Dissertations / Theses on the topic 'Cellular Proliferation'
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1
Gan, Lisha. "Corneal cellular proliferation and wound healing /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4505-5/.
2
Kranc, Kamil. "The role of Cited2 in cellular proliferation." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398233.
3
Sangfelt, Olle. "Effects of interferon on cellular proliferation and apoptosis /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19981014sang.
4
Stacy, Andrew Jared. "Regulation of ΔNp63α by TIP60 promotes cellular proliferation." Wright State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=wright1596151919161674.
5
Chakravarthy, Usha. "The effect of gamma radiation on intraocular cellular proliferation." Thesis, Queen's University Belfast, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317046.
6
Maiti, Baidehi. "E2F and survivin - key players in cellular proliferation and transformation." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1173801044.
7
Khav, Eddie. "Visualizing an RB-E2F Cellular Switch that Controls Cell Proliferation." Thesis, The University of Arizona, 2013. http://hdl.handle.net/10150/297627.
Abstract:
Mammalian cell proliferation is regulated by an Rb-E2F gene network. The input node of this network, Cyclin D, receives graded growth signals; the output node, E2F, generates an all-or-none response. That is, the Rb-E2F gene network functions as a cellular switch, converting analog growth signals into digital E2F activities. The On or Off of this Rb-E2F switch determines the On or Off of cell proliferation. To help better understand the analog/digital conversion mechanism, we constructed a reporter cell line to visualize the dynamic expression of Cyclin D and E2F genes by red and green fluorescence in individual cells, respectively.
8
Simmons, Ambrosia. "The Role of Polarity Complex Proteins in Neural Progenitor Proliferation." Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/552083.
Abstract:
Biomedical SciencesPh.D.
Cortical malformations arise from defects in any stage of brain development and often result in life-long disability ranging from epilepsy to developmental delay and even perinatal lethality. The neuroepithelium of the emergent cortex lays the foundation on which the future cortex will develop, and as such, neuroepithelial tissue and the neural progenitor cells (NPCs) which comprise it are critical to the proper growth and development of the cortex. Here I demonstrate the significance of neuroepithelial cell polarity determinants in cortical development and how they affect both junctional integrity and the regulation of NPC proliferation leading to a variety of cortical malformations. Until now, the role of basal polarity complex protein Lgl1 in cortical development remained elusive due to perinatal lethality in animal models. To bypass this, we developed a novel conditional knockout mouse model of Lgl1 in the neuroepithelium and show that Lgl1 is essential to the maintenance of neuroepithelial integrity and regulation of NPC proliferation. Loss of Lgl1 results in a displaced ventricular zone with widespread ectopic proliferation resulting in severe periventricular nodular heterotopia (PNH). Furthermore, Lgl1 loss reduces the cell cycle length resulting in hyperproliferation leading to neuronal overproduction. Together, this work identifies a novel genetic cause of PNH. Next, I aimed to characterize the interaction of Lgl1 with other polarity proteins and downstream signaling pathways in cortical development. Apical and basal polarity proteins have demonstrated mutual antagonism in the establishment/maintenance of epithelial polarity; however, little is known about the role of this antagonism on cortical size and structure or the signaling pathways through which it acts. To address these questions we generated multiple genetic mouse models to investigate the opposing roles of basal protein, Lgl1, and either apical proteins Pals1 or Crb2. Concurrent loss of Pals1 and Lgl1 was able to prevent heterotopic nodules and increase proliferation compared to loss of Pals1 alone. However, cortical size was severely diminished due to overriding effects of Pals1 on cell survival that was unmitigated by Lgl1 loss. Remarkably, loss of both Crb2 and Lgl1 restored the cortex and hippocampus to near normal morphology with a profound rescue of cortical size, suggesting their essential antagonism in both cortical and hippocampal development. Importantly, genetic manipulation through reduction of YAP/TAZ expression in the Lgl1 CKO eliminates periventricular nodules and restores cortical thickness to that of WT cortices. This important finding implicates Lgl1 in the regulation of YAP/TAZ in cortical development. Finally, we investigated a possible downstream target of Pals1 in cell survival, BubR1. My work demonstrates that loss of Pals1 reduces BubR1 expression, which is an essential regulator of the mitotic checkpoint and causative gene of the human disorder Mosaic Variegated Aneuploidy. I show that loss of BubR1 results in significant apoptosis across all cell types in the cortex leading to microcephaly. These data provide the first link between cell polarity determinants and mitotic regulation in the cortex and suggests that BubR1 reduction likely contributes to the decreased cell survival following Pals1 loss. Overall these findings implicate impaired polarity complex function in a wide variety of NPC defects resulting in multiple cortical malformations. My work shows that polarity proteins regulate every stage of the NPCs life cycle from cell division and proliferation to cell survival through regulation of mitosis and YAP/TAZ signaling.
Temple University--Theses
9
Reed, Jennifer. "Interferon-gamma increases CD4+ T cell survival and proliferation." Click here for download, 2006. http://wwwlib.umi.com/cr/villanova/fullcit?p1432655.
10
Anderson, Elizabeth. "Co-ordinate regulation of cellular proliferation and apoptosis in rodent liver." Thesis, University of Surrey, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441719.
11
Gardner, David Paul. "Epidermal growth factor receptor: Regulation of cellular proliferation and gene expression." Diss., The University of Arizona, 1993. http://hdl.handle.net/10150/186438.
Abstract:
Binding of epidermal growth factor (EGF) to the EGF receptor stimulates the tyrosine kinase activity of the receptor and initiates a signal transduction cascade culminating in a mitogenic response. In many tumor derived cell lines which overexpress EGF receptor, exposure to EGF results in growth inhibition. The mechanism for this is unclear. This work involves analysis of growth inhibition by EGF, mechanisms of EGF receptor overexpression and regulation of the EGF receptor gene. The first two studies utilize a cell line (PC-10) that overexpresses EGF receptor without gene amplification. PC-10 cells appear to adopt a novel mechanism to overexpress EGF receptor; one that involves stabilization of the receptor message rather than the more common gene amplification. PC-10 cells were found to be killed by EGF in a cell density dependent manner. However, chronic exposure to EGF subsequently allowed proliferation under conditions which previously resulted in cell death. These "adapted" cells had similar levels of EGF receptor on the cell surface and similar EGF binding parameters. The tyrosine kinase activity of the receptor in response to EGF in the adapted cells was significantly reduced both in vitro and in vivo. Evidence was also found that the signal transduction cascade initiated by EGF was altered by adaptation. These data provide evidence for a unique mechanism for EGF receptor-overexpressing cells to survive EGF toxicity, one that involves a reduction in the tyrosine kinase activity of the EGF receptor in the absence of a decrease in the number of EGF receptor. Finally, additional studies were carried out on the response of the EGF receptor gene to activation of protein kinase C (PKC) in A549 cells. Activation of PKC resulted in increased levels of EGF receptor mRNA. No induction of a transfected reporter gene containing EGF receptor regulatory DNA could be seen. Repression of the reporter gene, however, was consistently seen. The cis-element for repression was mapped to 233 base pairs in the EGF receptor regulatory region. Additional data support the hypothesis that a previously characterized repressor protein called GCF may be responsible for this repression.
12
Mosca, Matthieu. "Etude du mécanisme d'action de l'interféron alpha dans les néoplasmes myéloprolifératifs classiques." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS516/document.
