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Pyruvate carboxylase is a downstream target of p53 in regulating insulin secretionHu, Xin, 胡欣 January 2014 (has links)
Pyruvate carboxylase (PC), converting pyruvate to oxaloacetate (OAA), is a critical contributor to anaplerosis in pancreatic β-cell, the process that can replenish the intermediates in Krebs cycle. The level of PC is markedly high in pancreatic β-cell, about 7-fold higher than that in α-cell. PC activity is reduced in the islets of animals with type 2 diabetes. Moreover, the rate of pyruvate carboxylation catalyzed by PC is well correlated with glucose-stimulated insulin secretion (GSIS), further supporting the important role of PC in insulin secretion.
Tumor protein p53 or p53, best known for its role as a tumor suppressor, has been studied extensively for its broad influence and complex regulation. p53 suppresses tumor progression by responding to a wide variety of intrinsic and extrinsic cellular stress signals. Recent studies have revealed novel roles of p53 in response to metabolic stress, such as oxidative or nutrient stress. MDM2 is the major E3 ubiquitin ligases to control p53 activity negatively. p53 and MDM2 form a negative-feedback loop, where p53 stimulates the expression of MDM2, in turn MDM2 inhibits not only the stability but also the transcriptional activity of p53.
In the previous study, mice lacking Mdm2 specifically in pancreatic β-cells have been generated, and display impaired insulin secretion and glucose metabolism. Further study has suggested that the impaired insulin secretion is caused by downregulation of pyruvate carboxylase (PC). To explore the interaction of PC with MDM2-p53 pathway in regulating insulin secretion, we inserted human PC DNA into a shuttle vector pShuttle-CMV to generate a recombinant adenovirus containing human PC gene, that is then used to restore the level of PC in Mdm2 KO islet. The recovery of insulin secretion confirmed that the downregulation of PC leads to β-cell dysfunction. Given that MDM2 is the main E3 ubiquitin protein ligase to restrain p53 activity, abnormal high level of p53 is suggested to suppress the activity of PC in Mdm2 β-cell KO mice. The putative p53 response element is found in a sequence of PC intron gene, indicating that PC can be a downstream target of p53. Using pGL3 Luciferase Reporter Vector, it is verified that p53 suppresses the activity of PC by directly targeting PC. / published_or_final_version / Medicine / Master / Master of Medical Sciences
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Structural and functional characterization of the Fujinami sarcoma virus transforming proteinWeinmaster, Geraldine Ann January 1985 (has links)
The phosphorylation of the Fujinami sarcoma virus transforming
protein (FSV P140gag-fps) is complex, reversible and affects its tyrosine specific protein kinase activity and transforming function. The sites of phosphorylation within FSV P140gag-fps have been localized to various regions of the protein using partial proteolysis. The two major phosphotyrosine residues and a major phosphoserine residue are located in the C-terminal portion of the fps region, which contains the kinase active domain. A comparative tryptic phosphopeptide analysis of the gag-fps proteins of three FSV variants shows that the phosphotyrosine containing peptides have similar mobilities.
To determine whether tyrosine phosphorylation affects protein function and to evaluate the substrate specificity of the protein kinase intrinsic to FSV
P130gag-fps oligonucleotide-directed mutagenesis was used to change tyrosine-1073, the major site of P130gag-fps phosphorylation. Tyrosine-1073 was mutated to a phenylalanine and a glycine, amino acids that cannot be phosphorylated, and to the other commonly phosphorylated hydroxyamino acids, serine and threonine. Neither serine nor threonine were phosphorylated when substituted for tyrosine-1073 indicating a strict specificity for and oncogenic capacities. These data indicate that tyrosine phosphorylation
stimulates the biochemical and biological activities of FSV
P130gag-fps and suggest that tyrosine phosphorylation modulates protein function.
Mutations within the putative ATP-binding site of P130gag-fps at lysine-950 destroy both its kinase and transforming activities, supporting the idea that the tyrosine kinase activity intrinsic to P130gag-fps is essential for its transforming function. The mutant protein was also shown to be phosphorylated at a second tyrosine site, which has been previously identified in wild-type P130gag-fps as a site exclusively phosphorylated in vivo. Phosphorylation of secondary tyrosine residues within a mutant protein devoid of intrinsic tyrosine protein kinase activity suggests that the FSV P130gag-fps may be a target for phosphorylation by cellular tyrosine specific protein kinases. / Science, Faculty of / Microbiology and Immunology, Department of / Graduate
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Identification and characterization of N-terminal kinase like protein in hepatocellular carcinomaWang, Jian, 王健 January 2011 (has links)
published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy
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Overexpression of translationally controlled tumor protein (TCTP) predisposes to hepatocellular carcinoma陳漢文, Chan, Hon-man January 2012 (has links)
Hepatocellular carcinoma (HCC) is the most common tumors worldwide. In contrast to other cancers, the prognosis of HCC is extremely poor, with less that 5% of 5-year survival rate worldwide. From our previous studies, we isolated Chromodomain Helicases/ATPase DNA binding protein1-Like (CHD1L) gene from chromosome 1q21, and characterized it as a specific oncogene in HCC. By using 2D-PAGE and MALDI-TOF mass spectrometry approach, Translationally Controlled Tumor Protein (TCTP) was identified as a CHD1L target, which was preferentially expressed in CHD1L-transfected cells. TCTP is a highly conserved protein and expressed in almost all mammalian tissues. It has been reported that TCTP interacts with microtubules in a cell-cycle-dependent manner, and functions as a prosurvival factor and inhibiting apoptosis. To better understand the molecular mechanisms of HCC progression, the effect of TCTP overexpression in HCC and the mechanism by which TCTP regulated cell-cycle progression were elucidated in this study.
