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Loss Of Gprc5a Enhances Survival In Normal And Malignant Lung Epithelial Cells By Eliciting Persistent Stat3 Activation Induced By Autocrine Lif, Yulong Chen 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Loss Of Gprc5a Enhances Survival In Normal And Malignant Lung Epithelial Cells By Eliciting Persistent Stat3 Activation Induced By Autocrine Lif, Yulong Chen

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Signal transduction and activator of transcription 3 (Stat3) is activated by cytokines and growth factors in many cancers. Persistent activation of Stat3 plays important role in cell growth, survival, and transformation through regulating its targeted genes.

Previously, we found that mice with a deletion of the G protein-coupled receptor, family C, group 5, member a (Gprc5a) gene develop lung tumors indicating that Gprc5a is a tumor suppressor. In the present study, we examined he mechanism of Gprc5a-mediated tumor suppression. We found that epithelial cells from Gprc5a knockout mouse lung (Gprc5a-/- cells) survive better in vitro in medium deprived of exogenous ...


Role And Regulation Of Epha2 In Pancreatic Cancer, Pavel A. Levin 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Role And Regulation Of Epha2 In Pancreatic Cancer, Pavel A. Levin

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cancer cause of death in the US. Gemcitabine is the first-line therapy for this disease, but unfortunately it shows only very modest benefit. The focus of the current study was to investigate the role and regulation of EphA2, a receptor tyrosine kinase expressed in PDAC, to further understand this disease and identify new therapeutic targets.

The role of EphA2 was determined in PDAC by siRNA mediated silencing. In combination with gemcitabine, silencing of EphA2 caused a dramatic increase in apoptosis even in highly resistant cells in vitro. Furthermore, EphA2 silencing was found ...


Mutations In Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy, JeanMarie Houghton, Hanchen Li, Xueli Fan, Yingwang Liu, Jian Hua Liu, Varada P. Rao, Theofilos Poutahidis, Christine L. Taylor, Erin A. Jackson, Christine Hewes, Stephen Lyle, Anna M. Cerny, Glennice N. Bowen, Jan Cerny, Nathan F. Moore, Evelyn A. Kurt-Jones, Susan E. Erdman 2010 University of Massachusetts Medical School

Mutations In Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy, Jeanmarie Houghton, Hanchen Li, Xueli Fan, Yingwang Liu, Jian Hua Liu, Varada P. Rao, Theofilos Poutahidis, Christine L. Taylor, Erin A. Jackson, Christine Hewes, Stephen Lyle, Anna M. Cerny, Glennice N. Bowen, Jan Cerny, Nathan F. Moore, Evelyn A. Kurt-Jones, Susan E. Erdman

GSBS Student Publications

Neoplastic epithelia may remain dormant and clinically unapparent in human patients for decades. Multiple risk factors including mutations in tumor cells or the stromal cells may affect the switch from dormancy to malignancy. Gene mutations, including p53 mutations, within the stroma of tumors are associated with a worse clinical prognosis; however, it is not known if these stromal mutations can promote tumors in genetically at-risk tissue. To address this question, Apc(Min/+) and Apc(Min/+) Rag2(-/-) mice, which have a predilection to mammary carcinoma (as well as wild-type (wt) mice), received mesenchymal stem cells (MSC) with mutant p53 (p53MSC) transferred ...


Characterizing The Role Of Dna Repair Proteins In Telomere Length Regulation And Maintenance: Fanconi Anemia Complementation Group C Protein And 8-Oxoguanine Dna Glycosylase, David Beomjin Rhee 2010 University of Tennessee, Knoxville

Characterizing The Role Of Dna Repair Proteins In Telomere Length Regulation And Maintenance: Fanconi Anemia Complementation Group C Protein And 8-Oxoguanine Dna Glycosylase, David Beomjin Rhee

Doctoral Dissertations

Telomeres are the chromosome end structures consisting of telomere-associated proteins and short tandem repeat sequences, TTAGGG, in humans and mice. Telomeres prevent chromosome termini from being recognized as broken DNA ends. The structural integrity of DNA including telomeres is constantly threatened by a variety of DNA damaging agents on a daily basis. To counteract the constant threats from DNA damage, organisms have developed a number of DNA repair pathways to ensure that the integrity of genome remains intact. A number of DNA repair proteins localize to telomeres and contribute to telomere maintenance; however, it is still unclear as to what ...


