Contributions of PTEN to PML-IV-Mediated Cellular Senescence and Free Fatty Acid-Induced Oxidative Stress
Tumor suppressor PTEN functions differently in the cytoplasm and nucleus. Posttranslational modifications play important roles in regulating activities, functions and subcellular localizations of PTEN. Previously, our laboratory discovered that nuclear PTEN promotes acetylation of tumor suppressor p53. In the present study, we focus on contribution of nuclear PTEN to PML-IV-mediated cellular senescence and to high levels of free fatty acid (FFA)-induced oxidative stress.
PML-IV is a tumor suppressor and the major regulator of cellular senescence. We show that the C-terminal domain of PML-IV is required for induction of cellular senescence. Nuclear PTEN regulates cellular senescence via interaction with the C-terminus of PML-IV, which is essential for recruiting PTEN into PML-Nuclear Bodies (PML-NBs), enhancing p53 acetylation and inducing cellular senescence.
We also show that high FFA induces nuclear export of PTEN and down-regulates p53 acetylation and protein levels, which leads to inhibition of p53 downstream target GPx-1 and accumulation of ROS in endothelial cells. Furthermore, mTOR/S6K signaling induces phosphorylation of PTEN at Ser380, which decreases PTEN monoubiquitination, promotes PTEN nuclear export and leads to p53/GPx-1 inhibition. This study suggests that alterations of the two posttranslational modifications of PTEN caused by mTOR/S6K are responsible for oxidative stress induced by high FFA.
In summary, we show the regulation of cellular senescence by nuclear PTEN and provide a new mechanism of tumor suppression function of PTEN. We also demonstrate a novel pathway by which high levels of FFA induce oxidative stress through PTEN nuclear export and thus provide novel insight into the role of nuclear PTEN in metabolism.