Abstract LB-24: C-terminal PTEN is essential for maintenance of genomic stability and tumor suppression

Abstract

Abstract Tumor suppressor PTEN controls genomic stability and inhibits tumorigenesis. It is well established that the N-terminal phosphatase domain of PTEN dephosphorylates lipid PIP3 to PIP2, which antagonizes PI3K/AKT signaling. However, the C-terminal function of PTEN is much less defined. Here we describe a knock-in mouse model of a nonsense mutation that results in deletion of the entire Pten C-terminal region, referred to as PtenΔC. Mice heterozygous for PtenΔC develop multiple spontaneous tumors, including cancers of different origins and B cell lymphoma. We found that heterozygous deletion of the Pten C-terminal domain also causes genomic instability and common fragile site rearrangement. We found that Pten C terminal disruption induces p53 and its downstream targets, causing cell death by apoptosis. Simultaneous depletion of p53 promotes metastasis of thyroid cancer without influencing initiation of tumors, suggesting that p53 mainly suppresses tumor progression but not tumor initiation. This is the first evidence that PTEN and p53 plays distinct roles at different stages of tumor development. Our data highlight the essential role of the PTEN C-terminus in the maintenance of genomic stability and suppression of tumorigenesis. Finally, our work reveals a network of PTEN and p53 that controls cellular responses to environmental stresses. Citation Format: Wen H. Shen, Yuxin P. Yin. C-terminal PTEN is essential for maintenance of genomic stability and tumor suppression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-24. doi:10.1158/1538-7445.AM2014-LB-24