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Full-Text Articles in Cancer Biology

Investigating The Roles Of Tap63 And Tap73 In Cutaneous Squamous Cell Carcinoma And Lung Adenocarcinoma, Andrew J. Davis Aug 2018

Investigating The Roles Of Tap63 And Tap73 In Cutaneous Squamous Cell Carcinoma And Lung Adenocarcinoma, Andrew J. Davis

UT GSBS Dissertations and Theses (Open Access)

TP63 and TP73 (which encode p63 and p73, respectively) are highly conserved transcription factors with important roles in development and tissue homeostasis. Similar to their homolog, p53, both p63 and p73 have been shown to mediate tumor suppression in multiple tissue types. Interestingly, however, both genes are expressed as multiple isoforms, which appear to have different and, in many cases, antagonistic functions. Through the use of isoform-specific null alleles of p63 and p73 our lab and others have shown that the full-length N-terminal isoforms of p63 and p73 (referred to as TAp63 and TAp73, respectively) exhibit distinct functions in development ...


Sphingosine Kinase 1 Regulates Fascin Expression To Promote Metastasis In Triple Negative Breast Cancer, Sunil Acharya May 2018

Sphingosine Kinase 1 Regulates Fascin Expression To Promote Metastasis In Triple Negative Breast Cancer, Sunil Acharya

UT GSBS Dissertations and Theses (Open Access)

Distant metastasis is the primary cause of breast cancer–related mortality. To date, effective therapeutic drugs that target metastasis are still lacking. Triple negative breast cancer (TNBC) occurs in high frequency in young women and are more likely to recur and metastasize than are other breast cancer subtypes. Also, TNBC patients cannot benefit from currently available hormonal or targeted therapies, as they lack estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Thus, understanding the signaling pathways that promote TNBC metastasis and developing novel therapeutic approaches to target them are critical, in order to prolong the survival and ...


Characterization Of Notch1 And Pi3k-Pten-Akt/Mtor Pathway Interaction In Head And Neck Squamous Cell Carcinoma, Kyriante' Henry Dec 2017

Characterization Of Notch1 And Pi3k-Pten-Akt/Mtor Pathway Interaction In Head And Neck Squamous Cell Carcinoma, Kyriante' Henry

UT GSBS Dissertations and Theses (Open Access)

Head and neck squamous cell carcinoma (HNSCC) affects various mucosal sites of the upper aerodigestive tract, including the nasal and oral cavities, the nasopharynx, and the oropharynx. More than five hundred thousand new cases of HNSCC occurred in 2011 alone, with 50,000 reported cases in the United States. This trend made HNSCC the seventh most common non-skin cancer worldwide (Ferlay et al., 2015). Although significant epidemiological and pathological advancements have been made, survival rates have not improved much over the last 40 years, leaving a mortality rate that remains at approximately 50%. An unbiased drug screen demonstrated that HNSCC ...


Preclinical Development Of Therapeutic Strategies Against Triple-Negative And Inflammatory Breast Cancer, Angie M. Torres-Adorno Aug 2017

Preclinical Development Of Therapeutic Strategies Against Triple-Negative And Inflammatory Breast Cancer, Angie M. Torres-Adorno

UT GSBS Dissertations and Theses (Open Access)

Triple-negative (TNBC) and inflammatory (IBC) breast cancer are the most aggressive forms of breast cancer, accounting for 20% and 10% of cancer-related deaths, respectively. Among IBC cases, 30% are additionally classified with TNBC molecular pathology, a diagnosis that significantly worsens patient’s prognosis. The current lack of TNBC and IBC molecular understanding prevents the development of effective therapeutic strategies. To identify effective treatments, we explored aberrant apoptosis pathways and cell membrane fluidity as novel therapeutic targets.

We first identified an effective therapeutic strategy against TNBC and IBC by pro-apoptotic protein NOXA-mediated inhibition of the anti-apoptotic protein MCL1 following inhibition of ...


