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Articles 1 - 11 of 11

Full-Text Articles in Cell Biology

Role Of The Nuclear Receptor Pparγ In Clear Cell Renal And Bladder Urotheial Carcinoma, Danielle Sanchez Jan 2019

Role Of The Nuclear Receptor Pparγ In Clear Cell Renal And Bladder Urotheial Carcinoma, Danielle Sanchez

Publicly Accessible Penn Dissertations

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) has a well-characterized role in the developmental process of adipogenesis and transcriptional regulation of lipid metabolism. However, its expression patterns and functions in various cancer subtypes are less understood. My studies investigate the role of PPARγ in two distinct cancers of the urinary tract: clear cell renal cell carcinoma (ccRCC) and bladder urothelial carcinoma (UC). In ccRCC, I hypothesized that PPARγ activity contributes to the aberrant lipid accumulation phenotype characteristic of this disease, thereby promoting tumor progression. Through ChIP-seq, I demonstrated that PPARγ and its heterodimeric DNA binding partner retinoid X receptor ...


Tumor Interferon Signaling Initiates And Sustains A Multigenic Resistance Program To Immune Checkpoint Blockade, Joseph Lawrence Benci Jan 2017

Tumor Interferon Signaling Initiates And Sustains A Multigenic Resistance Program To Immune Checkpoint Blockade, Joseph Lawrence Benci

Publicly Accessible Penn Dissertations

Therapeutic blockade of the CTLA4 and/or PD1 immune checkpoint pathways has resulted in significant anti-tumor responses in broad variety of cancer types, but resistance is common. Using mouse models of metastatic melanoma and breast cancer in combination with CRISPR/Cas9 to selectively delete genes in our tumor cells, we demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB), and to combinations such as radiation plus anti-CTLA4. Furthermore, we show that this interferon driven resistance mechanism primarily occurs in ICB resistant tumors and not in ICB responsive tumors. Persistent type II interferon signaling allows ...


Modulation Of Antitumor Immunity By The Mek Inhibitor Trametinib: Implications For Targeted Therapy Of Cancer, Michael J. Allegrezza Jan 2016

Modulation Of Antitumor Immunity By The Mek Inhibitor Trametinib: Implications For Targeted Therapy Of Cancer, Michael J. Allegrezza

Publicly Accessible Penn Dissertations

Through rational drug design, much progress has been made to develop small molecules that specifically inhibit the oncogenic signaling pathways driving malignant growth. However, the normal function of immune cells depends upon many of the same pathways inhibited by such targeted cancer therapies. Because the immune system can influence the growth of many cancers, I hypothesized that most small molecule inhibitors would have activity on leukocytes relevant in cancer, and this activity would contribute to their antitumor mechanisms. In order to test this hypothesis, I first screened a panel of over 40 small molecule inhibitors for their activity on proliferating ...


Estrogens Impair Antitumor Immunity By Promoting The Accumulation Of Myeloid-Derived Suppressor Cells, Nikolaos Svoronos Jan 2016

Estrogens Impair Antitumor Immunity By Promoting The Accumulation Of Myeloid-Derived Suppressor Cells, Nikolaos Svoronos

Publicly Accessible Penn Dissertations

Estrogens are pleiotropic steroid hormones with pro- and anti-inflammatory effects that influence autoimmune disease and pregnancy. Both autoimmunity and pregnancy are similar to cancer with regard to the immune system. In established tumors, as is the case in autoimmune disease and pregnancy, the host is exposed to self or allogeneic antigens, which are capable of eliciting immune responses. However, for pregnancies to remain viable, autoimmune disease patients survive, and tumors to persist, the immune system must be at least partially tolerized to these challenges. Therefore, I hypothesize that, just as they appear to influence pregnancy and autoimmunity, estrogens’ ability to ...


Interplay Between P53 And Epigenetic Pathways In Cancer, Jiajun Zhu Jan 2016

Interplay Between P53 And Epigenetic Pathways In Cancer, Jiajun Zhu

Publicly Accessible Penn Dissertations

The human TP53 gene encodes the most potent tumor suppressor protein p53. More than half of all human cancers contain mutations in the TP53 gene, while the majority of the remaining cases involve other mechanisms to inactivate wild-type p53 function. In the first part of my dissertation research, I have explored the mechanism of suppressed wild-type p53 activity in teratocarcinoma. In the teratocarcinoma cell line NTera2, we show that wild-type p53 is mono-methylated at Lysine 370 and Lysine 382. These post-translational modifications contribute to the compromised tumor suppressive activity of p53 despite a high level of wild-type protein in NTera2 ...


Proliferation And Survival Mechanisms In Soft Tissue Sarcoma And Glioblastoma Tumors, Vera Mucaj Jan 2014

Proliferation And Survival Mechanisms In Soft Tissue Sarcoma And Glioblastoma Tumors, Vera Mucaj

Publicly Accessible Penn Dissertations

Soft tissue sarcomas and glioblastomas are two deadly tumors that are characterized by aggressive overproliferation, and regions of severe intratumoral nutrient and oxygen deprivation. The mechanisms by which tumors evade proliferation control signals and survive in a hostile microenvironment are active areas of investigation. This work describes two projects investigating loss of proliferation control in soft tissue sarcoma, as a result of Hippo pathway deregulation, and mechanisms of survival under stress in glioblastoma, as a result of decreased microRNA-124 (miR-124) levels. First, we demonstrate that the Hippo pathway is deregulated in soft tissue sarcoma patient samples, leading to overexpression of ...


