Investigating The Roles of P63 and P73 Isoforms to Therapeutically Treat P53-Altered Cancers

<p><strong>Investigating the roles of <em>p63</em> & <em>p73</em> isoforms to therapeutically treat</strong></p> <p><strong><em>p53</em></strong><strong>-altered cancers</strong></p> <p><strong>Avinashnarayan Venkatanarayan, M.S</strong>.</p> <p><strong>Supervisory Professor: Elsa R. Flores, Ph.D</strong>.</p> <p>The <em>TP53</em> tumor suppressor is mutated in approximately 50% of human cancers rendering cancer therapies ineffective. p53 reactivation suppresses tumor formation in mice. However, this strategy has proven difficult to implement therapeutically. An alternate approach to overcome p53 loss is to manipulate the p53-family members, <em>p63</em> and <em>p73</em>, which interact and share structural similarities to p53. <em>p63</em> and <em>p73</em>, unlike <em>p53</em> are less frequently mutated and have two major isoforms with distinct functions which makes them unique targets for therapeutic intervention. The full-length acidic transactivation (TA) isoforms of <em>p63</em> and <em>p73</em> function similar to <em>p53</em>. While the deltaN (ΔN) isoforms of <em>p63</em> and <em>p73</em>, which lack the acidic transactivation domain, are overexpressed in cancers and function in a dominant negative manner against <em>p53</em>, <em>TAp63</em> and <em>TAp73</em>. As result of the opposing isoform-specific function, the roles of <em>p63</em> and <em>p73</em> in tumorigenesis requires further characterization. In an attempt to identify novel therapeutic approaches to treat p53-altered cancers by utilizing the p53-family members, I aim to delineate the roles of ΔN isoforms of <em>p63</em> and <em>p73</em> in tumorigenesis.</p> <p>I have demonstrated that deletion of ΔNp63 or ΔNp73 in p53-deficient tumors mediates tumor regression through the upregulation of tumor suppressive isoforms, <em>TAp63</em> and <em>TAp73</em>. Upon loss of ΔNp63 or ΔNp73, TAp63 and TAp73 activate <em>IAPP</em> a metabolic regulator, which induces metabolic reprogramming resulting in tumor regression in p53-deficient mice. I have shown that <em>IAPP</em>, which encodes amylin, a 37-amino acid peptide functions as a tumor suppressor in p53-deficient cancers. IAPP functions through the calcitonin and RAMP3 receptors to limit glucose uptake and reduce glycolysis in the cancer cells resulting in ROS accumulation and apoptosis. Additionally, I have also shown that use of Pramlintide, a synthetic analog of IAPP, mediates tumor regression in p53-deficient mice and apoptosis in multiple p53-mutant human cancer cell lines.</p> <p>Further, to therapeutically treat p53-deficient cancers <em>in vivo</em>, liposomal nanoparticle siRNA’s targeting ΔNp63 and ΔNp73 were administered into p53-deficient mouse thymic lymphomas, which resulted in tumor regression. Taken together, my work has defined the isoform specific functions of <em>p63</em> and <em>p73</em> in tumorigenesis. Importantly, I have also demonstrated the use of pramlintide, a diabetic drug to treat p53-altered cancers. Thus, by understanding the interplay among the p53-family members, novel therapeutic methods could be designed to treat p53-altered human cancers.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2015

Author dc:creator

• Venkatanarayan, Avinashnarayan

Contributors dc:contributor

• Dr. Elsa R. Flores
• Dr. Mong Hong Lee
• Dr. Michael J. Galko

• p53-superfamily
• p63 & p73 isoforms and functions
• cancer metabolism
• Pramlintide therapy
• Liposomal siRNA delivery
• mouse models
• Cancer Biology
• Medicine and Health Sciences
• Molecular Biology
• Molecular Genetics
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/576

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1618