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Investigating Checkpoint Kinases 1/2 As Novel Therapeutic Targets In Head And Neck Squamous Cell Carcinoma, Mayur Arvind Gadhikar

Dissertations & Theses (Open Access)

Cisplatin, despite being the cornerstone chemotherapy for the treatment of head and neck squamous cell carcinoma (HNSCC), provides clinical benefits in just a subset of patients. This together with the lack of biomarkers predicting therapeutic responses, have led to unacceptably high rate of treatment failures in HNSCC. TP53 is the most frequently mutated gene in HNSCC, and the effect of p53 loss or mutation on cisplatin responses in HNSCC is poorly understood. In the current study, we hypothesized that HNSCC cells respond to cisplatin in a p53 dependent manner and unambiguously show that presence of wild-type TP53 (wtp53) confers sensitivity …

Reactive Oxygen Species And P21 Waf1/Cip1 Are Both Essential For, Alison Fitzgerald

Dissertations & Theses (Open Access)

Treatment of Head and Neck Squamous Cell Carcinoma, HNSCC, often requires multimodal therapy, including radiation therapy. The efficacy of radiotherapy in controlling locoregional recurrence, the most frequent cause of death from HNSCC, is critically important for patient survival. One potential biomarker to determine radioresistance is TP53, whose alterations are predictive of poor radiation response. The following work shows that the p53 transcriptional target, p21, is crucial in initiating and maintaining senescence in HNSCC, through its ability to regulate reactive oxygen species (ROS). With the use of a novel system to evaluate the impact of the TP53 missense mutations, we …

Targeting The Mdm2-P53 Axis For The Treatment Of Dedifferentiated Liposarcoma, Katelynn Bill

Dissertations & Theses (Open Access)

Dedifferentiated liposarcoma (DDLPS) is an aggressive malignancy characterized by a high rate of recurrence and dismal patient outcome. Minimal improvement in patient survival has been made in the last several decades, highlighting the crucial need for improved therapeutic strategies. A better understanding of the molecular deregulations underlying DDLPS would facilitate the discovery of improved therapeutic approaches. MDM2 is a well characterized oncoprotein and the most known negative regulator of p53. MDM2 amplification is considered the “hallmark” of DDLPS. Additionally, these tumors are known to harbor wild-type p53. We sought to take advantage of this knowledge and evaluate the role of …

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

Dissertations & 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 to sites …

P53 Maintains Hepatic Cell Identity During Liver Regeneration, Zeynep Hande Coban Akdemir

Dissertations & Theses (Open Access)

p53 MAINTAINS HEPATIC CELL IDENTITY DURING LIVER REGENERATION

Zeynep Hande Coban Akdemir, B.S.,M.A.

Advisory Professor: Michelle Craig Barton, Ph.D.

p53 is a tumor suppressor that has been well studied in tumor-derived, cultured cells. However, its functions in normal proliferating cells and tissues are generally overlooked. We propose that p53 functions during the G1-S transition can be studied in normal, differentiated cells during surgery-induced liver regeneration. Two-thirds partial hepatectomy (PH) of mouse liver offers a unique model to compare p53 functions in regenerating versus sham (control) cells. My hypothesis is that intersection of global expression analyses (microarray and RNA sequencing) and …