Abstract:
Les néoplasmes myéloprolifératifs classiques sont des maladies clonales dues à des mutations acquises de JAK2V617F ou de la Calréticuline (CALRm) au niveau des cellules souches hématopoïétiques (CSH) et conduisant à une surproduction de cellules myéloïdes. L’interféron alpha (IFNa) est le seul traitement curatif qui induit une réponse hématologique et moléculaire. Le but de notre projet est de comprendre son mécanisme d’action en utilisant une cohorte de 47 patients, des lignées cellulaires et des modèles de souris JAK2V617F. Ainsi, nous avons constaté que l’IFNa cible plus rapidement les CSH que les cellules matures chez les patients JAK2V617F, ce qui semble différent des patients CALRm. Grâce aux lignées cellulaires et aux souris, nous avons montré que JAK2V617F induit une pré-activation des voies de l’IFNa et une inhibition du cycle cellulaire des CSH. La découverte complète de ce mécanisme d’action conduira à l’amélioration du traitementClassical BCR-ABL-negative myeloproliferative neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocytemia (ET) and Primary Myelofibrosis (PMF). They are acquired clonal disorders of hematopoietic stem cells (HSC) leading to the hyperplasia of one or several myeloid lineages. They are due to three main recurrent mutations affecting the JAK/STAT signaling pathway: JAK2V617F and mutations in calreticulin (CALR) and thrombopoietin receptor (MPL). Interferon alpha (IFNα) is the only curative treatment that induces not only a hematological response of ET, PV and early MF but also a molecular response both on JAK2V617F or CALR mutated cells. In this study, we wanted to know how and with what kinetics IFN impacts the different mutated hematopoietic compartments. Thus, we have performed a prospective study with a cohort of 50 patients treated by IFNα for 3-5 years. The MPN diseases distribution was 44% ET, 45% PV and 11% MF. This cohort included 33 JAK2V617F-mutated patients, 11 CALR-mutated patients (7 type 1/type 1-like and 4 type 2/type 2-like), 2 both JAK2V617F- and CALR-mutated patients and 1 MPLW515K-mutated patient. At 4-month intervals, the JAK2V617F or/and CALR mutation variant allele frequency was measured in mature cells (granulocytes, platelets). Simultaneously, we have also determined the clonal architecture by studying the presence of the JAK2V617F or CALR mutations in colonies derived from the different hematopoietic stem and progenitor cell (HSPC) populations (CD90+CD34+CD38- HSC-enriched progenitors, CD90-CD34+CD38- immature progenitors and CD90- CD34+CD38+ committed progenitors). After a median follow-up of 30 months, we observed that IFNα targets more efficiently and rapidly the HSPC particularly in HSC-enriched progenitors, than the mature blood cells in JAK2V617F patients (p<.05). Moreover, homozygous JAK2V617F clones responded more rapidly than heterozygous clones in all hematopoietic cell compartments showing that the intensity of JAK2V617F signaling is correlated with the efficacy of IFNα. These observations were slightly increased after a median follow-up of 51 months. In contrast, with a median follow-up of 30 months for CALR mutated patients, IFNα targeted similarly the HSPC and the mature cells. Moreover, IFNα induced a less rapid response to target CALR-mutated HSPC than the JAK2V617F HSPC (p<.05). The role of associated mutations at diagnosis was also investigated in the IFNα-mediated HSPC molecular responses using a NGS targeted myeloid panel. While in JAK2V617F-mutated patients, we found that the number of associated mutations did not impact the HSPC molecular response of the JAK2V617F clone, in CALR-mutated patients, even if the number of cases was low, the only molecular responders were those not associated with other mutations. Using Ba/F3-MPL cellular models and primary cells, we observed that JAK2V617F was more prone to sensitize to IFNα signaling (increased Phospho-STAT1 and IFN-stimulating genes (ISGs)) compared to controls or CALRdel52 mutated cells.Altogether, our results show that IFNα differentially targets the human JAK2V617F- and CALR-mutated HSPC and mature cells. Moreover, the molecular response was dependent not only on the JAK2V617F or CALR mutated status but also on the presence of other associated mutations
13
Zettervall, Carl-Johan. "Signaling pathways in the activation and proliferation of Drosophila melanogaster blood cells." Doctoral thesis, Umeå : Umeå centrum för molekylär patogenes (UCMP), 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-513.
14
Conway-Campbell, Becky Lee. "A novel role for the nuclear growth hormone receptor in cellular proliferation /." St. Lucia, Qld, 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17889.pdf.
15
Harper, Jane Vera. "Investigation into the role of T-type calcium channels in cellular proliferation." Thesis, University of Reading, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397848.
16
Gaisford, Esme Ann. "Rab-Vesicle Trafficking is Required for Ras-Mediated Proliferation." Master's thesis, Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/314879.
Abstract:
Biomedical SciencesM.S.
The Ras superfamily consists of over 150 members including the well-known: H-Ras, K-Ras and N-Ras. We propose to target Ras related proliferation in cancer cells by inhibiting Rab vesicle formation. H-Ras, K-Ras and N-Ras are carcinogenic; activating mutations in Ras signaling are generally associated with increased proliferation and survival in cancer cells. Ras is mutated in up to 30% of all human cancers and represents an early survival mutation in cancer cells. Vesicle-bound Ras is trafficked to the plasma membrane, which facilitates interaction between Raf, and effector proteins. Previously, farnsesylation inhibitors, (FTIs) and GTP binding agonists of Ras have been tested as potential pharmacological inhibitors of Ras signaling. However, both drug types have proven ineffective in-vivo. Therefore, there are currently no effective pharmacological treatments to target Ras signaling. However, unpublished data from our lab has identified co-localization of Ras and Rab proteins, in vesicles. Rab proteins are associated with vesicle budding, and endosome development. Rab activity is driven by GTP binding and geranylgeranylation. Non-geranylgeranylated Rab is cytosolic, and does not facilitate endosome formation or vesicle trafficking. We propose that by targeting the Rab specific geranylgeranylation via Rab-specific geranylgeranyl transferase II, we will inhibit Ras associated proliferation. We will pursue this hypothesis by testing three objectives. First, we will produce and test Rab-geranylgeranyl transferase (RGGT)-shRNA to target Rab specific geranylgeranyl transferase. Second, we will illustrate the effect of RGGT knockdown on a downstream signaling target of Ras, specifically pERK levels. Finally, we will measure the direct effect of RGGT knockdown on Ras mediated cellular proliferation. Our results conclude that RGGT-shRNA is a potential target of Ras mediated tumor proliferation.
Temple University--Theses
17
Barnett, David. "Activation antigens in the proliferation and differentiation of normal and malignant human leucocytes." Thesis, Open University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293382.
18
Iqbal, Javaid. "Role of intra-cellular glucocorticoid regulation in vascular lesion development." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4810.
Abstract:
Atherosclerosis and post-angioplasty neointimal proliferation, which are leading causes of cardiovascular morbidity and mortality, develop as a result of chronic or acute vascular injury producing inflammatory and proliferative responses in the vessel wall. Glucocorticoids, the stress hormones produced by the adrenal cortex, have anti-inflammatory and anti-proliferative characteristics and can also influence systemic cardiovascular risk factors. The systemic levels of these hormones are controlled by the hypothalamic pituitary adrenal axis. However, there is also a tissue-specific pre-receptor regulation of these hormones by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD); type 1 regenerates active glucocorticoids within the cells and type 2 inactivates glucocorticoids. Whilst it has been shown that the inhibition of 11β-HSD1 has favourable effect on cardiovascular risk factors and the inhibition of 11β-HSD2 results in hypertension; the effect of these enzymes on vascular lesion development is not known. The work described in this thesis tested the hypothesis that 11β-HSD1 inhibition reduces vascular lesion development due to improvement in cardiovascular risk factors, whereas 11β-HSD2 inhibition leads to adverse vascular remodelling. Apolipoprotein-E deficient (ApoE-/-) mice fed on western diet were used to study atherosclerosis, whereas neointimal proliferation was investigated using a well-established mouse model of wire-angioplasty. Vascular lesions were assessed using novel imaging and standard histological techniques. 11β-HSD1 inhibition reduced the size of atherosclerotic lesions and improved markers of plaque stability with a reduction in lipid content and increase in collagen content of the plaques. This was associated with a reduction in weight gain and blood pressure but without any effect on lipid profile. 11β-HSD1 inhibition did not produce any significant effect on neointimal proliferation in C57Bl/6J mice. However in ApoE-/- mice, 11β-HSD1 inhibition reduced neointimal proliferation with corresponding increase in size of patent lumen and with an associated reduction in macrophage content of neointimal lesions. 11β-HSD2 deletion produced an outward remodelling in un-injured vessels but there was no effect on neointimal proliferation after wire-angioplasty. Administration of a selective mineralocorticoid antagonist, eplerenone, reduced neointimal lesions significantly but to a similar degree in both C57Bl/6J and 11β-HSD2-/- mice, associated with a significant reduction in macrophage content of lesions but without any effect on blood pressure. Data in this thesis highlight the potential therapeutic application of 11β-HSD1 inhibition in reducing the size and vulnerability of atherosclerotic plaques and also reduction in neointimal proliferation (and hence post-angioplasty restenosis) in high risk patients with „metabolic syndrome‟ phenotype. The results also indicate that 11β-HSD2 has a limited, if any, role to play in the development of neointimal lesions.
