scholarly journals The Estrogen-Occupied Estrogen Receptor Functions as a Negative Regulator to Inhibit Cell Proliferation Induced by Insulin/IGF-1: A Cell Context-Specific Antimitogenic Action of Estradiol on Rat Lactotrophs in Culture

Endocrinology ◽  
2002 ◽  
Vol 143 (7) ◽  
pp. 2750-2758 ◽  
Author(s):  
Kengo Kawashima ◽  
Koji Yamakawa ◽  
Wakaba Takahashi ◽  
Soichi Takizawa ◽  
Ping Yin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Proliferative Activity ◽  
Cell Number ◽  
Negative Regulator ◽  
Simultaneous Treatment ◽  
Wide Range ◽  
Dependent Inhibition ◽  
Context Specific ◽  
Basal Proliferation

Abstract Estrogens stimulate cell proliferation in typical estrogen-responsive tissues including the anterior pituitary gland. Here we report that 17-β estradiol (E2) has estrogen receptor-mediated mitogenic and antimitogenic actions on rat lactotrophs in primary culture, depending on the cell context. E2 did not affect basal proliferation at 2 d after treatment, but it increased it at 4 d. Insulin markedly increased proliferative activity, which was inhibited by simultaneous treatment with E2, even after only 2 d of treatment. This antimitogenic action on insulin-induced proliferation was also observed with other estrogens but not with nonestrogenic steroids. Treatment with antiestrogens in combination with E2 antagonized both the mitogenic and antimitogenic actions of E2. Antiestrogen treatment alone inhibited basal proliferation, and it mimicked the inhibitory action of E2 on insulin-induced proliferation with less potency. In parallel with cell proliferation, an insulin-induced increase in the cell number of cyclin D1-immunoreactive lactotrophs was inhibited by E2 treatment. Although the antimitogenic action of E2 was seen with a wide range of doses of insulin or IGF-1, proliferation was stimulated rather than inhibited by E2 when cells were treated with serum or forskolin/isobutylmethylxanthine instead of insulin, indicating a mitogen-specific, but not proliferative activity-dependent, inhibition by E2. The results of estrogen-occupied estrogen receptors as negative regulators of proliferation suggest a novel interaction between estrogen and growth factors in the regulation of proliferation in estrogen-responsive cells.

scholarly journals The Modified Human DNA Repair EnzymeO6-Methylguanine-DNA Methyltransferase Is a Negative Regulator of Estrogen Receptor-Mediated Transcription upon Alkylation DNA Damage

2001 ◽  
Vol 21 (20) ◽  
pp. 7105-7114 ◽  
Author(s):  
Alvin K. C. Teo ◽  
Hue Kian Oh ◽  
Rahmen B. Ali ◽  
Benjamin F. L. Li
Keyword(s):  
Cell Proliferation ◽  
Dna Repair ◽  
Estrogen Receptor ◽  
Dna Methyltransferase ◽  
Negative Regulator ◽  
Creb Binding Protein ◽  
Transcription Activator ◽  
Precise Control ◽  
Methylguanine Dna Methyltransferase ◽  
Human Dna

ABSTRACT Cell proliferation requires precise control to prevent mutations from replication of (unrepaired) damaged DNA in cells exposed spontaneously to mutagens. Here we show that the modified human DNA repair enzyme O 6-methylguanine-DNA methyltransferase (R-MGMT), formed from the suicidal repair of the mutagenic O 6-alkylguanine (6RG) lesions by MGMT in the cells exposed to alkylating carcinogens, functions in such control by preventing the estrogen receptor (ER) from transcription activation that mediates cell proliferation. This function is in contrast to the phosphotriester repair domain of bacterial ADA protein, which acts merely as a transcription activator for its own synthesis upon repair of phosphotriester lesions. First, MGMT, which is constitutively present at active transcription sites, coprecipitates with the transcription integrator CREB-binding protein CBP/p300 but not R-MGMT. Second, R-MGMT, which adopts an altered conformation, utilizes its exposed VLWKLLKVV peptide domain (codons 98 to 106) to bind ER. This binding blocks ER from association with the LXXLL motif of its coactivator, steroid receptor coactivator-1, and thus represses ER effectively from carrying out transcription that regulates cell growth. Thus, through a change in conformation upon repair of the 6RG lesion, MGMT switches from a DNA repair factor to a transcription regulator (R-MGMT), enabling the cell to sense as well as respond to mutagens. These results have implications in chemotherapy and provide insights into the mechanisms for linking transcription suppression with transcription-coupled DNA repair.