Genetic Polymorphisms Of Cyp2e1, Gstp1, Nqo1 And Mpo And The Risk Of Nasopharyngeal Carcinoma In A Han Chinese Population Of Southern China, Xiuchan Guo, Yi Zeng, Hong Deng, Jian Liao, Yuming Zheng, Ji Li, Bailey Kessing, Stephen J. O'Brien 2010 Chinese Center for Disease Control; National Cancer Institute at Frederick

Genetic Polymorphisms Of Cyp2e1, Gstp1, Nqo1 And Mpo And The Risk Of Nasopharyngeal Carcinoma In A Han Chinese Population Of Southern China, Xiuchan Guo, Yi Zeng, Hong Deng, Jian Liao, Yuming Zheng, Ji Li, Bailey Kessing, Stephen J. O'Brien

Biology Faculty Articles

Background

Southern China is a major area for endemic nasopharyngeal carcinoma (NPC). Genetic factors as well as environmental factors play a role in development of NPC. To investigate the roles of previously described carcinogen metabolism gene variants for NPC susceptibility in a Han Chinese population, we conducted a case-control study in two independent study population groups afflicted with NPC in Guangdong and Guangxi Provinces of southern China.

Methods

Five single nucleotide polymorphisms (SNPs) of CYP2E1-rs2031920, CYP2E1-rs6413432, GSTP1-rs947894, MPO-rs2333227 and NQO1-rs1800566 were genotyped by PCR-based RFLP, sequencing and TaqMan assay in 358 NPC cases and 629 ...


Release Of Hmgb1 In Response To Pro-Apoptotic Glioma Killing Strategies: Efficacy And Neurotoxicity, Marianela Candolfi, Kader Yagiz, David Foulad, Gabrielle Alzadeh, Matthew Tesarfreund, AKM Ghulam Muhammad, Mariana Puntel, Kurt Kroeger, Chunyan Liu, Sharon Lee, James Curtin, Gwendalyn D. King, Jonathan Lerner, Katsuaki Sato, Yohei Mineharu, Weidong Xiong, Pedro R. Lowenstein, Maria Castro 2010 Cedars-Sinai Medical Center

Release Of Hmgb1 In Response To Pro-Apoptotic Glioma Killing Strategies: Efficacy And Neurotoxicity, Marianela Candolfi, Kader Yagiz, David Foulad, Gabrielle Alzadeh, Matthew Tesarfreund, Akm Ghulam Muhammad, Mariana Puntel, Kurt Kroeger, Chunyan Liu, Sharon Lee, James Curtin, Gwendalyn D. King, Jonathan Lerner, Katsuaki Sato, Yohei Mineharu, Weidong Xiong, Pedro R. Lowenstein, Maria Castro

Articles

Purpose In preparation for a Phase I clinical trial utilizing a combined cytotoxic/immunotherapeutic strategy using adenoviruses expressing Flt3L (Ad-Flt3L) and thymidine kinase (Ad-TK) to treat glioblastoma (GBM), we tested the hypothesis that Ad-TK+GCV would be the optimal tumor killing agent in relation to efficacy and safety when compared to other pro-apoptotic approaches. Experimental Design and Results The efficacy and neurotoxicity of Ad-TK+GCV was compared with Ads encoding the pro-apoptotic cytokines (TNF-α, TRAIL, FasL), alone or in combination with Ad-Flt3L. In rats bearing small GBMs (day 4), only Ad-TK+GCV or Ad-FasL improved survival. In rats bearing large ...


Clinically Relevant Doses Of Chemotherapy Drugs Selectively And Reversibly Block Glioblastoma Neurosphere Proliferation In Vitro: A Dissertation, Alicia M. Mihaliak 2010 University of Massachusetts Medical School

Clinically Relevant Doses Of Chemotherapy Drugs Selectively And Reversibly Block Glioblastoma Neurosphere Proliferation In Vitro: A Dissertation, Alicia M. Mihaliak

GSBS Dissertations and Theses

My thesis research began with a project in which we were trying to determine the function of embryonic stem cell (ESC)-specific miRNAs. Using luciferase constructs containing miRNA binding sites, luciferase expression was inhibited by endogenous miRNAs in ESCs, and by exogenous miRNAs in HeLa cells. Inhibition of luciferase expression by miRNAs was inhibited in HeLa cells using 2’O-methyl-oligonucleotides. In ESCs, 2’O-methyl-oligonucleotides were only effective in partially inhibiting miR290 function. Partial inhibition of miR290 did not result in any obvious phenotypic changes in mESCs. Later studies using 2’O-methyl-oligonucleotides in ESCs were also unsuccessful. The function of ESC-specific ...