Mechanisms Underlying The Sensitivity And Resistance Of Gastric Cancer Cells To Met Inhibitors, Rebecca Schroeder Aug 2017

Mechanisms Underlying The Sensitivity And Resistance Of Gastric Cancer Cells To Met Inhibitors, Rebecca Schroeder

UT GSBS Dissertations and Theses (Open Access)

MET amplification has been clinically credentialed as a therapeutic target in gastric cancer, but the molecular mechanisms underlying sensitivity and resistance to MET inhibitors are still not well understood. Using whole-genome mRNA expression profiling, we identified autophagy as a top molecular pathway that was activated by the MET inhibitor crizotinib in drug-sensitive human gastric cancer cells, and functional studies confirmed that crizotinib increased autophagy levels in the drug sensitive cells in a concentration-dependent manner. We then used chemical and molecular approaches to inhibit autophagy in order to define its role in cell death. The clinically available inhibitor of autophagy, chloroquine ...


The Role Of The Diras Family Members In Regulating Ras Function, Cancer Growth And Autophagy, Margie Nicole Sutton May 2017

The Role Of The Diras Family Members In Regulating Ras Function, Cancer Growth And Autophagy, Margie Nicole Sutton

UT GSBS Dissertations and Theses (Open Access)

DIRAS3 is a maternally imprinted tumor suppressor gene that is downregulated by multiple mechanisms across several tumor types. When re-expressed, DIRAS3 decreases proliferation, inhibits motility, and induces autophagy and tumor dormancy. DIRAS3 encodes a 26 kDa small GTPase with 60% homology to Ras and Rap, differing from oncogenic Ras family members by a 34-amino acid N-terminal extension that is required for its tumor suppressive function in ovarian cancer. By assessing the structure-function relationship, I found that DIRAS3 inhibits Ras-induced transformation and is a natural antagonist of Ras/MAPK signaling. DIRAS3 binds directly to Ras and disrupts cluster formation inhibiting the ...


Microenvironment-Induced Pten Loss By Exosomal Microrna Primes Brain Metastasis Outgrowth, Lin Zhang Dec 2016

Microenvironment-Induced Pten Loss By Exosomal Microrna Primes Brain Metastasis Outgrowth, Lin Zhang

UT GSBS Dissertations and Theses (Open Access)

Development of life-threatening cancer metastases at distant organs requires disseminated tumor cells’ adaptation to and co-evolution with the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interplay between metastatic tumor cells and extrinsic signals at individual metastatic organ sites critically impacts the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumor cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that primary tumor cells with normal expression of PTEN, an important ...


Regulation Of Breast Cancer Initiation And Progression By 14-3-3zeta, Chia-Chi Chang Aug 2016

Regulation Of Breast Cancer Initiation And Progression By 14-3-3zeta, Chia-Chi Chang

UT GSBS Dissertations and Theses (Open Access)

14-3-3ζ is a ubiquitously expressed family member of proteins that have been implicated to have oncogenic potential through its interactions and involvement in cancer initiation and progression. 14-3-3ζ belongs to the highly conserved 14-3-3ζ protein family and modulates numerous pathways in cancer. Overexpression of 14-3-3ζ is an early event, occurs in more than 40% of human breast cancer cases, and is associated with disease recurrence and poor prognosis. Metabolic reprogramming is a hallmark of cancer. Cancer cells elevate aerobic glycolysis to produce metabolic intermediates and reducing equivalents, thereby facilitating cellular adaptation to the adverse environment and sustaining fast proliferation. Interestingly ...