scholarly journals RNF152 Negatively Regulates mTOR Signalling and Blocks Cell Proliferation in the Floor Plate

2019 ◽  
Author(s):  
Minori Kadoya ◽  
Noriaki Sasai
Keyword(s):  
Cell Proliferation ◽  
Neural Tube ◽  
Neural Progenitor Cells ◽  
Cell Number ◽  
Floor Plate ◽  
Proliferation Rate ◽  
Negative Regulator ◽  
Downstream Effector ◽  
Plate Cell ◽  
Mtor Signalling

AbstractThe neural tube is composed of a number of neural progenitors and postmitotic neurons distributed in a quantitatively and spatially precise manner. The floor plate, located in the ventral-most region of the neural tube, has a lot of unique characteristics, including a low cell proliferation rate. The mechanisms by which this region-specific proliferation rate is regulated remain elusive.Here we show that the activity of the mTOR signalling pathway, which regulates the proliferation of the neural progenitor cells, is significantly lower in the floor plate than in other domains of the embryonic neural tube. We identified the forkhead-type transcription factor FoxA2 as a negative regulator of mTOR signalling in the floor plate. We demonstrate that FoxA2 transcriptionally induces the expression of the E3 ubiquitin ligase RNF152, which together with its substrate RagA, regulates cell proliferation via the mTOR pathway. Silencing of RNF152 led to the aberrant upregulation of the mTOR signal and aberrant cell division in the floor plate. Taken together, the present findings suggest that floor plate cell number is controlled by the negative regulation of mTOR signalling through the activity of FoxA2 and its downstream effector RNF152.

Icariin Stimulates hFOB 1.19 Osteoblast Proliferation and Differentiation via OPG/RANKL Mediated by the Estrogen Receptor

2020 ◽  
Vol 22 (1) ◽  
pp. 168-175 ◽  
Author(s):  
Lin-Jun Sun ◽  
Chong Li ◽  
Xiang-hao Wen ◽  
Lu Guo ◽  
Zi-Fen Guo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Protein Expression ◽  
Chinese Herb ◽  
Human Osteoblast ◽  
Osteoblast Cells ◽  
Expression Ratio ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Mrna And Protein Expression

Background:: Icariin (ICA), one of the main effective components isolated from the traditional Chinese herb Epimedium brevicornu Maxim., has been reported to possess extensive pharmacological actions, including enhanced sexual function, immune regulation, anti-inflammation, and antiosteoporosis. Methods:: Our study was designed to investigate the effect of ICA on cell proliferation and differentiation and the molecular mechanism of OPG/RANKL mediated by the Estrogen Receptor (ER) in hFOB1.19 human osteoblast cells. Results:: The experimental results show that ICA can stimulate cell proliferation and increase the activity of Alkaline Phosphatase (ALP), Osteocalcin (BGP) and I Collagen (Col I) and a number of calcified nodules. Furthermore, the mRNA and protein expression of OPG and RANKL and the OPG/ RANKL mRNA and protein expression ratios were upregulated by ICA. The above-mentioned results indicated that the optimal concentration of ICA for stimulating osteogenesis was 50ng/mL. Subsequent mechanistic studies comparing 50ng/mL ICA with an estrogen receptor antagonist demonstrated that the effect of the upregulated expression is connected with the estrogen receptor. In conclusion, ICA can regulate bone formation by promoting cell proliferation and differentiation and upregulating the OPG/RANKL expression ratio by the ER in hFOB1.19 human osteoblast cells.

