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Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress
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Dissertation
Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress
2015
Overview
Loss of function of the phosphatase and tensin homolog (PTEN) tumor suppressor is frequently found in many human malignancies. PTEN antagonizes the Phosphatidylinositide 3-kinase (PI3K) pathway (1) by dephosphorylating the 3 position of phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] (PIP3). PIP3 serves as a second messenger whose levels in the plasma membrane are elevated following cell stimulation with growth factors, mediated by the activity of PI3Ks. Proteins containing pleckstrin homology (PH) domains physically interact with PIP3, bringing them into close proximity with other PH domain-containing proteins and facilitating further functional interactions that serve to propagate the membranous signal. Although the cytoplasmic role of PTEN in antagonizing PI3K signaling has been well studied, PTEN also resides in the nucleus, where its function remains poorly understood. Here, I demonstrate that SUMOylation (SUMO) of PTEN controls its nuclear localization. Consistent with its restricted cytoplasmic localization, a SUMO-deficient PTEN mutant is fully competent for regulating PI3K signaling. Upon exposure to genotoxic stress, SUMO-PTEN is rapidly excluded from the nucleus in an ATM-dependent manner, identifying a connection between these two major tumor suppressors. Further, ATM phosphorylated PTEN on threonine 398, and a PTEN mutant that cannot be phosphorylated at this position (PTEN T398A) resist nuclear exclusion following genotoxic stress. Judging by various readouts of the DNA damage response, cells lacking nuclear PTEN are hypersensitive to DNA damage and display impaired homologous recombination-mediated repair of double-strand DNA breaks. Moreover, unlike cells with Wt PTEN, PTEN-deficient cells are susceptible to killing by a combination of genotoxic stress and a small molecule inhibitor of PI3K both in vitro and in vivo. The synergistc effect of genotoxic stress and PI3K inhibition on PTEN-null cells is dependent on the simultaneous inhibition of both p110α and p110β isoform. Further in vivo studies revealed that effective inhibition of PI3K pathway can be achieved with a discontinuous administration schedule in order to reduce the adverse effects associated with this treatment. My findings have considerable implications for individualizing therapy for patients with PTEN-deficient tumors.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9781339358840, 1339358840