¬¬Define The Epigenetic Profiles And Subtype-Specific Genes Of Breast Cancer, Wenqian Li Aug 2016

¬¬Define The Epigenetic Profiles And Subtype-Specific Genes Of Breast Cancer, Wenqian Li

UT GSBS Dissertations and Theses (Open Access)

Molecular profiling has identified 5 distinct subtypes of breast cancer, luminal A, luminal B, HER2-enriched, basal-like, and claudin-low breast cancer. These 5 subtypes correlate with hormone response, patient prognosis, and response to therapy. Although steady state gene expression patterns have been explored using expression microarrays, very little is known about the initial, disease-driving transcriptional changes in these cancers or epigenetic changes associated with the differential gene expression signatures. Defining these changes may provide new insights into the mechanisms by which these subtypes arise, as well as new avenues for breast cancer prevention, diagnosis, and treatment. Using Chromatin Immunoprecipitation sequencing and ...


Defining The Functions Of Usp22 And Usp44 In Regulation Of H2bub1 Levels, Xianjiang Lan Aug 2016

Defining The Functions Of Usp22 And Usp44 In Regulation Of H2bub1 Levels, Xianjiang Lan

UT GSBS Dissertations and Theses (Open Access)

Aberrant levels of histone ubiquitination are involved in various human diseases including neurodegenerative disorders and cancers. Particularly, Histone H2B monoubiquitination (H2Bub1) is highly associated with gene regulation in both normal cells and diseases. Many deubiquitinases (mainly USPs) are defined to regulate global H2Bub1 levels. However, how these USPs are regulated and how they contribute to diseases are not well understood.

USP22, part of the deubiquitination module (DUBm) in the SAGA complex, is a well-defined regulator of H2Bub1 levels. ATXN7, another crucial subunit of the SAGA DUBm, is involved in a neurodegenerative disease, spinocerebellar ataxia type 7 (SCA7), due to a ...


Novel Mechanisms Of Β-Adrenergic Signaling In Prostate Cancer Progression, Mohit Hulsurkar Aug 2016

Novel Mechanisms Of Β-Adrenergic Signaling In Prostate Cancer Progression, Mohit Hulsurkar

UT GSBS Dissertations and Theses (Open Access)

Prostate cancer is the second leading cause of cancer death among American men. The American Cancer Society estimates that 180,890 men will be will be diagnosed with prostate cancer in 2016 in the USA. (http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics). Androgen deprivation therapy (ADT) is the standard treatment for early stage prostate cancer. But most patients relapse with aggressive variants of prostate cancer, with survival time between 1-3 years. In order to develop cure for such aggressive variants of prostate cancer, our present understanding of the mechanisms underlying its progression needs to be advanced.

Recently, it has ...


The Roles Of Malt1 In Nf-Κb Activation And Solid Tumor Progression, Deng Pan May 2016

The Roles Of Malt1 In Nf-Κb Activation And Solid Tumor Progression, Deng Pan

UT GSBS Dissertations and Theses (Open Access)

The transcription factor NF-κB plays a central role in many aspects of biological processes and diseases, such as inflammation and cancer. Although it has been suggested thatNF-κB is critical in tumorigenesis and tumor progression, the molecular mechanism by which NF-κB is activated in solid tumor remains largely unknown. In the current work, we focus on growth factor receptor-induced NF-κB activation and tumor progression, including epidermal growth factor receptor (EGFR)-induced NF-κB in lung cancer and heregulin receptor (HER2)-induced NF-κB in breast cancer. We found that Mucosa-associated lymphoma translocation protein 1 (MALT1), also known as paracaspase, is required for EGFR-induced ...


Characterization Of Stem Cell Turnover In A Living Epithelial Bilayer, Elizabeth Sumner May 2016

Characterization Of Stem Cell Turnover In A Living Epithelial Bilayer, Elizabeth Sumner

UT GSBS Dissertations and Theses (Open Access)

Homeostatic maintenance of epithelia requires the renewal and replacement of old or dying cells while sustaining a functional barrier. Imbalance between cell production and elimination are hypothesized to underlie many pathological conditions. However, our knowledge of cell turnover within living tissues remains largely restricted to static images due to the limited ability to study epithelia in their native context. Here we report that clearance of damaged basal stem cells promotes compensatory proliferation of neighboring stem cells to maintain overall population numbers in a bilayered epithelium. Time-lapse imaging and electron microscopy experiments reveal that dying cells are rapidly cleared as nearby ...