Pathogenesis Of The Helicobacter Induced Mucosal Disease: A Dissertation, Calin Stoicov 2010 University of Massachusetts Medical School

Pathogenesis Of The Helicobacter Induced Mucosal Disease: A Dissertation, Calin Stoicov

GSBS Dissertations and Theses

Helicobacter pylori causes chronic gastritis, peptic ulceration and gastric cancer. This bacterium is one of the most prevalent in the world, but affects mostly the populations with a lower socioeconomical status. While it causes gastric and duodenal ulcers in only 20% of infected patients, less then 1% will develop gastric adenocarcinoma. In fact, H. pylori is the most important risk factor in developing gastric cancer. Epidemiological studies have shown that 80% of gastric cancer patients are H. pylori positive. The outcome of the infection with this bacterium depends on bacterial factors, diet, genetic background of the host, and coinfection with ...


Regulation Of Wrn Function By Acetylation And Sirt1-Mediated Deacetylation In Response To Dna Damage: A Dissertation, Kai Li 2010 University of Massachusetts Medical School Worcester

Regulation Of Wrn Function By Acetylation And Sirt1-Mediated Deacetylation In Response To Dna Damage: A Dissertation, Kai Li

GSBS Dissertations and Theses

Werner syndrome (WS) is an autosomal recessive disorder associated with premature aging and cancer predisposition. WS cells show increased genomic instability and are hypersensitive to DNA-damaging agents. WS is caused by mutations of the WRN gene. WRN protein is a member of RecQ DNA helicase family. In addition to a conserved 3’–5’ helicase activity, the WRN protein contains unique 3’–5’ exonuclease activity. WRN recognizes specific DNA structures as substrates that are intermediates of DNA metabolism. WRN physically and functionally interacts with many other proteins that function in telomere maintenance, DNA replication, and DNA repair. The function of WRN ...


Nk Cells And Gammadelta T Cells Mediate Resistance To Polyomavirus-Induced Tumors, Rabinarayan Mishra, Alex T. Chen, Raymond M. Welsh, Eva Szomolanyi-Tsuda 2010 University of Massachusetts Medical School

Nk Cells And Gammadelta T Cells Mediate Resistance To Polyomavirus-Induced Tumors, Rabinarayan Mishra, Alex T. Chen, Raymond M. Welsh, Eva Szomolanyi-Tsuda

Open Access Publications by UMMS Authors

NK and gammadelta T cells can eliminate tumor cells in many experimental models, but their effect on the development of tumors caused by virus infections in vivo is not known. Polyomavirus (PyV) induces tumors in neonatally infected mice of susceptible strains and in adult mice with certain immune deficiencies, and CD8+ alphabeta T cells are regarded as the main effectors in anti-tumor immunity. Here we report that adult TCRbeta knockout (KO) mice that lack alphabeta but have gammadelta T cells remain tumor-free after PyV infection, whereas TCRbeta x delta KO mice that lack all T cells develop tumors. In addition ...


A Tale Of Two Arfs: Tumor Suppressor And Anti-Viral Functions Of P14arf: A Dissertation, Michael W. Straza 2010 University of Massachusetts Medical School

A Tale Of Two Arfs: Tumor Suppressor And Anti-Viral Functions Of P14arf: A Dissertation, Michael W. Straza

GSBS Dissertations and Theses

Animals have evolved complicated and overlapping mechanisms to guard against the development of cancer and infection by pathogenic organisms. ARF, a potent tumor suppressor, positively regulates p53 by antagonizing p53’s negative regulator, MDM2, which in turn results in either apoptosis or cell cycle arrest. ARF also has p53-independent tumor suppressor activity. The CtBP transcriptional co-repressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is a target for negative regulation by ARF. ARF targets CtBP to the proteasome for degradation, which results in the up regulation of proapoptotic BH3-only proteins, and ...