Regulation Of Cell Signaling By Mig6 And Sprouty2 In Cancers With Egfr Mutations, Alice Macdonald Walsh Jan 2014

Regulation Of Cell Signaling By Mig6 And Sprouty2 In Cancers With Egfr Mutations, Alice Macdonald Walsh

Publicly Accessible Penn Dissertations

Epidermal growth factor receptor (EGFR) mutation and overexpression promote tumorigenesis in multiple cancers. Understanding the complex EGFR regulatory network is critical for developing effective therapeutic interventions. To this end, this work investigated the functions of two incompletely characterized regulators of EGFR trafficking and signaling, mitogen-inducible gene 6 (MIG6) and Sprouty2 (SPRY2), in two cancer settings where EGFR mutation is common, non-small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM). In NSCLC cells, results indicate that MIG6, an endogenous inhibitor of EGFR activity and endocytic adaptor, is surprisingly responsible for at least half of EGFR endocytosis, suggesting that a substantial fraction ...


Control Of The Tumor Suppressor P53 By Regulating Mdm2 Activity And Stability, Ruchira S. Ranaweera Jan 2013

Control Of The Tumor Suppressor P53 By Regulating Mdm2 Activity And Stability, Ruchira S. Ranaweera

Publicly Accessible Penn Dissertations

p53 is a tumor suppressor that is widely mutated or deleted in cancer cells. Mdm2, an E3 ubiquitin ligase, is the master regulator of p53. It targets p53 for proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. There are complex regulatory mechanisms balancing the activity and stability of Mdm2 in a cell. Mdm2 has an extremely short half-life in the unstressed cell and its regulation is not well understood. Like most E3 ligases, Mdm2 can autoubiquitinate. Previously, the sole function of autoubiquitination was thought to be to signal Mdm2 degradation. Here I show that ...


Epigenetic Basis For The Oncogenic Potential Of Idh Mutations, Chao Lu Jan 2013

Epigenetic Basis For The Oncogenic Potential Of Idh Mutations, Chao Lu

Publicly Accessible Penn Dissertations

Although many complex diseases including cancer manifest aberrant cellular metabolism and chromatin structure, the molecular connection between two processes remains poorly understood. The metabolite, α-ketoglurate (αKG), is a critical co-factor for a number of chromatin modifying enzymes. Its structural analogue, 2-hydroxyglutarate (2HG), was recently identified as the product of cancer-associated mutations in isocitrate dehydrogenases (IDH). To determine whether metabolic perturbation can disrupt chromatin remodeling and transcription, I investigated the epigenetic consequences of 2HG-producing IDH mutations. In this thesis, 2HG was demonstrated to be a competitive inhibitor for αKG-dependent chromatin modifiers including TET family DNA hydroxylases and jumonji-C histone demethylases. Expression ...


The Multifunctional Protein Daxx: Studies Of Its Biology And Regulation, And Discovery Of A Novel Function, Trisha Agrawal Jan 2013

The Multifunctional Protein Daxx: Studies Of Its Biology And Regulation, And Discovery Of A Novel Function, Trisha Agrawal

Publicly Accessible Penn Dissertations

Daxx, a multifunctional protein with a diverse set of proposed functions, is ubiquitously expressed and highly conserved through evolution. A primarily nuclear protein, Daxx is able to regulate apoptosis, transcription, and cellular proliferation. Despite many studies into the function of Daxx, its precise role in the cell remains enigmatic. Herein, evidence is presented to expand upon the known anti-apoptotic function of Daxx, to establish Daxx as a novel molecular chaperone, and to further its repertoire of transcriptional targets. As an apoptotic inhibitor, Daxx is known to regulate p53 by stabilizing its main negative regulator, Mdm2, via formation of a ternary ...


Hypoxic Regulation Of Myc And Epidermal Barrier Development, Waihay J. Wong Jan 2012

Hypoxic Regulation Of Myc And Epidermal Barrier Development, Waihay J. Wong

Publicly Accessible Penn Dissertations

Low O2 tension, or hypoxia,activates a complex transcriptional program via hypoxia-inducible factors (HIFs) to facilitate adaptation to low-O2 conditions. This work describes two instances of HIF activity in normal tissue development and disease progression. First, HIF is partly responsible for MYC inhibition in hypoxic human colon carcinoma cells. Hypoxic MYC down-regulation requires the E3 ubiquitin ligases FBXW7 and DDB1, as well as cytosolic cathepsins. Reduced MYC protein correlated with hypoxic inhibition of RNA polymerase III-dependent MYC target genes, suggesting that MYC suppression under hypoxia occurs independently of its binding partner MAX. MYC overexpression in hypoxic cells induced ...