Trim24 Orchestrates Metabolic Reprogramming And Emt In Breast Cancer, Kaushik Thakkar May 2016

Trim24 Orchestrates Metabolic Reprogramming And Emt In Breast Cancer, Kaushik Thakkar

UT GSBS Dissertations and Theses (Open Access)

In this dissertation, I report the oncogenic functions of an epigenetic regulator Tripartite Motif Protein 24 (TRIM24) coupled with metabolic reprogramming and epithelial mesenchymal transition (EMT) in breast cancer. TRIM24 was first established by our laboratory as a previously unknown negative regulator of p53 via its RING domain, as a co-regulator of nuclear receptors and a PHD/Bromodomain reader of specific histone modifications. TRIM24 expression correlates with poor prognosis of breast cancer, but the mechanisms of TRIM24-mediated oncogenesis are unknown. In the first part of my thesis, I found that TRIM24 is aberrantly expressed in early stages of breast cancer ...


In Vivo Kinome Screen Reveals Non-Canonical Cdk-Driven Metabolic Adaptation In Brain Metastasis, Frank J. Lowery Iii May 2016

In Vivo Kinome Screen Reveals Non-Canonical Cdk-Driven Metabolic Adaptation In Brain Metastasis, Frank J. Lowery Iii

UT GSBS Dissertations and Theses (Open Access)

Brain metastasis, which frequently arises from breast cancer, lung cancer, melanoma, and colorectal cancer, remains a severely unmet medical need and its incidence continues to rise while treatment options remain palliative. To better understand the biology underlying its aggressive, incurable nature, I performed an unbiased in vivo kinome screen to identify potential driver kinases of experimental brain metastasis in a nude xenograft model using the human breast cancer cell line MDA-MB-231. Several of the kinase pools led to decreased brain metastasis-specific survival in nude mice, shortening survival time by up to 50% relative to controls. Targeted next-generation sequencing (NGS) was ...


The Tumor Suppressor Notch Inhibits Head And Neck Squamous Cell Carcinoma (Hnscc) Tumor Growth And Progression By Modulating Proto-Oncogenes Axl And Ctnnal1 (Α-Catulin), Shhyam Moorthy, Shhyam Moorthy Dec 2015

The Tumor Suppressor Notch Inhibits Head And Neck Squamous Cell Carcinoma (Hnscc) Tumor Growth And Progression By Modulating Proto-Oncogenes Axl And Ctnnal1 (Α-Catulin), Shhyam Moorthy, Shhyam Moorthy

UT GSBS Dissertations and Theses (Open Access)

Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common malignancy worldwide, with roughly 300,000 cancer related deaths occurring globally each year. The survival of patients with HNSCC has not changed significantly over the past decade, leading investigators to search for promising molecular targets. To identify new treatment targets and biomarkers that could better guide therapy, we previously characterized the genomic alterations from primary HNSCC patient samples. We were among the first to discover that NOTCH1 is one of the most frequently mutated genes in this cancer type. The spectrum of inactivating NOTCH1 mutations in HNSCC ...


Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd Dec 2015

Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd

UT GSBS Dissertations and Theses (Open Access)

Normal Glycolytic Enzyme Activity is Critical for Hypoxia Inducible Factor-1α Activity and Provides Novel Targets for Inhibiting Tumor Growth

By Geoffrey Grandjean

Advisory Professor: Garth Powis, D. Phil

Unique to proliferating cancer cells is the observation that their increased need for energy is provided by a high rate of glycolysis followed by lactic acid fermentation in a process known as the Warburg Effect, a process many times less efficient than oxidative phosphorylation employed by normal cells to satisfy a similar energy demand [1]. This high rate of glycolysis occurs regardless of the concentration of oxygen in the cell and is ...