19
Zapata, Garin Claire-Alix. "Glycogen regulates cellular proliferation in the context of aging, tumorigenesis, and hepatic regeneration." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/667163.
Abstract:
Glycogen is a branched polysaccharide that serves as an intracellular store of glucose that can be mobilized to maintain homeostasis or to fuel cellular processes. Glycogen is synthesized by glycogen synthase, which is present in two different isoforms: liver glycogen synthase (LGS) is mainly expressed in the liver, while muscle glycogen synthase (MGS) is expressed everywhere else. Recent studies are starting to uncover new roles for glycogen besides just being a glucose depot. Importantly, glycogen metabolism has been implicated in the normal aging process in species ranging from Saccharomyces cerevisiae to humans. However, the implication of glycogen in senescence, a hallmark of aging, is less well understood. Senescence is a tumor suppressive response that results in an irreversible cell cycle arrest, and can be induced by a variety of cellular stressors. Glycogen has previously been shown to accumulate in the context of senescence, however the significance of this remains unclear. Taking this into account, we aim to elucidate the role of glycogen in proliferation specifically in the context of aging, tumorigenesis and hepatic regeneration.
To achieve this, we used two knock-out (KO) models where glycogen synthesis is disrupted: 1) mouse embryonic fibroblasts (MEFs) isolated from MGS KO embryos and, 2) LGS KO mice which lack hepatic glycogen. These two models allowed us to test what occurs in proliferative contexts when glycogen is absent both in vitro and in vivo.
First, we subjected WT MEFs to replicative senescence (RS), where MEFs were passaged every time the plate reached confluence, until cells entered a growth arrested state (senescence). We determined that glycogen accumulates, and further observed that MGS is activated during senescence.
To test whether the presence of glycogen affects the senescent response, we subjected glycogen-free MEFs to RS, and observed that they exhibit various markers of senescence: flattened cell morphology, positive senescence- associated B-gal staining, and an increased expression of senescence protein markers. Interestingly, MGS KO MEF overcome the senescent phase faster than WTs by becoming immortalized at an earlier time point. After transcriptomic analysis, we determined that MGS WT MEFs show an enrichment of the TGF-b pathway during senescence, while MGS KO MEFs are depleted. Furthermore, we found that the transcriptional signatures of senescent MGS KO MEFs are transcriptionally more similar to actively proliferating cells than to senescent WT MEFs. These results suggest that in the absence of glycogen, MEFs enter a pseudo-senescent state allowing them to immortalize faster than wild type counterparts.
Once immortalized, MGS KO MEFs continue exhibiting a proliferative advantage over wild types, in addition to increased migratory and clonogenic capacities.
Furthermore, we tested the metabolic consequence of removing glycogen by performing live cell analysis, which reveals a metabolic shift towards glycolysis. These results bring the Warburg effect to mind, suggesting that glycogen-free cells reprogram their metabolism to satisfy their energetic needs.
Lastly, we question whether glycogen is important in proliferative contexts in vivo. For this, we used LGS KO mice and subjected them to two hepatic proliferative challenges: hepatic regeneration through partial hepatectomy (Phx) and hepatocellular carcinoma (HCC) induction.
After Phx, we showed that there is a higher proportion of LGS KO hepatocytes in the S phase of the cell cycle which suggests that glycogen is an important regulator of hepatocytic proliferation.
In the pathological proliferative context of N-nitrosodiethylamine (DEN), we showed that LGS KO mice present higher mortality and tumor burden than controls. Therefore, our results suggest that glycogen is playing a protective role in animals exposed to DEN.
In conclusion, our results indicate that glycogen is an important modulator in the context of cellular proliferation and aging, and positions this polysaccharide as a novel target for therapeutic interventions to combat aging and possibly, cancer.
20
Berlato, Davide <1973>. "Cellular Proliferation in the Prognosis of Intermediate Grade Mast Cell Tumour in Dogs." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6241/.
Abstract:
This was a retrospective study including ninety samples of dogs with a histological diagnosis of intermediate grade cutaneous mast cell tumour (MCT). The objectives of the study were to validate Minichromosome Maintenance Protein 7 (MCM7) as a prognostic marker in MCTs and to compare the ability of mitotic index (MI), Ki67 and MCM7 to predict outcome. The median survival for the entire population was not reached at 2099 days. The mean survival time was 1708 days. Seventy-two cases were censored after a median follow up of 1136 days and eighteen dogs died for causes related to the MCT after a median of 116 days. For each sample MI, Ki67 and MCM7 were determined. The Receiver Operating Characteristic (ROC) curve was obtained for each prognostic marker to evaluate the performance of the test, expressed as area under the curve, and whether the published threshold value was adequate. Kaplan-Meier and corresponding logrank test for MI, Ki67 and MCM7 as binary variables was highly significant (P<0.0001). Multivariable regression analysis of MI, Ki67 and MCM7 corrected for age and surgical margins indicated that the higher risk of dying of MCT was associated with MCM7 > 0.18 (Hazard Ration [HR] 14.7; P<0.001) followed by MI > 5 (HR 13.9; P<0.001) and Ki67 > 0.018 (HR 8.9; P<0.001). Concluding, the present study confirmed that MCM7 is an excellent prognostic marker in cutaneous MCTs being able to divide Patnaik intermediate grade tumours in two categories with different prognosis. Ki67 was equally good confirming its value as a prognostic marker in intermediate grade MCTs. The mitotic index was extremely specific, but lacked of sensitivity. Interestingly, mitotic index, Ki67 and MCM7 were independent from each other suggesting that their combination would improve their individual prognostic value.
21
Millen, Jennifer Elena. "Phosphodiesterase 4 expression and proliferation rates in a cellular model of pulmonary hypertension." Thesis, University of Glasgow, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425277.
22
Carpenter, Nicholas. "Design and synthesis of inhibitors of critical target proteins implicated in cellular proliferation." Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/55644/.
Abstract:
Cyclin-Dependent Kinases (CDKs) are a family of protein kinases that control progression through the eukaryotic cell cycle. CDKs become activated when they form a complex with the appropriate cyclin protein, and are fully activated by phosphorylation. CDK inhibitors regulate the activity of CDK/cyclin complexes through competitive inhibition with ATP for the active site. This inhibition prevents the CDK/cyclin complex phosphorylating its substrates and cell cycle progression stops. Alterations in CDK control through cyclin overexpression, CDK inhibitor underexpression or CDK mutation are responsible for tumour development Therefore CDK inhibition has become a novel therapeutic approach to cancer treatment. Hymenialdisine and Kenpaullone have recently been identified as potent CDK inhibitors. The crystal structures of these two compounds as inhibitors of CDK2 show that Kenpaullone can form two hydrogen bonds to residue Leu83, while Hymenialdisine forms these two hydrogen bonds and a third to Glu81. These hydrogen bonds have been shown to be significant towards their potency, and are formed from the azepinone fused to a heterocycle feature of both structures. The aim of this thesis is to explore the structure activity relationship associated with the novel azepinone motif of the two CDK inhibitors Kenpaullone and Hymenialdisine via analogues of the lead structure 3,4-d%ydoazepino 3,4-indole-l,5(2//,10//)-dione, trivially named indoloazepinone. These analogues focus on alterations to the hydrogen bonding pattern, the size of the azepinone ring, extensions from the ketone functional group and bromination at the 7-posititon. The compounds synthesized in the study were assayed against MCF-7 breast cancer and A549 non small cell lung cancer (NSCLC) cell lines showing good growth inhibition. An accumulation of proliferating cancer cells in the GQ/Gl stage was demonstrated for a selected compound. Further assays against CDK2/cyclin A showed generally moderate inhibition, with good inhibition for one compound, while assays against CDK2 showed no inhibition.
