Digital Commons Network^™

Novel Mechanisms Of Protein Kinase C Α Regulation And Function, Xinyue Li

Theses & Dissertations

Protein kinase Cα (PKCα) is a member of the PKC family of serine/threonine kinases, which have been implicated in regulation of many cellular processes, including cell proliferation, differentiation, survival, and transformation. A large body of evidence from the Black laboratory and others support an anti-proliferative function of PKCα in normal epithelial tissues, including the intestinal mucosa and endometrial epithelium. PKCα is also tumor suppressive in epithelial cancers, such as colorectal cancer (CRC) and endometrial cancer (EC). However, a major obstacle to harnessing the tumor suppressive functions of PKCα to benefit patients is the widespread loss of PKCα expression in tumors. …

Post-Transcriptional Control Of The Epithelial-To-Mesenchymal Transition (Emt) In Ras-Driven Colorectal Cancers, Chaitra Rao

Theses & Dissertations

Colorectal cancer (CRC) originates from epithelial cells lining the colon or rectum of the gastrointestinal tract. Most cancer deaths result from a tumor spreading to distant organs; however epithelial cells do not normally migrate from their tissue of origin. To do so, epithelial cells undergo biochemical changes allowing them to acquire behavior similar to motile mesenchymal cells termed the epithelial-to-mesenchymal transition (EMT), which contributes to tumor invasion and metastasis. Our study demonstrated that CRC cells require a molecular scaffold, Kinase Suppressor of Ras 1 (KSR1), and ERK to promote the EMT-like phenotype through the preferential translation of Epithelial Stromal Interaction …

The Role Of Histone Chaperone Fact Complex In Base Excision Repair Pathway And Its Therapeutic Potential In Colon Cancer And Medulloblastoma, Heyu Song

Theses & Dissertations

Base excision repair (BER) pathway is required for the removal of damaged bases caused by alkylation, oxidation and ring-saturation. Human apurinic/apyrimidinic endonuclease 1 (APE1) plays a central role in BER pathway. Although repair of damaged bases by recombinant APE1 has been well investigated in vitro, how APE1 gains access to damaged bases in the context of chromatin is largely unknown. A prominent member of the histone chaperone family, FACT (Facilitates Chromatin Transcription) is thought to reorganize nucleosomes through the destabilization of multiple intra-nucleosome contacts. FACT complex is composed of two polypeptides identified as SPT16 (Suppressor of Ty 16) and SSRP1 …

Functional Signature Ontology-Based Identification And Validation Of Novel Therapeutic Targets And Natural Products For The Treatment Of Cancer, Beth Neilsen

Theses & Dissertations

Multiple studies have revealed that Ras-driven tumors acquire vulnerabilities by adapting cellular mechanisms that promote uncontrolled proliferation and suppress apoptosis. Kinase Suppressor of Ras 1 (KSR1) modulates ERK activation downstream of oncogenic Ras, and knockdown of KSR1 selectively kills malignant, Ras-driven cancer cells, but does not kill immortalized, non-transformed human colon epithelial cells (HCECs). KSR1^-/- mice are fertile and phenotypically normal, but resistant to Ras-driven tumor formation suggesting KSR1 represents a vulnerability in cancer cells.

To identify additional vulnerabilities in cancer, a screening approach termed Functional Signature Ontology (FUSION) was used to screen 14,355 genes and 1,200 natural product …

Molecular Mechanisms Regulating Myc And Pgc1Β Expression In Colon Cancer, Jamie L. Mccall

Theses & Dissertations

Identification and characterization of pathways specific to tumor cell survival, but absent in normal tissues, provide opportunities to develop effective cancer therapies with reduced toxicity to the patient. Kinase suppressor of Ras 1 (KSR1) is required for the survival of colorectal cancer (CRC) cells, but dispensable in normal cells. Using KSR1 as a reference standard, we identified EPH (erythropoietin-producing hepatocellular carcinoma) receptor (EPHB4) as a KSR1 functional analog.

We show here that, like KSR1, EPHB4 is aberrantly overexpressed in human CRC cells and selectively required for their survival. Both KSR1 and EPHB4 support tumor cell survival by promoting the expression …

Lgr5 Activates Tgfβ Signaling And Suppresses Metastasis In Colon Cancer, Xiaolin Zhou

Theses & Dissertations

Metastasis is the major cause of death in colorectal cancer patients, mainly due to the ineffectiveness of current therapies once metastases begin to form. Further insight into the biology of colorectal cancer metastasis is, therefore, essential in order to gain a greater understanding of this process and ultimately to develop better cancer therapies to prevent or target metastasis. LGR5 is leucine-rich repeat containing G protein-coupled receptor (GPCR) and was discovered as a marker for proliferating adult stem cells in the small intestine. LGR5 and its homologs LGR4 and LGR6 are receptors of R-spondins (RSPOs), which are secreted agonists of canonical …