Heterocyclization of 2-(2-phenylhydrazono)cyclohexane-1,3-dione to Synthesis Thiophene, Pyrazole and 1,2,4-triazine Derivatives with Anti-Tumor and Tyrosine Kinase Inhibitions

2020 ◽  
Vol 20 (10) ◽  
pp. 1209-1220
Author(s):  
Rafat M. Mohareb ◽  
Ensaf S. Alwan
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Proliferative Activity ◽  
Cancer Cell Lines ◽  
Thiazole Derivatives ◽  
Wide Range ◽  
Cytotoxic Compounds ◽  
Triazine Derivatives ◽  
Target Molecules

Background: Recently tetrahydrobenzo[b]thiazole derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the thiazole nucleus were known. Objective: This work aimed to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from the arylhydrazonocyclohexan-1,3-dione followed by their heterocyclization reactions to produce anticancer target molecules. Methods: The arylhydrazone derivatives 3a-c underwent different heterocyclization reactions to produce thiophene, thiazole, pyrazole and 1,2,4-triazine derivatives. The anti-proliferative activity of twenty six compounds among the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. Results: Anti-proliferative evaluations, tyrosine and Pim-1 kinase inhibitions were perform for most of the synthesized compounds where the varieties of substituent through the aryl ring and the thiophene moiety afforded compounds with high activities. Conclusion: The compounds with high anti-proliferative activity towards the cancer cell lines showed that compounds 3b, 3c, 5e, 5f, 8c, 9c, 11c, 12c, 14e, 14f and 16c were the most cytotoxic compounds. Further tests of the latter compounds toward the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 5e, 5f, 8c, 9c, 12c, 14e, 14f and 16c were the most potent of the tested compounds toward the five tyrosine kinases and compounds 6d, 11a, 20b and 21e were of the highest inhibitions towards Pim-1 kinase. Pan Assay Interference Compounds (PAINS) for the most cytotoxic compounds showed zero PAINS alert and can be used as lead compounds.

Qualitative Analysis of Underlying Factors Affecting Vaccine Hesitancy in Iran- A Study Protocol (Preprint)

2020 ◽  
Author(s):  
Salime Goharinezhad
Keyword(s):  
Vaccine Coverage ◽  
Deep Understanding ◽  
World Health ◽  
Vaccine Hesitancy ◽  
Slight Reduction ◽  
Cultural Variation ◽  
Global Public Health ◽  
Factors Affecting ◽  
Wide Range ◽  
Context Specific

BACKGROUND World Health Organization declared the vaccine hesitancy as a global public health threat in 2019. Since even a slight reduction in vaccine coverage rates can lead to a decrease in herd immunity, it is imperative to explore the underlying factors affecting vaccine hesitancy. in specific contexts, considering socioeconomic and cultural variation, to ensure interventions targeting hesitancy are well formulated and intervened. OBJECTIVE The main objective of this study is to identify underlying factors affecting vaccine hesitancy in Iran. METHODS A framework qualitative study will be conducted in the west of Tehran province in 2020. Participants in the study will be recruited hesitance-parents who extracted from the SIB system (an electronic health record in Iran) to maximize diversity. Interviews will be analyzed based on ''Determinants of Vaccine Hesitancy Matrix'' which developed by the WHO-SAGE Working Group. RESULTS deep understanding from the context-specific reasons for vaccine hesitancy cause to formulate better strategies to address them. The ultimate goal of this study is to inform future policies to increase the uptake of the vaccine in Iran. CONCLUSIONS This result of study will show variety opinions about vaccination among different types of socioeconomic and demographic households. The wide range of reasons related to vaccine hesitancy imply to more comprehensive, context-specific interventions. Today, the most important intervention issues focus on improving information about effectiveness and safety of vaccines, while other interventions for promoting vaccination is need to addressed.

scholarly journals Zebrafish Blunt-Force TBI Induces Heterogenous Injury Pathologies That Mimic Human TBI and Responds with Sonic Hedgehog-Dependent Cell Proliferation across the Neuroaxis

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 861
Author(s):  
James Hentig ◽  
Kaylee Cloghessy ◽  
Manuela Lahne ◽  
Yoo Jin Jung ◽  
Rebecca A. Petersen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Proliferative Response ◽  
Injury Severity ◽  
Granule Cell Layer ◽  
Dependent Manner ◽  
Adult Zebrafish ◽  
Post Injury ◽  
Blunt Force ◽  
Shh Pathway ◽  
Wide Range