23
Brennan, Tracy A. "Abrogation of Cbl-PI3K Interaction Increases Bone Volume and Osteoblast Proliferation." Diss., Temple University Libraries, 2011. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/107475.
Abstract:
Cell BiologyPh.D.
Cbl is a multivalent protein that interacts with a number of signaling molecules that affect cell proliferation, migration and apoptosis. Although it is a downstream effector of growth factors, cytokines and integrin signaling all of which influence bone mass, very few studies have examined the role of Cbl in osteoblast proliferation and differentiation. To examine the role(s) of Cbl in the skeletal system we have focused specifically on phosphorylation of CblY737 since it is a unique to Cbl (not present on other family members) and upon phosphorylation by Src family kinases it provides a binding site for the p85 subunit of PI3K which regulates signaling events that modulate apoptosis and survival. To determine the role of tyrosine 737 we are using CblYF/YF knock-in mice (YF) where tyrosine 737 has been substituted to phenylalanine. YF mice had increased bone volume (WT 9%; YF 14%; p= 0.05 vs WT), trabecular thickness, and trabecular numbers. Although the increased bone volume is partly attributed to the decreased bone resorption, static and dynamic parameters of bone formation indicated that numbers of osteoblasts (WT 13 N.OB/BS; YF 20 N.OB/BS; p=0.05 vs WT) and bone formation rates were also upregulated in the CblYF/YF mice. To investigate the role of osteoblast differentiation in increased bone formation, we differentiated osteoblast and assessed ALP activity and Alizarin Red S staining. Both WT and YF osteoblasts had similar levels of ALP activity and mineral deposition during differentiation. To determine if the increased numbers of osteoblasts were due to increased survival and/or proliferation, we performed in vitro experiments with calvarial osteoblasts from age-matched WT and YF pups. MTT assay and TUNEL-staining, for cell viability, showed abrogation of Cbl-PI3K interaction did not affect osteoblast survival. Interestingly, inhibition of PI3K activity with LY294002 showed comparable survival between the WT and YF osteoblasts. We next examined proliferation and found that there was a 2-fold increase in the rate of the proliferation for the YF osteoblasts. This result was further substantiated by colony forming unit assay using bone marrow stromal cells. To establish the role of extracellular factors on osteoblast increased proliferation, various growth factors were assessed (EGF, FGF, IGF, PDGF). Treatment with the growth factors has no differential effects on the WT versus YF osteoblasts. We next used conditioned media from differentiated osteoclasts and bone marrow cells to treat MC3T3-E1, preosteoblast cell line. The osteoclast media from YF osteoclasts did not increase osteoblast proliferation. However, YF bone marrow conditioned media increased proliferation of the MC3T3-E1. Cytokine assays were done to determine the factor(s) that were increased in the YF conditioned media compared to the WT conditioned media. SDF-1 was found to be increased in the YF conditioned media compared to the WT conditioned media. Taken together, this suggests that the abrogation of Cbl-PI3K interaction leads to increased bone formation due to osteoclast resorption deficiency and increased osteoblast proliferation, which may be caused in part by increased SDF-1 expression in the bone marrow niche.
Temple University--Theses
24
Fettig, Amy E. "Identification of cellular targets influenced by ectopic expression of TAL1 and LMO1 genes." Virtual Press, 2001. http://liblink.bsu.edu/uhtbin/catkey/1222830.
Abstract:
Cancer has been a disease, which has generated intense research interest for many years. Misexpression of two oncoproteins, TAL 1 and LMO 1, has been found to help induce a particular type of leukemia, called T-cell acute lymphoblastic leukemia (T-ALL). Presently, it is not completely understood how these proteins induce leukemogenesis or what other cellular proteins they interact with to drive this progression. In this study, a series of experiments were conducted to identify downstream targets of TALI and LMO1. Using retroviral gene transfer, both genes were introduced, either singly or in combination, into a murine T-cell line called AKR-DP-603. Empty vectors were introduced as controls. In order to assay the effects of TALI and LMO I expression on expression of other proteins, a series of Western blots were completed on all populations of engineered cells. It was determined that there were differences in expression of Bcl-2 and p16 as indicated by differences in band intensities on the blots. This is important because it implies an effect on protein levels by TAL 1 and LMO 1. However, there were no differences in protein expression levels for Bax or cyclin D1. This suggests that TAL1 and LMOI do not have any regulatory effects on these proteins. In addition, apoptotic assays were completed on all populations of cells. The results of both a TUNEL assay and ethidium bromide/acridine orange staining protocol showed TAL1- and LMO1expressing cells to have an increase in cell survival under starvation conditions and a lower frequency of apoptosis. Statistical analysis verified significant difference in the apoptosis assays. The data suggests an up-regulation of anti-apoptotic proteins. The finding of this research allow a clearer understanding of the process of leukemogenesis and may lead to a development of better cancer treatments.Department of Biology
25
Sorensin, Troels Seyffart. "Characterisation of DP-1." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243913.
26
Miettinen, Teemu P. "On connections between Metazoan cellular metabolism and cell size." Thesis, University of Dundee, 2015. https://discovery.dundee.ac.uk/en/studentTheses/3cdc8663-1167-4a8b-ad5c-698c20695664.
Abstract:
All animal cells maintain cell size homeostasis, where cell growth (increase in size) is balanced with proliferation (reduction in size via cell division). Yet, different cell types have different sizes and there are physiologically relevant situations where animal cells undergo major cell size changes. So how is cell size regulated? And why is cell size regulated? Are there specific cellular processes that have different functionality in different sized cells? This thesis investigates these questions from the perspective of cellular metabolism. Using a Cyclin dependent kinase 1 knockout mouse model with different degrees of hepatocytes enlargement, gene expression levels were correlated with cell size in vivo. This revealed that the relative expression of mitochondrial and lipid biosynthesis genes are downregulated with increasing cell size. However, mitochondrial content of the liver samples was not decreased, suggesting that cell functions and cell contents scale differently with cell size. To better investigate how mitochondrial functions scale with cell size in non-mutant cells, a novel and high throughput flow cytometry based single-cell analysis method called CoSRA was developed. Using fluorescence mitochondrial probes CoSRA revealed that, while mitochondrial content increases linearly with cell size, mitochondrial membrane potential is decreased in the very smallest and the largest cells. These effects were independent of cell cycle and all animal cell types examined displayed similar effects. Similar nonlinearity was observed in mitochondrial respiration. Furthermore, cell-to-cell variability in mitochondrial membrane potential was minimised in cells which are close to the median cell size of the whole population. The cell size dependence of mitochondrial functions was regulated by mitochondrial dynamics. It was also investigated if mitochondrial functions or lipid biosynthesis are capable of regulating cell size in human cell culture models. Various mitochondrial inhibitions increased cell size by reducing proliferation. Similar results were seen with inhibitions on lipid biosynthesis and especially with inhibitions of mevalonate pathway. Systematic dissection of the mevalonate pathway revealed that protein geranylgeranylation is required for maintaining normal cell size and proliferation ratio. Geranylgeranylation of the recycling endosome regulating protein RAB11 was identified to be at least partially responsible for the cell size regulation by the mevalonate pathway. Furthermore, the link from the mevalonate pathway to RAB11 was found to regulate basal autophagic flux, thus providing a novel connection from lipid biosynthesis to other growth regulating processes. In conclusion, this thesis provides evidence for cell size dependent metabolism, where mitochondrial functions do not increase linearly with cell size. This provides conceptual insights into organelle scaling with cell size and a potential mechanism for maintenance of cell size homeostasis. In addition, mitochondria and lipid synthesis are identified as critical processes for normal cell size homeostasis.
