Abstract 5258: PTEN levels are controlled by a nuclear transport receptor in lung cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The maintenance of PTEN protein levels is critical for tumor suppression. Yet, the ubiquitination system has been shown to affect PTEN levels both adversely through degradation, as well as positively through nuclear import, and it has remained unclear how these two processes are integrated to prevent cancer. Here we show, that a nuclear import receptor is at the heart of a failsafe system that maintains PTEN levels by mediating its nuclear transport. Loss of import receptor function not only leads to cytoplasmic PTEN accumulation but also prompts PTEN degradation through a novel component of the PTEN ubiquitination system. By testing the consequences of importin loss in vivo, we found that hypomorphic mice developed lung adenocarcinoma, which presented with aberrant cytoplasmic PTEN localization and degradation, as predicted by our in vitro findings. Since the corresponding human locus suffers frequent deletion as well as inactivating mutations in lung cancer, we propose that this import receptor is a novel tumor suppressor that antagonizes PI 3-Kinase signaling in settings with at least one intact PTEN gene. Citation Format: Muhan Chen, Tali M. Herzka, Martha E. Zeeman, Kendra S. Plafker, Matthias Minderer, Mireia Castillo-Martin, Carlos Cordon-Cardo, Scott M. Plafker, Lloyd C. Trotman. PTEN levels are controlled by a nuclear transport receptor in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5258. doi:10.1158/1538-7445.AM2013-5258