CHD1L is a unique oncogene belongs to SNF2-like subfamily. Mechanistic studies found that CHD1L protein directly binds to the promoter region (nt -733 to -1,027) of TCTP and activated TCTP transcription. Investigation of clinical HCC specimens found that overexpression of TCTP was not only significantly associated with the advanced tumor stage (P = 0.037) and overall survival time of HCC patients (P = 0.034), but also an independent marker associated with poor prognostic outcomes. Functional studies demonstrated that TCTP has tumorigenic abilities and overexpression of TCTP contributed to the mitotic defects of tumor cells. Further mechanistic studies demonstrated that TCTP promoted the ubiquitin-proteasome degradation of Cdc25c during mitotic progression, which caused the failure in the dephosphorylation of Cdk1 on Tyr 15 and decreased Cdk1 activity. The consequence of chromosome missegregation and mitotic catastrophe results in aneuploidy, which is frequently observed in cancer.
In addition, the correlation between TCTP overexpression and metastatic potential of HCC was elucidated by examined the expression levels of TCTP using a tissue microarray (TMA) containing 60 pairs of primary HCCs and their matched metastases. Further studies demonstrated that overexpression of TCTP shows high incidence of extrahepatic metastasis and positive correlation was found between TCTP and MMP-2 or MMP-9 (Spearmen correlation coefficient=0.466, and 0.352, respectively, P<0.001 for both). In vitro functional studies showed that TCTP protein associated with promoter regions of MMP-2 and MMP-9 and activates their transcriptions. Molecular analyses revealed that TCTP served as a JunD coactivator and formed complexes with JunD and bind with consensus AP-1 sites on MMP-2 and MMP-9 promoters to enhance their expression in HCC cells. More importantly, high co-expression of TCTP and MMP-2 or MMP-9 was significantly associated with poor disease-free survival (log rank= 8.146, and 11.677 respectively, P =0.017 and 0.003 respectively).
In summary, two novel molecular mechanisms (CDH1L/TCTP/Cdc25C/Cdk1) and (TCTP/JunD/MMP-2, MMP-9) were revealed during HCC progression and metastasis. Also, the prognostic value of TCTP and MMP-2 or MMP-9 coexpression for HCC was highlight in this study. / published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy
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Therapeutic reactivation of the p53 tumor suppressor protein in HPV-positive cervical cancer cells by the creosote bush lignan 3'-O-methyl-nordihydroguaiaretic acidAllen, Kristi Lynne. January 2007 (has links)
Thesis (Ph.D.)--Kent State University, 2007. / Title from PDF t.p. (viewed Mar. 11, 2009). Advisor: Angelo L. DeLucia. Keywords: human papillomavirus, E6 oncogene, lignan, p53, apoptosis. Includes bibliographical references (p. 132-144).
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Structural characterisation and analysis of human cripto-1Taylor, Charles Dariush January 2008 (has links)
No description available.