27
Kwon, Jungeun Sarah, and Jungeun Sarah Kwon. "Controlling Depth of Cellular Quiescence by an Rb-E2f Network Switch." Diss., The University of Arizona, 2017. http://hdl.handle.net/10150/625623.
Abstract:
Development, tissue renewal and longevity of multi-cellular organisms require the ability to switch between a proliferative state and quiescence, a reversible arrest from the cell cycle. The balance of quiescence and proliferation underlies the fundamental feature of generating and maintaining the appropriate number of cells, which is essential for tissue architecture, regeneration, and function. Disruption of quiescence and proliferation balance leads to hypo- or hyper-proliferative diseases. To date, the regulatory mechanism of proliferation has been well established, while cellular quiescence has remained a phenotypic description without a clearly defined molecular control mechanism. Simply, quiescence has long been considered a passive counterpart to proliferation. However, recent findings have revealed that quiescence is an actively maintained state exhibiting a unique gene expression pattern.
While quiescence has been traditionally considered as a state (namely G0) outside of the cell cycle, it is in fact a collection of heterogeneous states. In studies conducted in the 70's and 80's using fibroblasts and lymphocytes, it has been observed that the longer the cells were kept under quiescence inducing conditions such as contact inhibition, the deeper the cells moved into quiescence. Deep quiescent cells are still able to reenter the cell cycle upon growth stimulation but they exhibit a longer pre-DNA synthesis phase [1-4]. Shallow quiescent state has also been recently reported in muscle and neural stem cells termed GAlert and "prime" quiescent state, respectively. Heterogeneous quiescent depth entails that cells vary in their sensitivity to growth signals, representing an important yet underappreciated layer of complexity in cell growth control. The cellular mechanisms that control the depth of quiescence remains elusive. In my thesis work, I first investigate the strengths of serum stimulation required for cells to exit deep and shallow quiescence as a determinant of quiescence depth. Through model simulations and experimental measurements, I further demonstrate that various components of the Rb-E2F pathway control quiescence depth with varying efficacy.
The Rb-E2F pathway interacts with diverse cellular pathways that respond to environmental signals to jointly modulate quiescence depth. Given that certain circadian clock genes (e.g., Cry) affect key components in the Rb-E2F pathway, I tested the effect of Cry activity on quiescence depth. I found that increased Cry activity resulted in deeper quiescence, contrary to our anticipation based on the literature. Next, we constructed a library of mathematical models that represent possible interactions between Cry and the Rb-E2F pathway. We computationally searched this model library for links that could explain the experimental observations. The modeling search suggested that Cry upregulation may lead to increased expression of cyclin dependent kinase inhibitor (e.g., p21), which in turn drives cells into deeper quiescence. This model prediction was confirmed by my follow-up experiments. Collectively, my thesis work establishes an integrated modeling and experimental framework that will help us to further investigate diverse cellular mechanisms controlling the heterogeneous quiescence depth.
28
Chen, Jingbo, and 陳靜波. "Calcium signaling pathways and cell proliferation in human cardiac fibroblast." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41290434.
29
Chen, Jingbo. "Calcium signaling pathways and cell proliferation in human cardiac fibroblast." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41290434.
30
Haubst, Nicole. "Cellular and Molecular Mechanisms regulating Cell Proliferation during the Forebrain Development of the Mouse." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-44694.
31
Cao, Tingting, and 曹婷婷. "Oncogene EIF5A2 promotes cell growth and proliferation by reprograming cellular metabolism in hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208001.
32
Kumar, Neil. "A computational and experimental study of HER2-signaling effects on cellular migration and proliferation." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/39263.
Abstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2007.Includes bibliographical references.
The fundamental question posed in this thesis is: how does a cell 'decide' to behave in a particular way? The human body is comprised of [approx.] 1014 cells that interpret extracellular information and respond with such behavior as migration, proliferation, apoptosis, or differentiation. Thirty years of research in the related fields of biochemistry, molecular biology, and genetics have demonstrated that, in most cases, the cellular decision-making process cannot be described or predicted by regulation of only one gene or one protein alone. Instead, it has become clear that cellular behavior is a function of information flow through multiple intracellular molecules. Furthermore, the molecules responsible for the control of cell behavior comprise a surprisingly short list, indicating that factors such as signaling dynamics and intensity coupled with combinatorial control are essential to produce the wide array of observed cell behavior. The identification of protein kinases as transducers of large amounts of intracellular information led us to pose the hypothesis that the quantitative regulation of key kinases governs cellular behavior. The goal of this thesis was to identify rules governing multi-kinase behavioral control and to then, on the basis of these rules, predict changes in cell function in response to changes in receptor expression, ligand treatment, and pharmacological intervention.
(cont.) A human mammary epithelial cell (HMEC) system with varying levels of the human epidermal growth factor receptor 2 (HER2) was chosen to explore cell decision processes. HER2 overexpression is found in 30% of breast cancers and correlates with poor prognosis and increased metastasis. In particular, we investigated the effects of HER2 overexpression on signaling networks and resultant cell proliferation and migration in the presence of epidermal growth factor (EGF) or heregulin (HRG), two EGFR-family ligands that promote HER2 heterodimerization. To investigate HER2-mediated signaling and cell behavior we developed and applied high-throughput experimental techniques to measure kinase activity and phosphorylation as well as cell proliferation and migration. Measurement of -~100 different kinases downstream of HER2 resulted in the identification of network signaling mechanisms. Application of a novel high-throughput migration assay enabled the identification of HER2-mediated increases in cell migration due to increases in the directional persistence of movement. Linear mapping techniques related to partial least squares regression (PLSR) defined and predicted cell behavior in response to HER2 overexpression.
(cont.) Combining quantitative datasets of both biological signals and behavior using PLSR, we identified subsets of kinase phosphorylation events that most critically regulate HER2-mediated migration and proliferation. Importantly, we demonstrated that our models provide predictive ability through a priori predictions of cell behavior in HER2-overexpressing cells. Application of linear models in response to pharmacological inhibition resulted in the a priori prediction of cell migration, and identified an EGFR kinase inhibitor Gefitinib as a potent inhibitor of HER2-mediated migration. In conclusion, the application of computational linear modeling to quantitative biological signaling and behavior datasets captured systems-level regulation of cell behavior and, based on this, predicted cell migration and proliferation in response to HER2 overexpression and pharmacological inhibition. Further application of quantitative measurement together with linear modeling should enable the identification of salient cell signal-cell response elements to understand how cells make decisions and to predict how those decisions can be therapeutically manipulated.
by Neil Kumar.
Ph.D.
33
Buschmann, Mary McVey. "Laminin-332-Mediated Proliferation Control: Mechanisms Regulating Formation of the Epithelium." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1275661166.
34
Tea, Jonathan. "Social Stress Reduces Cellular Proliferation and Neurogenesis in the Forebrain of Male Zebrafish (Danio Rerio)." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/36903.
