Cullin-1 Promotes Cell Proliferation in Human Breast Cancer and is Related to Diabetes

2016 ◽  
Vol 31 (4) ◽  
pp. 375-381
Author(s):  
Yun-Hai Zhou ◽  
Jiazeng Xia ◽  
Wen-Huan Xu ◽  
Xiqi Zhu ◽  
Xiao-Hong Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Poor Prognosis ◽  
Cell Cycle Progression ◽  
Disease Free Survival ◽  
Ubiquitin Proteasome System ◽  
Cycle Progression ◽  
Previous Diagnosis ◽  
Ubiquitin Proteasome ◽  
Clinicopathological Variables

Aim Breast carcinoma (BCA) and diabetes mellitus (DM) are two major health problems in women and the general population. Cullin-1 is reported to be an important tumor-related protein involved in cell-cycle progression, signal transduction and transcription. The aim of this work is to investigate the role of Cullin-1 in the development of BCA and to find potential relationships between Cullin-1 and diabetes in BCA patients. Methods To evaluate the function of Cullin-1, we entered 168 patients with primary invasive BCA in this study. Pairs of BCA tissues and adjacent noncancerous tissues from these patients were collected between 2006 and 2008. We used immunohistochemistry to analyze the correlation between Cullin-1 expression and clinicopathological variables and patient survival. In addition, we investigated the role of Cullin-1 in BCA cell proliferation. Results Cullin-1 expression was upregulated in BCA tissues. Enhanced immunoreactivity for Cullin-1 in BCA tissues was inversely correlated with overall survival and disease-free survival, which suggested a poor prognosis in BCA patients. Strong expression of Cullin-1 was more frequently observed in patients with estrogen receptor negativity and HER2 positivity. We also found that Cullin-1 expression was increased in BCA patients with a previous diagnosis of diabetes. Conclusions Our results demonstrate that increased Cullin-1 expression is significantly correlated with poor prognosis in patients with BCA. Cullin-1 might regulate BCA cell proliferation through the ubiquitin-proteasome system. Thus, Cullin-1 might be an important marker and a therapeutic target in BCA.

scholarly journals A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development

2017 ◽  
Vol 27 (6) ◽  
pp. 905-913 ◽  
Author(s):  
Kristina Ames ◽  
Dayse S. Da Cunha ◽  
Brenda Gonzalez ◽  
Marina Konta ◽  
Feng Lin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Cell Cycle Progression ◽  
Germline Development ◽  
Cycle Progression ◽  
Stem Cell Proliferation

scholarly journals The ubiquitin-proteasome system: A novel target for anticancer and anti-inflammatory drug research

2008 ◽  
Vol 13 (3) ◽  
Author(s):  
Halina Ostrowska
Keyword(s):  
Cell Cycle Progression ◽  
Control Cell ◽  
Ubiquitin Proteasome System ◽  
Cycle Progression ◽  
System A ◽  
Intracellular Proteins ◽  
Ubiquitin Proteasome ◽  
Novel Target ◽  
Transcriptional Pathway ◽  
Control Cell Cycle Progression

AbstractThe ubiquitin-proteasome system is responsible for the degradation of most intracellular proteins, including those that control cell cycle progression, apoptosis, signal transduction and the NF-κB transcriptional pathway. Aberrations in the ubiquitin-proteasome system underlie the pathogenesis of many human diseases, so both the ubiquitin-conjugating system and the 20S proteasome are important targets for drug discovery. This article presents a few of the most important examples of the small molecule inhibitors and modulators targeting the ubiquitin-proteasome system, their mode of action, and their potential therapeutic relevance in the treatment of cancer and inflammatory-related diseases.

scholarly journals PSMC2 Regulates Cell Cycle Progression Through the p21/Cyclin D1 Pathway and Predicts a Poor Prognosis in Human Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Yiwei Liu ◽  
Hairong Chen ◽  
Xiangcheng Li ◽  
Feng Zhang ◽  
Lianbao Kong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Luciferase Reporter ◽  
Cycle Progression ◽  
Cox Regression Analysis

Proteasome 26S subunit ATPase 2 (PSMC2) plays a pathogenic role in various cancers. However, its function and molecular mechanism in hepatocellular carcinoma (HCC) remain unknown. In this study, tissue microarray (TMA) analysis showed that PSMC2 is highly expressed in HCC tumors and correlates with poor overall and disease-free survival in HCC patients. Multivariate Cox regression analysis revealed that PSMC2 is an independent prognostic factor for HCC patients. Furthermore, our results showed that PSMC2 knockdown inhibited cell proliferation and suppressed tumorigenesis in vivo. Knockdown of PSMC2 increased the expression of p21 and therefore decreased the expression of cyclin D1. Dual-luciferase reporter assays indicated that depletion of PSMC2 significantly enhanced the promoter activity of p21. Importantly, PSMC2 knockdown-induced phenotypes were also rescued by downregulation of P21. Taken together, our data suggest that PSMC2 promotes HCC cell proliferation and cell cycle progression through the p21/cyclin D1 signaling pathway and could be a promising diagnostic and therapeutic target for HCC patients.

scholarly journals Tuning the proteasome to brighten the end of the journey

2016 ◽  
Vol 311 (5) ◽  
pp. C793-C804 ◽  
Author(s):  
Thibault Mayor ◽  
Michal Sharon ◽  
Michael H. Glickman
Keyword(s):  
Cell Cycle Progression ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Cellular Proteins ◽  
Regulatory Mechanisms ◽  
Protein Homeostasis ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Age Related ◽  
Ubiquitin Proteasome

Degradation by the proteasome is the fate for a large portion of cellular proteins, and it plays a major role in maintaining protein homeostasis, as well as in regulating many cellular processes like cell cycle progression. A decrease in proteasome activity has been linked to aging and several age-related neurodegenerative pathologies and highlights the importance of the ubiquitin proteasome system regulation. While the proteasome has been traditionally viewed as a constitutive element of proteolysis, major studies have highlighted how different regulatory mechanisms can impact its activity. Importantly, alterations of proteasomal activity may have major impacts for its function and in therapeutics. On one hand, increasing proteasome activity could be beneficial to prevent the age-related downfall of protein homeostasis, whereas inhibiting or reducing its activity can prevent the proliferation of cancer cells.