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Identification of tumor-associated proteins in human prostatic epithelial cell lines & squamous cell carcinoma of head and neck byproteomic technologyChen, Jia, 陳珈 January 2004 (has links)
published_or_final_version / abstract / Molecular Biology / Master / Master of Philosophy
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Bmi-1 promotes the invasion and metastasis and its elevated expression is correlated with advanced stage of breast cancer. / CUHK electronic theses & dissertations collectionJanuary 2010 (has links)
Background. B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi-1) acts as an oncogene in various cancer such as non-small cell lung cancer, colon cancer, gastric cancer, bladder cancer and nasopharyngeal cancer (NPC). / Methods. Immunohistochemistry was performed to evaluate Bmi-1 expression in 252 breast cancer samples. The correlations were analyzed between Bmi-1 expression and clinicopathologic parameters, including age, tumor size, lymph nodal involvement, distant metastasis, clinical stages, hormone receptor (ER, PR) and Human Epidermal Growth Factor Receptor 2 (HER-2). The overall survivals were compared by Kaplan-Meier analysis based on Bmi-1 expression. / Results. Bmi-1 expression was significantly increased in primary cancer tissues than in matched adjacent non-cancerous tissues ( P<0.001). Only 35.9% (14 of 39) of adjacent non-cancerous tissues displayed high expression compared with 72.2% (182 of 252) in primary cancer tissues. Among adjacent non-cancerous tissues, no Bmi-1 staining signal was detected in 30.8% (12 in 39) samples. Only 28.2% (11 in 39) samples showed nucleus staining and the remaining 41.0% (16 in 39) samples exhibited cytoplasm staining. Of those cancer tissues, however, 75.4% (190 in 252) was stained in the nucleus and 24.6% (62 in 252) located in the cytoplasm. The elevated Bmi-1 expression was correlated with advanced clinicopathologic classifications (T, N, M) and clinical stages (P<0.001, respectively). A high level of Bmi-1 expression displayed unfavorable overall survival ( P<0.001). The overall survival rate, assessed by the Kaplan-Meier method, was 85.1% (57 in 67) in low Bmi-1 expression group, whereas it was only 59.9% (103 in 172) in high Bmi-1 expression group. In addition, Bmi-1 serves as a high risk for breast cancer and the relative risk increased almost four fold in patients with high Bmi-1 expression compared with that with low Bmi-1 expression by univariate Cox regression analyses. After the adjustment of the confounding factors, Bmi-1 was still found to predict the poor survival (P=0.042), which indicated Bmi-1 was an independent prognostic factor. The overexpression of Bmi-1 increased the mobility and invasiveness in 76N-TERT and MCF-10A, concurrent EMT-like molecular changes, the stabilization of Snail protein and the activation of Akt/GSK3beta pathway. Consistent with these observations, the repression of Bmi-1 in MDA-MB-435S remarkably attenuated the cellular mobility, invasiveness and transformation, as well as tumorigenesis and spontaneous lung metastases in nude mice. In addition, the repression of Bmi-1 reversed the EMT markers and inhibited the Akt/GSK3beta/Snail pathway. However, ectopic Bmi-1 alone was not able to lead to the phenotype of HMECs. Additionally, discordant mRNA expression levels of Bmi-1 and E-cadherin were detected between primary cancer tissues and matched adjacent non-cancerous tissues. The mRNA level of Bmi-1 was strongly up-regulated in breast cancer tissues compared with paired non-cancerous tissues ( P=0.001), whereas the mRNA level of E-cadherin was markedly down-regulated (P=0.042). Furthermore, there was a converse correlation between Bmi-1 and E-cadherin expression at the transcriptional level ( P=0.041). (Abstract shortened by UMI.) / Guo, Baohong. / Adviser: Kung, Hsiang Fu. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 161-183). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
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The role of TAL1 and the atypical NF-KB heterodimer p65/c-Rel in T-cell acute lymphoblastic leukemia / Role of T-cell acute lymphoblastic leukemia 1 and the atypical nuclear factor kappa B heterodimer p65/c-Rel in T-cell acute lymphoblastic leukemiaMahl, Sarah Elisabeth 20 July 2013 (has links)
T-ALL accounts for 15% of childhood leukemias and approximately 60% of patients overexpress TAL1. TAL1/SCL encodes a transcription factor that regulates hematopoiesis by dimerizing with additional transcription factors including E12, E47, and GATA-1. TAL1 has also been found to repress expression of NF-κB1, potentially promoting formation of an NF-κB p65/c-Rel heterodimer that encourages cell survival by up-regulating IAPs and IκB. However, the correlation between TAL1 and p65/c-Rel expression and their effects on downstream targets like IKK, IκB, and other anti-apoptotic proteins is poorly understood. Jurkat cells, expressing TAL1, were treated with TNFα and/or etoposide to induce apoptosis and experiments were performed to assess the expression of proteins of interest. Caspase-8 activity assays were also performed to help delineate the apoptotic signal present in these cells. Determining if interactions between TAL1, NF-κB, and other downstream targets help promote apoptotic resistance will further research into better, more targeted treatments for T-ALL. / Department of Biology
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Does the apoptotic activity of cells ectopically expressing TAL1 and LMO1 revert to normal after RNA interference induced silencing of TAL1 and LMO1?Girardi, Jerilyn K. January 2008 (has links)
T-cell acute lymphoblastic leukemia (T-ALL) is a childhood cancer created through genetic alterations; most commonly upregulation of TALI and LMOI oncoproteins. T-ALL is treated with radiation and chemotherapy, but malignant T-cells are resistant to apoptotic stimulation. To study this disorder, AKR-DP-603 cells were transduced to express both oncoproteins. Western blots verified protein expression and each population was treated with etoposide. Caspase-3 and Annexin-V/FITC apoptosis assays were performed following treatment. When the response of control cells was compared to engineered cells, no difference was observed from the Annexin-V/FITC assay, and only LM01 cells showed a difference in the caspase-3 assay. Furthermore, cells were transfected with siRNA to TALI and LM01 and the apoptotic response was re-tested. Complete silencing was verified by Western and apoptotic activity varied in the TALI population for both assays. These differences might indicate that cells resisted etoposide induction and following silencing were sensitized apoptotic induction. / Department of Biology
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