Abstract:
Many animals, including zebrafish (Danio rerio), form social hierarchies as a result of competition for limited resources. Socially subordinate fish experience chronic activation of the hypothalamic-pituitary-interrenal (HPI) axis, leading to prolonged elevation of plasma cortisol, the glucocorticoid end-product of HPI axis activation. Elevated cortisol levels can reduce cellular proliferation and neurogenesis in the brain. Thus, the present study tested the hypothesis that social stress suppresses cellular proliferation in the brain of subordinate zebrafish via a cortisol-mediated mechanism. Cellular proliferation was assessed using the incorporation of 5-bromo-2'-deoxyuridine (BrdU), a thymidine analogue, as a marker. After 48 and 96 h of social interaction, significantly lower numbers of BrdU-positive cells were present in the forebrain of subordinate male zebrafish compared to dominant or control fish, suggesting a suppression of cellular proliferation in fish experiencing chronic social stress. Treatment of interacting male zebrafish with metyrapone, a cortisol synthesis inhibitor, attenuated the suppression of cellular proliferation in subordinate fish. Subordinate female zebrafish did not experience elevation of plasma cortisol or suppression of cellular proliferation in the forebrain. Collectively, these data provide evidence that cortisol plays a role in regulating cellular proliferation in the forebrain of male zebrafish during social interactions.
35
Raibon, Audrey. "Le facteur d'initiation de la traduction eIF3f dans le muscle squelettique : étude in vitro et obtention de modèles animaux." Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON1T023/document.
Abstract:
Le facteur d'initiation de la traduction eIF3f est une des sous-unités constituant le facteur d'initiation de la traduction eIF3. Au niveau musculaire la surexpression de eIF3f dans les myotubes induit une hypertrophie associée à une augmentation de la synthèse protéique. A l'inverse, l'inhibition de l'expression de eIF3f entraîne une atrophie associée à une diminution de la synthèse protéique. Ce travail de thèse a permis (i) in vitro de mettre en évidence les fonctions inhibitrices du facteur eIF3f au cours de la prolifération des myoblastes C2C12 et par une étude transcriptomique sur les fractions polysomales de caractériser les ARNm recrutés par eIF3f dans des conditions hypertrophiques; et (ii) de créer des lignées de souris inactivées pour eIF3f (souris KO eIF3f) et surexprimant eIF3f dans le muscle (souris transgénique eIF3f K5-10R) afin d'étudier in vivo l'impact de la modification de l'expression de eIF3f sur la régulation de la masse musculaireThe eukaryotic initiation factor eIF3f is one of the subunits of the translation initiator complex eIF3 required for several steps in the initiation of mRNA translation. In skeletal muscle, recent studies have demonstrated that eIF3f overexpression in myotubes exerts a hypertrophic activity associated to an increase in protein synthesis. This thesis shed light on muscle eIF3f functions by (i) characterizing in vitro the antiproliferative activity of this factor in C2C12 myoblasts and the RNAs recruited by eIF3f on polysomal fractions in hypertrophied myotubes and (ii) generating mice strains inactivated for eIF3f (eIF3f KO mice) and overexpressing eIF3f specifically in muscle (eIF3f K5-10R transgenic mice) to study in vivo the impact of eIF3f modulation on the muscular mass homeostasis
36
Matthews, Benjamin Phillip. "The oncogenic protein E2a-Pbx1 alters cellular proliferation or apoptosis in haematopoietic and fibroblast tissues." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0003/MQ45287.pdf.
37
Chen, Long-Qi. "The effects of antireflux surgery on esophageal function, cellular proliferation and apoptosis for Barrett's esophagus." [Montréal] : Université de Montréal, 2003. http://wwwlib.umi.com/cr/umontreal/fullcit?pNQ82721.
Abstract:
Thèse (Ph. D.)--Université de Montréal, 2003."NQ-82721." "Thèse présentée à la faculté des études supérieures en vue de l'obtention du grade de docteur de philosophie (Ph. D.) en sciences biomédicales." Version électronique également disponible sur Internet.
38
Wazin, Fatima. "Spred: a negative regulator of cellular processes involved in lens and eye development." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/22989.
Abstract:
The transparent and refractive properties of the lens are extremely dependent on the its precise cellular structure, with constant regulation of cell behaviour throughout life. Cell signalling pathways play a crucial role in regulating cellular processes in both mammalian growth and development, and are in turn frequently regulated by inhibitory molecules, including the Spred family, to modulate and attenuate the impact of growth factor stimulation. Due to Spred’s strong expression in lens and its ability to negatively regulate growth factor-induced ERK/MAPK pathways that are essential for many biological events, we hypothesised that Spred proteins play a role in regulating lens development, and that lens epithelial cell proliferation and fibre differentiation are tightly managed by the Spred proteins. To test this, we characterised mice deficient for Spred proteins, systemically and specifically in the eye and/or lens, demonstrating that levels of ERK1/2 phosphorylation are increased, leading to aberrant lens cellular behaviour resulting in impaired lens and eye growth. Characterising the mutant mouse lines deficient for Spred, we demonstrated that Spred 1 and Spred 2 are not necessary for early lens development or for the initial formation of the primary fibre cells, however both proteins are required for the continual growth of the lens and subsequently eye growth. Furthermore, we have established both in vivo and in vitro that Spred proteins are able to antagonise pERK1/2 levels, key enzymes that regulate lens cellular processes, namely epithelial cell proliferation and fibre differentiation. Moreover, we observe an eloquent compensatory mechanism for Spreds with related RTK-antagonists, namely, Sprouty proteins. It is evident from this study that when the regular lens cell cycle and other cellular processes are disrupted, it leads to developmental abnormalities and/or pathology resulting in the loss of lens transparency. From this, we propose that later in life, Spred proteins may indirectly influence TGFβ−induced EMT, through the crosstalk and communication between the ERK/MAPK and TGFβ-Smad signalling pathways. The findings presented in this study implicate an important role for both Spred1 and Spred2 proteins in normal lens and eye development by negatively regulating ERK/MAPK-signalling. Taken together, Spred proteins may be a putative target for developing novel therapeutic-treatments for not only cataract, but other pathologies where cellular proliferation and differentiation is dysregulated.
39
Suryo, Rahmanto Yohan. "THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL ROLES OF MELANOTRANSFERRIN." Thesis, The University of Sydney, 2007. http://hdl.handle.net/2123/2439.