Novel Therapeutic Targets For Ph+ Chromosome Leukemia And Its Leukemia Stem Cells: A Dissertation, Cong Peng 2010 University of Massachusetts Medical School

Novel Therapeutic Targets For Ph+ Chromosome Leukemia And Its Leukemia Stem Cells: A Dissertation, Cong Peng

GSBS Dissertations and Theses

The human Philadelphia chromosome (Ph) arises from a translocation between chromosomes 9 and 22 [t(9;22)(q34;q11)]. The resulting chimeric BCR-ABLoncogene encodes a constitutively activated, oncogenic tyrosine kinase that induces chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). The BCR-ABL tyrosine kinase inhibitor (TKI), imatinib mesylate, induces a complete hematologic and cytogenetic response in the majority of CML patients, but is unable to completely eradicate BCR-ABL–expressing leukemic cells, suggesting that leukemia stem cells are not eliminated. Over time, patients frequently become drug resistant and develop progressive disease despite continued treatment. Two major reasons cause ...


The Role Of The Transcription Factor Atf4iin Tumor Progression Under Nutrient Deprivation And Hypoxia, Jiangbin Ye 2010 University of Pennsylvania

The Role Of The Transcription Factor Atf4iin Tumor Progression Under Nutrient Deprivation And Hypoxia, Jiangbin Ye

Publicly Accessible Penn Dissertations

The transcription factor ATF4 regulates the expression of mRNAs involved in amino acid metabolism, redox homeostasis and ER stress responses. Its overexpression in human solid tumors suggests an important role in tumor biology. Here we report that inhibition of ATF4 expression blocks proliferation and survival of transformed cells, despite an initial activation of cytoprotective macroautophagy. Knockdown of ATF4 significantly reduced the levels of asparagine synthetase (ASNS). Overexpression of ASNS or supplementation of asparagine in trans, reverses the proliferation block and increases survival in ATF4 knockdown cells. Both amino acid and glucose deprivation, stresses found in solid tumors, activate the upstream ...


Mechanisms Of The Downregulation Of Prolactin Receptor And Their Role In Cell Proliferation, Bentley J. Varghese 2010 University of Pennsylvania

Mechanisms Of The Downregulation Of Prolactin Receptor And Their Role In Cell Proliferation, Bentley J. Varghese

Publicly Accessible Penn Dissertations

Cells react to diverse stimuli by expressing specific receptors that recognize these stimuli and initiate specific signaling pathways that enable a cell to change with the environment. Downregulation of these signaling receptors represents the most direct method for limiting the magnitude and duration of downstream signal transduction. For cell surface transmembrane receptors, ligand-stimulated endocytosis is a major mechanism by which the ability of a cell to react to a ligand is restricted. In order to investigate the downregulation of the prolactin receptor (PRLr), we investigated the mechanism and key determinants in the endocytosis and downregulation of PRLr. In Chapter 2 ...


Functions Of Dna Damage Response Factors In Lymphocyte Development And Transformation, Bu Yin 2010 University of Pennsylvania School of Medicine

Functions Of Dna Damage Response Factors In Lymphocyte Development And Transformation, Bu Yin

Publicly Accessible Penn Dissertations

DNA double strand breaks (DSBs) can activate cell cycle checkpoints or apoptosis, and lead to genomic alterations that drive malignant transformation. The H2AX core histone variant is phosphorylated in chromatin around DSBs by kinases such as ATM and DNA-PKcs. However, how H2AX suppresses chromosome breaks and translocations in cells and prevents tumorigenesis in mice and humans is not well understood. V(D)J recombination is a genetically programmed DNA damage and repair process that assembles the variable region exons of antigen receptor genes in developing lymphocytes. Using an inducible V(D)J recombination system, I found that H2AX is phosphorylated ...


