Date of Award
Doctor of Philosophy
Robert A. Kirken
Lymphocyte proliferation and differentiation is coordinated with high precision in healthy humans and is vital to maintaining a normal immune system. Imbalance of these events can result in the development of autoimmune diseases, immunodeficiencies and hematopoietic malignancies. These pathologies, specifically leukemia and lymphoma have a high incidence of relapse and mortality due to limited treatment options. Therefore, there is a critical need to characterize the signal transduction pathways and understand molecular hallmarks that mediate T cell activation in order to develop new strategies for diagnosis and treatments of these diseases.
Prohibitins (PHB1 and PHB2) have been proposed to play important roles in cancer development and disease progression. In this study we used immunoprecipitation coupled to mass spectrometry to identify new forms of PHB regulation. We report four novel interleukin 2 (IL-2) inducible phosphosites in PHB2. To elucidate the potential regulatory role of these sites we generated phosphospecific polyclonal antibodies against one key phosphoresidue Threonine-62, to characterize its function. In addition, evidence is provided for PHB1 and PHB2 upregulation in tumor cell lines and localization mainly at the mitochondria. These proteins were also upregulated during reactive oxygen species (ROS)-mediated apoptosis. Similarity, PHB1 and PHB2 protein levels were significantly higher in tumor cells isolated from leukemia and lymphoma patients and determined to mainly localize to the mitochondria, possibly to maintain mitochondria integrity, which may facilitate the energy requirements of these tumor cells. Therefore, prohibitins may serve not only as biomarkers for cancer, but also act as molecular target for therapeutic intervention in hematopoietic malignancies.
Received from ProQuest
Elisa Robles Escajeda
Robles Escajeda, Elisa, "The Prohibitin Protein Complex Promotes Mitochondrial Stabilization And Cell Survival In Hematologic Malignancies" (2017). Open Access Theses & Dissertations. 738.