Abstract:
Melanotransferrin or melanoma tumour antigen p97 (MTf) is a transferrin homologue that is found predominantly bound to the cell membrane via a glycosylphosphatidylinositol anchor. The molecule is a member of the transferrin super-family that binds iron through a single high affinity iron(III)-binding site. Melanotransferrin was originally identified at high levels in melanoma cells and other tumours, but at lower levels in normal tissues. Since its discovery, the function of MTf has remained intriguing, particularly regarding its role in cancer cell iron transport. In fact, considering the crucial role of iron in many metabolic pathways e.g., DNA and haem synthesis, it is important to understand the function of melanotransferrin in the transport of this vital nutrient. Melanotransferrin has also been implicated in diverse physiological processes, such as plasminogen activation, angiogenesis, cell migration and eosinophil differentiation. Despite these previous findings, the exact biological and molecular function(s) of MTf remain elusive. Therefore, it was important to investigate the function of this molecule in order to clarify its role in biology. To define the roles of MTf, six models were developed during this investigation. These included: the first MTf knockout (MTf -/-) mouse; down-regulation of MTf expression by post-transcriptional gene silencing (PTGS) in SK-Mel-28 and SK-Mel-2 melanoma cells; hyper-expression of MTf expression in SK-N-MC neuroepithelioma cells and LMTK- fibroblasts cells; and a MTf transgenic mouse (MTf Tg) with MTf hyperexpression. The MTf -/- mouse was generated through targeted disruption of the MTf gene. These animals were viable, fertile and developed normally, with no morphological or histological abnormalities. Assessment of Fe indices, tissue Fe levels, haematology and serum chemistry parameters demonstrated no differences between MTf -/- and wild-type (MTf +/+) littermates, suggesting MTf was not essential for Fe metabolism. However, microarray analysis showed differential expression of molecules involved in proliferation such as myocyte enhancer factor 2a (Mef2a), transcription factor 4 (Tcf4), glutaminase (Gls) and apolipoprotein d (Apod) in MTf -/- mice compared with MTf +/+ littermates. Considering the role of MTf in melanoma cells, PTGS was used to down-regulate MTf mRNA and protein levels by >90% and >80%, respectively. This resulted in inhibition of cellular proliferation and migration. As found in MTf -/- mice, melanoma cells with suppressed MTf expression demonstrated up-regulation of MEF2A and TCF4 in comparison with parental cells. Furthermore, injection of melanoma cells with decreased MTf expression into nude mice resulted in a marked reduction of tumour initiation and growth. This strongly suggested a role for MTf in proliferation and tumourigenesis. To further understand the function of MTf, a whole-genome microarray analysis was utilised to examine the gene expression profile of five models of modulated MTf expression. These included two stably transfected MTf hyper-expression models (i.e., SK-N-MC neuroepithelioma and LMTK- fibroblasts) and one cell type with downregulated MTf expression (i.e., SK-Mel-28 melanoma). These findings were then compared with alterations in gene expression identified using the MTf -/- mouse. In addition, the changes identified from the microarray data were also assessed in another model of MTf down-regulation in SK-Mel-2 melanoma cells. In the cell line models, MTf hyper-expression led to increased proliferation, while MTf down-regulation resulted in decreased proliferation. Across all five models of MTf down- and upregulation, three genes were identified as commonly modulated by MTf. These included ATP-binding cassette sub-family B member 5 (Abcb5), whose change in expression mirrored MTf down- or up-regulation. In addition, thiamine triphosphatase (Thtpa) and Tcf4 were inversely expressed relative to MTf levels across all five models. The products of these three genes are involved in membrane transport, thiamine phosphorylation and proliferation/survival, respectively. Hence, this study identifies novel molecular targets directly or indirectly regulated by MTf and the potential pathways involved in its function, including modulation of proliferation. To further understand the function of MTf, transgenic mice bearing the MTf gene under the control of the human ubiquitin-c promoter were generated and characterised. In MTf Tg mice, MTf mRNA and protein levels were hyper-expressed in a variety of tissues compared with control mice. Similar to the MTf -/- mice, these animals exhibited no gross morphological, histological, nor Fe status changes when compared with wild-type littermates. The MTf Tg mice were also born in accordance with classical Mendelian ratios. However, haematological data suggested that hyper-expression of MTf leads to a mild, but significant decrease in erythrocyte count. In conclusion, the investigations described within this thesis clearly demonstrate no essential role for MTf in Fe metabolism both in vitro and in vivo. In addition, this study generates novel in vitro and in vivo models for further investigating MTf function. Significantly, the work presented has identified novel role(s) for MTf in cell proliferation, migration and melanoma tumourigenesis.
40
Suryo, Rahmanto Yohan. "THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL ROLES OF MELANOTRANSFERRIN." Faculty Medicine, Department of Pathology, 2007. http://hdl.handle.net/2123/2439.
Abstract:
Doctor of Philosophy(PhD)Melanotransferrin or melanoma tumour antigen p97 (MTf) is a transferrin homologue that is found predominantly bound to the cell membrane via a glycosylphosphatidylinositol anchor. The molecule is a member of the transferrin super-family that binds iron through a single high affinity iron(III)-binding site. Melanotransferrin was originally identified at high levels in melanoma cells and other tumours, but at lower levels in normal tissues. Since its discovery, the function of MTf has remained intriguing, particularly regarding its role in cancer cell iron transport. In fact, considering the crucial role of iron in many metabolic pathways e.g., DNA and haem synthesis, it is important to understand the function of melanotransferrin in the transport of this vital nutrient. Melanotransferrin has also been implicated in diverse physiological processes, such as plasminogen activation, angiogenesis, cell migration and eosinophil differentiation. Despite these previous findings, the exact biological and molecular function(s) of MTf remain elusive. Therefore, it was important to investigate the function of this molecule in order to clarify its role in biology. To define the roles of MTf, six models were developed during this investigation. These included: the first MTf knockout (MTf -/-) mouse; down-regulation of MTf expression by post-transcriptional gene silencing (PTGS) in SK-Mel-28 and SK-Mel-2 melanoma cells; hyper-expression of MTf expression in SK-N-MC neuroepithelioma cells and LMTK- fibroblasts cells; and a MTf transgenic mouse (MTf Tg) with MTf hyperexpression. The MTf -/- mouse was generated through targeted disruption of the MTf gene. These animals were viable, fertile and developed normally, with no morphological or histological abnormalities. Assessment of Fe indices, tissue Fe levels, haematology and serum chemistry parameters demonstrated no differences between MTf -/- and wild-type (MTf +/+) littermates, suggesting MTf was not essential for Fe metabolism. However, microarray analysis showed differential expression of molecules involved in proliferation such as myocyte enhancer factor 2a (Mef2a), transcription factor 4 (Tcf4), glutaminase (Gls) and apolipoprotein d (Apod) in MTf -/- mice compared with MTf +/+ littermates. Considering the role of MTf in melanoma cells, PTGS was used to down-regulate MTf mRNA and protein levels by >90% and >80%, respectively. This resulted in inhibition of cellular proliferation and migration. As found in MTf -/- mice, melanoma cells with suppressed MTf expression demonstrated up-regulation of MEF2A and TCF4 in comparison with parental cells. Furthermore, injection of melanoma cells with decreased MTf expression into nude mice resulted in a marked reduction of tumour initiation and growth. This strongly suggested a role for MTf in proliferation and tumourigenesis. To further understand the function of MTf, a whole-genome microarray analysis was utilised to examine the gene expression profile of five models of modulated MTf expression. These included two stably transfected MTf hyper-expression models (i.e., SK-N-MC neuroepithelioma and LMTK- fibroblasts) and one cell type with downregulated MTf expression (i.e., SK-Mel-28 melanoma). These findings were then compared with alterations in gene expression identified using the MTf -/- mouse. In addition, the changes identified from the microarray data were also assessed in another model of MTf down-regulation in SK-Mel-2 melanoma cells. In the cell line models, MTf hyper-expression led to increased proliferation, while MTf down-regulation resulted in decreased proliferation. Across all five models of MTf down- and upregulation, three genes were identified as commonly modulated by MTf. These included ATP-binding cassette sub-family B member 5 (Abcb5), whose change in expression mirrored MTf down- or up-regulation. In addition, thiamine triphosphatase (Thtpa) and Tcf4 were inversely expressed relative to MTf levels across all five models. The products of these three genes are involved in membrane transport, thiamine phosphorylation and proliferation/survival, respectively. Hence, this study identifies novel molecular targets directly or indirectly regulated by MTf and the potential pathways involved in its function, including modulation of proliferation. To further understand the function of MTf, transgenic mice bearing the MTf gene under the control of the human ubiquitin-c promoter were generated and characterised. In MTf Tg mice, MTf mRNA and protein levels were hyper-expressed in a variety of tissues compared with control mice. Similar to the MTf -/- mice, these animals exhibited no gross morphological, histological, nor Fe status changes when compared with wild-type littermates. The MTf Tg mice were also born in accordance with classical Mendelian ratios. However, haematological data suggested that hyper-expression of MTf leads to a mild, but significant decrease in erythrocyte count. In conclusion, the investigations described within this thesis clearly demonstrate no essential role for MTf in Fe metabolism both in vitro and in vivo. In addition, this study generates novel in vitro and in vivo models for further investigating MTf function. Significantly, the work presented has identified novel role(s) for MTf in cell proliferation, migration and melanoma tumourigenesis.
41
Koh, Kar Mun. "Effects of Alternating Current Electrical Stimulation on the Cellular Chemistry and Proliferation of C2C12 Muscle Cells." Thesis, North Dakota State University, 2016. https://hdl.handle.net/10365/28058.