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.

On the role of TRPC1 in control of Ca2+ influx, cell volume, and cell cycle

2012 ◽  
Vol 303 (6) ◽  
pp. C625-C634 ◽  
Author(s):  
C. P. Madsen ◽  
T. K. Klausen ◽  
A. Fabian ◽  
B. J. Hansen ◽  
S. F. Pedersen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Volume ◽  
Volume Regulation ◽  
Cell Cycle Progression ◽  
Regulatory Volume Decrease ◽  
Cell Volume Regulation ◽  
S Phase ◽  
Cycle Progression

Ca+ signaling plays a crucial role in control of cell cycle progression, but the understanding of the dynamics of Ca2+ influx and release of Ca2+ from intracellular stores during the cell cycle is far from complete. The aim of the present study was to investigate the role of the free extracellular Ca2+ concentration ([Ca2+]o) in cell proliferation, the pattern of changes in the free intracellular Ca2+ concentration ([Ca2+]i) during cell cycle progression, and the role of the transient receptor potential (TRP)C1 in these changes as well as in cell cycle progression and cell volume regulation. In Ehrlich Lettré Ascites (ELA) cells, [Ca2+]i decreased significantly, and the thapsigargin-releasable Ca2+ pool in the intracellular stores increased in G1 as compared with G0. Store-depletion-operated Ca2+ entry (SOCE) and TRPC1 protein expression level were both higher in G1 than in G0 and S phase, in parallel with a more effective volume regulation after swelling [regulatory volume decrease (RVD)] in G1 as compared with S phase. Furthermore, reduction of [Ca2+]o, as well as two unspecific SOCE inhibitors, 2-APB (2-aminoethyldiphenyl borinate) and SKF96365 (1-(β-[3-(4-methoxy-phenyl)propoxyl-4-methoxyphenethyl)1H-imidazole-hydrochloride), inhibited ELA cell proliferation. Finally, Madin-Darby canine kidney cells in which TRPC1 was stably silenced [TRPC1 knockdown (TRPC1-KD) MDCK] exhibited reduced SOCE, slower RVD, and reduced cell proliferation compared with mock controls. In conclusion, in ELA cells, SOCE and TRPC1 both seem to be upregulated in G1 as compared with S phase, concomitant with an increased rate of RVD. Furthermore, TRPC1-KD MDCK cells exhibit decreased SOCE, decreased RVD, and decreased proliferation, suggesting that, at least in certain cell types, TRPC1 is regulated during cell cycle progression and is involved in SOCE, RVD, and cell proliferation.

scholarly journals The NLRP3/eIF2 axis drives cell cycle progression in acute myeloid leukemia

2021 ◽  
Author(s):  
Michela Luciano ◽  
Constantin Blöchl ◽  
Julia Vetter ◽  
Laura Urwanisch ◽  
Theresa Neuper ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Nlrp3 Inflammasome ◽  
Cell Cycle Progression ◽  
Mononuclear Cells ◽  
Inflammasome Activation ◽  
Cycle Progression ◽  
Eif2α Phosphorylation

Aberrant activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome mediates numerous inflammatory diseases. Oncogenes can activate the NLRP3 inflammasome and thereby promote myeloproliferative neoplasia, suggesting a crucial role of NLRP3 in the malignant transformation of hematopoietic cells. Here, we show that bone marrow-derived mononuclear cells of AML patients display enhanced expression of NLRP3, IL-1β; and IL-18 and that high-level expression of NLRP3 is linked to poor survival of AML patients. Pharmacological and genetic inhibition of NLRP3 inflammasome activation attenuated cell proliferation of MOLM-13 AML cells in vitro. In vivo, genetic inhibition of NLRP3 in MOLM-13 AML cells resulted in reduced engraftment potential in xenografts, along with reduced splenomegaly and organ infiltration. Differential proteomic analysis revealed the eIF2 pathway as potential target of NLRP3 in AML, with a significant increase of eIF2α; phosphorylation upon NLRP3 inhibition. NLRP3 inhibition also caused a strong decrease in cyclin - dependent kinases CDK4 and CDK6, accompanied by an upregulation of the CDK inhibitor p21 (CDKN1A) and a marked arrest of cell cycle progression in the G0/G1 phase, consistent with the role of eIF2α; phosphorylation as negative cell cycle regulator. Taken together, we show that inhibition of the NLRP3 inflammasome reduces AML cell proliferation by promoting eIF2α; phosphorylation, which in turn enhances the expression of cell cycle arrest genes such as p21. Thus, the study uncovers the NLRP3/eIF2 axis as new driver of AML proliferation and proposes a novel therapeutic treatment of AML by targeted inhibition of NLRP3 activation.

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