Direct Regulation Of Apoptosis By Linear Ubiqutin Chain Assembly Complex (Lubac) And Feedback Regulation Of Lubac Function By Caspases, Donghyun Joo Aug 2015

Direct Regulation Of Apoptosis By Linear Ubiqutin Chain Assembly Complex (Lubac) And Feedback Regulation Of Lubac Function By Caspases, Donghyun Joo

UT GSBS Dissertations and Theses (Open Access)

Tumor Necrosis Factor-alpha (TNF-α) is a cytokine that plays a role in various cellular processes such as proliferation, differentiation (mainly through NF-κB signaling) and death (via apoptosis signaling). Recently, linear ubiquitination by LUBAC (linear ubiquitin chain assembly complex) was reported to have a regulatory function in TNF-α mediated NF-κB activation. Although LUBAC is suggested to control not only NF-kB signaling but also the apoptosis pathway, the precise mechanism of apoptosis regulation remains unknown. Moreover, NF-κB and apoptosis pathways have opposed but fundamental functions for various cellular processes. Although these two pathways actively interplay to balance the death and survival, the ...


Understanding The Role Of Sumoylation In Regulating Lkb1 Function, Joan W. Ritho May 2015

Understanding The Role Of Sumoylation In Regulating Lkb1 Function, Joan W. Ritho

UT GSBS Dissertations and Theses (Open Access)

Energy homeostasis in a cell is critical for its survival during metabolic stress. Liver kinase B1 (LKB1), one of the key regulators of cellular energy balance, was initially discovered as a tumor suppressor mutated in patients with Peutz-Jeghers syndrome. Germline mutations in LKB1 predispose patients to develop several benign and malignant tumors including gastrointestinal and lung cancers. In 2003, several groups demonstrated that LKB1is a major upstream kinase of the energy sensor AMP-activated protein kinase (AMPK), directly associating it with the regulation of energy balance in cells. During energy stress, LKB1 phosphorylates AMPK at threonine 172 (T172) resulting in AMPK ...


Regulation Of Cell Adhesion By The Ferm Proteins, Ptpn14 And Merlin, Patty Dimarco Hewitt May 2015

Regulation Of Cell Adhesion By The Ferm Proteins, Ptpn14 And Merlin, Patty Dimarco Hewitt

UT GSBS Dissertations and Theses (Open Access)

Cell-cell adhesion is critical for the control of tissue organization and homeostasis. A family of proteins that regulate cell-cell adhesions is the FERM (4.1 protein, Ezrin, Radixin, Moesin) domain-containing proteins.One FERM domain protein, the non-receptor tyrosine phosphatase PTPN14, is mutated or deleted in several human cancers suggesting that it may be involved in tumor development and/or progression. Additionally, the loss of the FERM domain protein Merlin is associated with tumor development and metastasis.Both PTPN14 and Merlin have been shown to localize and possibly regulate adherens junction (AJ) functions. This work sought to determine ...


Igfbp2 Potentiates Egfr-Stat3 Signaling In Glioma, Yingxuan Chua May 2015

Igfbp2 Potentiates Egfr-Stat3 Signaling In Glioma, Yingxuan Chua

UT GSBS Dissertations and Theses (Open Access)

Gliomas are clinically challenging brain tumors with dismal survival rates due to its infiltrative nature and ineffective standard therapy. Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogenic protein that has both extracellular and intracellular functions. Despite a clear causal role in cancer development, the contributions of intracellular IGFBP2 to tumor development and progression are poorly understood. Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of EGFR, which subsequently activates STAT3 signaling. Furthermore, we demonstrate that IGFBP2 augments the nuclear accumulation of EGFR to potentiate STAT3 transactivation activities, via ...