Abstract:
The objective of this study was to investigate the effects of electrical stimulation on the cellular chemistry and proliferation of C2C12 muscle cell line. The cells were cultured under the condition of AC electrical stimulation using interdigitated electrode arrays. This research was conducted by applying electrical signals for up to 24 hours to C2C12 muscle cells. After 24 hours, the electrical impedance, cell morphology, proliferation and viability were recorded. The results demonstrated that electrical stimulation have a positive impact on the cell growth of C2C12. These results obtained would aid in future study on improving the techniques of culturing C2C12 muscle cells and also in the field of electrical conductivity in cell proliferation. Lastly, the results obtained also would provide essential information to the studies related to gene and protein expression of cellular and subcellular components after being exposed to electrical stimulation.
42
Epstein, Andrew Michael. "Fragile X Protein Regulates Cellular Proliferation and Oocyte Polarity by Controlling cb1 Levels During Drosophila Oogenesis." Thesis, The University of Arizona, 2008. http://hdl.handle.net/10150/193434.
Abstract:
Fragile X Protein (FMRP) is an RNA binding protein linked to the most common form of inherited mental retardation, Fragile X syndrome (FraX). Despite its ubiquitous expression and presence of non-neuronal phenotypes, FMRP function remains understudied outside of neural and synaptic development. In addition to severe cognitive deficits, FraX etiology also includes postpubescent macroorchidism, which is thought to occur due to overproliferation of the germline. Using a Drosophila model for FraX, I have shown that FMRP controls germline proliferation as well as dorso-ventral polarity during oogenesis. dFmr1 null ovaries exhibit egg chambers with increased numbers of germ cells and ventralized embryos. The number of cyclin E and phosphohistone H3 positive cells is increased in dFmr1 germaria compared to wild-type, suggesting that the mutant germline cells exhibit defects in proliferation. In addition, BrdU incorporation is increased during vitellogenesis, consistent with a prolonged S phase for endoreplicating nurse cells. Here I report the FMRP controls the levels of cbl mRNA in the ovary and that the overproliferation and polarity defects found in dFmr1 ovaries can be rescued by reducing cbl dosage in half. These data suggest a model whereby FMRP regulates cellular proliferation and polarity during oogenesis by controlling the E3 ubiquitin ligase cbl.
43
Lindsey, Jenifer Ann. "The consequence of prostanoid synthesis and release by human peripheral blood monocytes on immune function and cell proliferation /." The Ohio State University, 1985. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487259580261459.
44
Walsh, Erin. "Crossreactivity of alpha9beta1 integrin with p75NTR in modulation of proinvasive activities of glioma cells." Diss., Temple University Libraries, 2011. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/143048.
Abstract:
BiologyPh.D.
Gliomas are the most common and difficult to treat tumors of the central nervous system. Current treatments often fail to slow progression of disease due to the high invasive nature of glioma leading to a high percentage of recurrence. Our previous studies have demonstrated that the levels of alpha; 9 beta; 1 integrin found on high grade glioma were significantly increased in comparison to normal brain tissue where the levels were negligible. We also found that interaction between alpha; 9 beta; 1 integrin and nerve growth factor (NGF) plays a major role in progression of experimental tumor. Another receptor for NGF the common neurotrophin receptor p75NTR is also overexpressed in high grade glioma. p75NTR forms a high affinity complex with the specific NGF receptor, TrkA leading to an increase in cell proliferation and survival. In the absence of an association, p75NTR is involved in transferring pro-apoptotic signals through the JNK pathway. We have found that the α 9 integrin subunit of α 9 β 1 forms a stable, cation independent complex with p75NTR on the cell membrane of glioma both in vitro using glioma derived immortalized cells lines and in vivo using glioma tissue. The co-expression of p75NTR with α 9 β 1 integrin led to optimization of integrin-dependent cellular activities such as cell survival, proliferation, and migration. Co-expression of p75NTR was also required for implanted glioma cells to migrate in a glioma-like perivascular manner away from the site of implantation as was seen in the in vivo quail chorioallantoic membrane assay.
Temple University--Theses
45
Takayama, Sachiko. "Integrating nuclear receptor and signaling pathways involved in cell proliferation and differentiation /." view abstract or download file of text, 2006. http://proquest.umi.com/pqdweb?did=1251819331&sid=1&Fmt=2&clientId=11238&RQT=309&VName=PQD.
Abstract:
Thesis (Ph. D.)--University of Oregon, 2006.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 88-100). Also available for download via the World Wide Web; free to University of Oregon users.
46
Mohan, Abhinav. "ROLE OF E-CADHERIN FORCE IN THE SPATIAL REGULATION OF CELL PROLIFERATION." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4659.
Abstract:
Cell proliferation and contact inhibition play a major role in maintaining epithelial cell homeostasis. A hallmark of epithelial cells is strong cell-cell junctions. These junctions include E-Cadherin, a type of adherens junction that is critical for both barrier function and contact inhibition. Prior experiments by other groups have shown that adherens junctions are subject to mechanical tension. Externally applied forces (e.g. stretch) results in changes in E-Cadherin forces that coordinate proliferation. My current work tests the hypothesis that E-Cadherin forces mediate the spatial regulation of cell proliferation even in the absence of externally applied forces.
47
Clubbs, Elizabeth Ann. "INFLUENCE OF SOY ISOFLAVONES ON THE PROLIFERATION AND DIFFERENTIATION OF PROSTATE EPITHELIAL CELLS." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1208956436.
48
Blessing, Sina Carola [Verfasser]. "The role of Not4 in cellular homeostasis during proliferation and differentiation in Saccharomyces cerevisiae / Sina Carola Blessing." Konstanz : Bibliothek der Universität Konstanz, 2018. http://d-nb.info/1174143207/34.
49
Li, Bo. "The role of BK channel in cellular proliferation and differentiation in human osteoblast and osteoblast-like cells." Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/35876/.
Abstract:
Both excitable and non-excitable cells possess plasma membrane ion channels and evidence has accumulated over the last 30 or so years that these channels perhaps play key roles in the cell life and death. This Thesis investigated the characteristics and putative functions of one class of potassium channel, the BK channel in osteoblast-like cells and primary osteoblasts from human, rat and mouse. The properties and functions were defined in vitro using a combination of patch-clamp, reverse transcription-polymerase chain reaction (RT-PCR) and functional assays for cell growth and mineralisation. RT-PCR showed the presence of KCNMA1, KCNMB1, KCNMB2, KCNMB3 and KCNMB4, the gene for BK channel α, β1, β2, β3 and β4 subunits respectively. The channel was voltage-dependent with a mean unitary conductance of 315 pS in cell-attached patches, a conductance of 124 pS in excised outside-out and 151 pS in inside-out patches. The channel was blocked by TEA (0.3 mM), TBuA (1 mM), TPeA (1-10 μM), THeA (1-3 μM), tetrandrine (5-30 μM) and paxilline (10 μM) and was activated by isopimaric acid (20 μM). Notably iberiotoxin (IbTX) (90 nM) only blocked a proportion of the channels tested (2/5). Osteoblast-like MG63 cell number changed in response to BK channel modulators. It increased significantly with TEA and tetrandrine at low concentrations (1 mM, 3 μM respectively), and reduced at high concentrations (>10 mM, >10 μM respectively). It was not affected by IbTX (20-300 nM) or slotoxin (300 nM). The increase in cell number by TEA was blocked by isopimaric acid. In addition, TPeA and THeA caused a decrease of osteoblast-like SaOS2 cell mineralisation at the concentrations (3 and 0.3 μM, respectively) increased MG63 cell numbers. The BK channel has a distinctive pharmacology and represents a new target for therapeutic strategies in modulating osteoblast proliferation.
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Goode, Nigel Thomas. "Protein Kinase "C" activity and c-fos expression in cellular proliferation control of a murine macrophage tumour." Thesis, Royal Veterinary College (University of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522534.