Blunt-force traumatic brain injury (TBI) affects an increasing number of people worldwide as the range of injury severity and heterogeneity of injury pathologies have been recognized. Most current damage models utilize non-regenerative organisms, less common TBI mechanisms (penetrating, chemical, blast), and are limited in scalability of injury severity. We describe a scalable blunt-force TBI model that exhibits a wide range of human clinical pathologies and allows for the study of both injury pathology/progression and mechanisms of regenerative recovery. We modified the Marmarou weight drop model for adult zebrafish, which delivers a scalable injury spanning mild, moderate, and severe phenotypes. Following injury, zebrafish display a wide range of severity-dependent, injury-induced pathologies, including seizures, blood–brain barrier disruption, neuroinflammation, edema, vascular injury, decreased recovery rate, neuronal cell death, sensorimotor difficulties, and cognitive deficits. Injury-induced pathologies rapidly dissipate 4–7 days post-injury as robust cell proliferation is observed across the neuroaxis. In the cerebellum, proliferating nestin:GFP-positive cells originated from the cerebellar crest by 60 h post-injury, which then infiltrated into the granule cell layer and differentiated into neurons. Shh pathway genes increased in expression shortly following injury. Injection of the Shh agonist purmorphamine in undamaged fish induced a significant proliferative response, while the proliferative response was inhibited in injured fish treated with cyclopamine, a Shh antagonist. Collectively, these data demonstrate that a scalable blunt-force TBI to adult zebrafish results in many pathologies similar to human TBI, followed by recovery, and neuronal regeneration in a Shh-dependent manner.

scholarly journals Atypical role of sprouty in p21 dependent inhibition of cell proliferation in colorectal cancer

2015 ◽  
Vol 55 (9) ◽  
pp. 1355-1368 ◽  
Author(s):  
Qiong Zhang ◽  
Katherine Shim ◽  
Kevin Wright ◽  
Alexander Jurkevich ◽  
Sharad Khare
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Dependent Inhibition

scholarly journals Peroxisomal Proliferator-activated Receptor-α-dependent Inhibition of Endothelial Cell Proliferation and Tumorigenesis

2007 ◽  
Vol 282 (24) ◽  
pp. 17685-17695 ◽  
Author(s):  
Ambra Pozzi ◽  
Maria Raquel Ibanez ◽  
Arnaldo E. Gatica ◽  
Shilin Yang ◽  
Shouzuo Wei ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Endothelial Cell Proliferation ◽  
Dependent Inhibition

scholarly journals Müllerian Inhibiting Substance Is Required for Germ Cell Proliferation during Early Gonadal Differentiation in Medaka (Oryzias latipes)

Endocrinology ◽  
2007 ◽  
Vol 149 (4) ◽  
pp. 1813-1819 ◽  
Author(s):  
Eri Shiraishi ◽  
Norifumi Yoshinaga ◽  
Takeshi Miura ◽  
Hayato Yokoi ◽  
Yuko Wakamatsu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Germ Cell ◽  
Germ Cells ◽  
Sex Differentiation ◽  
Somatic Cells ◽  
Oryzias Latipes ◽  
Cell Number ◽  
Gonadal Differentiation ◽  
Loss Of Function ◽  
Germ Cell Proliferation

Müllerian inhibiting substance (MIS) is a glycoprotein belonging to the TGF-β superfamily. In mammals, MIS is responsible for the regression of Müllerian ducts in the male fetus. However, the role of MIS in gonadal sex differentiation of teleost fish, which have no Müllerian ducts, has yet to be clarified. In the present study, we examined the expression pattern of mis and mis type 2 receptor (misr2) mRNAs and the function of MIS signaling in early gonadal differentiation in medaka (teleost, Oryzias latipes). In situ hybridization showed that both mis and misr2 mRNAs were expressed in the somatic cells surrounding the germ cells of both sexes during early sex differentiation. Loss-of-function of either MIS or MIS type II receptor (MISRII) in medaka resulted in suppression of germ cell proliferation during sex differentiation. These results were supported by cell proliferation assay using 5-bromo-2′-deoxyuridine labeling analysis. Treatment of tissue fragments containing germ cells with recombinant eel MIS significantly induced germ cell proliferation in both sexes compared with the untreated control. On the other hand, culture of tissue fragments from the MIS- or MISRII-defective embryos inhibited proliferation of germ cells in both sexes. Moreover, treatment with recombinant eel MIS in the MIS-defective embryos dose-dependently increased germ cell number in both sexes, whereas in the MISRII-defective embryos, it did not permit proliferation of germ cells. These results suggest that in medaka, MIS indirectly stimulates germ cell proliferation through MISRII, expressed in the somatic cells immediately after they reach the gonadal primordium.

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