Regulation Of Dna Damage Processing By Covalent Modification Of Thymine Dna Glycosylase, Ryan D. Mohan 2010 The University of Western Ontario

Regulation Of Dna Damage Processing By Covalent Modification Of Thymine Dna Glycosylase, Ryan D. Mohan

Electronic Thesis and Dissertation Repository

Thymine DNA glycosylase (TDG) is an essential DNA repair enzyme mediating excision of uracil and thymine mispaired with guanine within CpG contexts. Unrepaired, these lesions result in G:C to A:T transitions which are major contributors to genome instability. Interestingly, TDG interacts functionally with transcriptional regulators and participates in directed cytosine demethylation at promoters. TDG is subject to multiple post-translational modifications (PTM) and we undertook an analysis of how these regulate TDG function. Initially, we examined TDG regulation by small ubiquitin-like modifier (SUMO) and identified a novel SUMO binding motif (SBM1, residues 144-148). We hypothesized that SBM1, along with ...


Xenoestrogen-Specific Mechanisms Of Developmental Reprogramming Correlate With Gene Expression And Tumor Development, Kristen L. Greathouse 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Xenoestrogen-Specific Mechanisms Of Developmental Reprogramming Correlate With Gene Expression And Tumor Development, Kristen L. Greathouse

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Environmental exposures during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life in a process known as developmental reprogramming. We have shown that neonatal exposure to the xenoestrogen diethylstilbestrol (DES) can developmentally reprogram the reproductive tract in genetically susceptible Eker rats giving rise to complete penetrance of uterine leiomyoma. Based on this, we hypothesized that xenoestrogens, including genistein (GEN) and bisphenol A (BPA), reprogram estrogen-responsive gene expression in the myometrium and promote the development of uterine leiomyoma. We proposed the mechanism that is responsible for the developmental reprogramming of gene expression was through ...


The Consequences Of Disrupting The Mdm2-P53 Balance In Hematopoiesis, Hussein A. Abbas 2010 University of Texas Graduate School of Biomedical Sciences at Houston

The Consequences Of Disrupting The Mdm2-P53 Balance In Hematopoiesis, Hussein A. Abbas

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

The bone marrow accommodates hematopoietic stem cells and progenitors. These cells provide an indispensible resource for replenishing the blood constituents throughout an organism’s life. A tissue with such a high turn-over rate mandates intact cycling checkpoint and apoptotic pathways to avoid inappropriate cell proliferation and ultimately the development of leukemias. p53, a major tumor suppressor, is a transcription factor that regulates cell cycle, and induces apoptosis and senescence. Mice inheriting a hypomorphic p53 allele in the absence of Mdm2, a p53 inhibitor, have elevated p53 cell cycle activity and die by postnatal day 13 due to hematopoietic failure. Hematopoiesis ...


Survival Prediction For Brain Tumor Patients Using Gene Expression Data, Vinicius Bonato 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Survival Prediction For Brain Tumor Patients Using Gene Expression Data, Vinicius Bonato

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Brain tumor is one of the most aggressive types of cancer in humans, with an estimated median survival time of 12 months and only 4% of the patients surviving more than 5 years after disease diagnosis. Until recently, brain tumor prognosis has been based only on clinical information such as tumor grade and patient age, but there are reports indicating that molecular profiling of gliomas can reveal subgroups of patients with distinct survival rates. We hypothesize that coupling molecular profiling of brain tumors with clinical information might improve predictions of patient survival time and, consequently, better guide future treatment decisions ...


Delta Like Ligand 4 Is A Critical Regulator Of Bone Marrow Cell Differentiation Into Pericytes/Vascular Smooth Muscle Cells And Is Essential For The Vasculogenesis That Supports The Growth Of Ewing’S Sarcoma, Keri L. Stewart 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Delta Like Ligand 4 Is A Critical Regulator Of Bone Marrow Cell Differentiation Into Pericytes/Vascular Smooth Muscle Cells And Is Essential For The Vasculogenesis That Supports The Growth Of Ewing’S Sarcoma, Keri L. Stewart

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

We have previously shown that vasculogenesis, the process by which bone marrow-derived cells are recruited to the tumor and organized to form a blood vessel network de novo, is essential for the growth of Ewing’s sarcoma. We further demonstrated that these bone marrow cells differentiate into pericytes/vascular smooth muscle cells(vSMC) and contribute to the formation of the functional vascular network. The molecular mechanisms that control bone marrow cell differentiation into pericytes/vSMC in Ewing’s sarcoma are poorly understood. Here, we demonstrate that the Notch ligand Delta like ligand 4 (DLL4) plays a critical role in this ...


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