Dna Polymerase Θ (Polq) And The Cellular Defense Against Dna Damage, Matthew J. Yousefzadeh May 2015

Dna Polymerase Θ (Polq) And The Cellular Defense Against Dna Damage, Matthew J. Yousefzadeh

UT GSBS Dissertations and Theses (Open Access)

In mammalian cells, DNA polymerase θ (POLQ) is an unusual specialized DNA polymerase whose in vivo function is under active investigation. The protein is comprised of an N-terminal helicase-like domain, a C-terminal DNA polymerase domain, and a large central domain that spans between the two. This arrangement is also found in the Drosophila Mus308 protein, which helps confer resistance to DNA interstrand crosslinking agents. Homologs of POLQ and Mus308 are found in eukaryotes, including plants, but a comparison of phenotypes suggests that not all of these genes are functional orthologs. Flies with defective Mus308 are sensitive to DNA interstrand crosslinking ...


Mdm2-Mediated Degradation Of Sirt6 Phosphorylated By Akt1 Promotes Tumorigenesis And Trastuzumab Resistance In Breast Cancer, Umadevi Thirumurthi Dec 2014

Mdm2-Mediated Degradation Of Sirt6 Phosphorylated By Akt1 Promotes Tumorigenesis And Trastuzumab Resistance In Breast Cancer, Umadevi Thirumurthi

UT GSBS Dissertations and Theses (Open Access)

Sirtuin6 (SIRT6) is one of the members of the Sirtuin family and functions as a longevity assurance gene by promoting genomic stability. It also regulates various cancer-associated pathways and was recently established as a bonafide tumor suppressor in colon cancer. This suggests that SIRT6 is an attractive target for pharmacological activation in cancer treatment, and hence, identification of potential regulators of SIRT6 would be an important and critical contribution towards cancer treatment. Here, we show that AKT1 phosphorylates SIRT6 at Ser338 and induces MDM2-SIRT6 interaction, priming SIRT6 for degradation via the MDM2-dependent ubiquitin-proteasome pathway. Blocking SIRT6 Ser338 phosphorylation ...


Novel Posttranslational Modification In Lkb1 Activation And Function, Szu-Wei Lee Dec 2014

Novel Posttranslational Modification In Lkb1 Activation And Function, Szu-Wei Lee

UT GSBS Dissertations and Theses (Open Access)

Cancer cells display dramatic alterations in cellular metabolism to meet their needs of increased growth and proliferation. In the last decade, cancer research has brought these pathways into focus, and one emerging issue that has come to attention is that many oncogenes and tumor-suppressors are intimately linked to metabolic regulation (Jones and Thompson, 2009). One of the key tumor-suppressors involved in metabolism is Liver Kinase B1 (LKB1). LKB1 is the major upstream kinase of the evolutionarily conserved metabolic sensor—AMP-activated protein kinase (AMPK). Activation of the LKB1/AMPK pathway provides a survival advantage for cells under energy stress. LKB1 forms ...


Lkb1 Deficient Non-Small Cell Lung Cancer Cells Are Vulnerable To Energy Stress Induced By Atp Depletion, Chao Yang Dec 2014

Lkb1 Deficient Non-Small Cell Lung Cancer Cells Are Vulnerable To Energy Stress Induced By Atp Depletion, Chao Yang

UT GSBS Dissertations and Theses (Open Access)

Lung cancer is the second most frequent cancer in United States, which represents about 13.5% of new cancer cases every year. It accounts for about 27.2% of all cancer related deaths, which is more than the sum of deaths caused by prancretic, breast and colorectal. On average, only about 16% of lung cancer patients survive beyond 5 years. LKB1 is the third most mutated gene in lung cancer. It has been shown that LKB1 is mutated in at least 15% to 30% of NSCLC. Tumor with LKB1 mutation is associated with poor differentiation, high metastasis and worse response ...


Egfr Modulates Microrna Maturation In Response To Hypoxia Through Phosphorylation Of Argonaute2, Jia Shen Aug 2014

Egfr Modulates Microrna Maturation In Response To Hypoxia Through Phosphorylation Of Argonaute2, Jia Shen

UT GSBS Dissertations and Theses (Open Access)

MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at posttranscriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in regulatory roles to cope with a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumor. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumor cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here, we show that EGFR ...


