, we found that CDK1-induced ULK1-ATG13 phosphorylation positively regulates mitotic autophagy and Taxol chemosensitivity, and some phosphorylation sites occur in cancer patients. Moreover, double knockout of ULK1 and ATG13 could block cell cycle progression and significantly decrease cancer cell proliferation in cell line and mouse models. Our results not only bridge the mutual regulation between the core machineries of autophagy and mitosis, illustrate the mitotic autophagy regulation mechanism, but also provide ULK1-ATG13 as potential targets for cancer therapy.

Sign in / Sign up

Export Citation Format

Share Document