Strategies To Sensitize Bladder Cancer Cells To Small Molecule Inhibitors Targeting The Pi3k Pathway, Giovanni Nitti Aug 2014

Strategies To Sensitize Bladder Cancer Cells To Small Molecule Inhibitors Targeting The Pi3k Pathway, Giovanni Nitti

UT GSBS Dissertations and Theses (Open Access)

After many years of cancer research, it is well accepted by the scientific community that the future cure for this disease lies in a personalized therapeutic approach. Anticipating therapeutic outcome based on the genetic signature of a tumor has become the new paradigm. The PI3K pathway represents an ideal target for bladder cancer, as many of the key proteins of this pathway are altered or mutated in this particular type of cancer. Several small molecule inhibitors have been developed to target this pathway, but their efficacy has been shown to be heterogeneous among different cell lines and mostly cytostatic but ...


Brit1/Mcph1 Mediates The Dna Damage Response By Inducing P53 Stability And Promoting Atr Signaling, Edward Wang Aug 2014

Brit1/Mcph1 Mediates The Dna Damage Response By Inducing P53 Stability And Promoting Atr Signaling, Edward Wang

UT GSBS Dissertations and Theses (Open Access)

The BRCT-repeat inhibitor of hTERT (BRIT1)/MCPH1 protein promotes the process of homologous recombination (HR) to repair DNA double strand breaks (DSBs). In response to DSBs, BRIT1 foci form at damaged sites, and recruits downstream repair proteins including 53BP1, MDC1, NBS1, and the SWI/SNF complex to the DSB region to promote DNA repair. BRIT1 copy number deficiency correlates with increased genomic instability in ovarian cancer specimens and breast cancer cell lines. Here, we propose that additional functions of BRIT1 include a direct interaction with the p53 tumor suppressor protein to promote p53 stability, and binding and recruitment of TopBP1 ...


The Role Of K63-Linked Ubiquitination Cycles In Akt Kinase Activation, Wei-Lei Yang Aug 2013

The Role Of K63-Linked Ubiquitination Cycles In Akt Kinase Activation, Wei-Lei Yang

UT GSBS Dissertations and Theses (Open Access)

Akt (also known as protein kinase B) serves a central regulator in PI3K/Akt signaling pathways to regulate numerous physiological functions including cell proliferation, survival and metabolism. Akt activation requires the binding of Akt to phospholipid PIP3 on the plasma membrane and subsequent phosphorylation of Akt by its kinases. Growth factor-mediated membrane recruitment of Akt is a crucial step for Akt activation. However, the mechanism of Akt membrane translocation is unclear. Protein ubiquitination is a significant posttranslational modification that controls many biological functions such as protein trafficking and signaling activation. Therefore, we hypothesize that ubiquitination may be involved in Akt ...


Characterization Of Jak, Stat, And Src Interactions In Head And Neck Squamous Cell Carcinoma, Reshma Jaseja, Reshma Jaseja Aug 2013

Characterization Of Jak, Stat, And Src Interactions In Head And Neck Squamous Cell Carcinoma, Reshma Jaseja, Reshma Jaseja

UT GSBS Dissertations and Theses (Open Access)

Recurrence of Head and Neck Squamous Cell Carcinoma (HNSCC) is common; thus, it is essential to improve the effectiveness and reduce toxicity of current treatments. Proteins in the Src/Jak/STAT pathway represent potential therapeutic targets, as this pathway is hyperactive in HNSCC and it has roles in cell migration, metastasis, proliferation, survival, and angiogenesis. During short-term Src inhibition, Janus kinase (Jak) 2, and signal transducer and activator of transcription (STAT) 3 and STAT5 are dephosphorylated and inactivated. Following sustained Src inhibition, STAT5 remains inactive, but Jak2 and STAT3 are reactivated following their early inhibition. To further characterize the mechanism ...