Abstract 1353: Protein tyrosine phosphatases PTP-1B, SHP-2 and PTEN facilitate Rb/E2F-associated apoptotic signaling

Abstract

Abstract To maintain tissue homeostasis, apoptosis is functionally linked to cell proliferation via the retinoblastoma tumor suppressor (Rb)/E2F complex. Rb/E2F-associated apoptosis is a robust apoptotic response initiated by loss of constitutive Rb/E2F transcriptional repression and mediated by caspase-8. It is characterized by inactivation of focal adhesion kinase (FAK) through dephosphorylation by protein tyrosine phosphatase(s). In the current work, we report that three protein tyrosine phosphatases, PTP-1B, SHP-2, and PTEN, are involved in Rb/E2F-associated apoptosis. Induction of apoptosis in an osteoscarcoma cell line that conditionally expresses a dominant negative mutant of E2F-1 (ER-dnE2F-1) by treatment with 4-hydroxytamoxifen (4-OHT) led to a significant increase in levels of PTP-1B, SHP-2, and PTEN mRNA expression in comparison to untreated cells. Chromatin immunoprecipitation assays showed that E2F-1 specifically binds to putative E2F-1 binding sites identified within the three PTP promoters. Knockdown of SHP-2, PTEN, or PTP-1B using siRNA increased cell viability and decreased cell death in 4-OHT-treated ER-dnE2F-1 cells compared to control. Consistent with this observation, knockdown of SHP-2 or PTEN significantly inhibited caspase-8 activity in 4-OHT-treated ER-dnE2F1 cells in comparison to control while knockdown of SHP-2, PTEN, or PTP-1B significantly inhibited caspase-3 activity in 4-OHT-treated ER-dnE2F-1 cells compared to control. Combined, our results indicated PTP-1B, SHP-2, and PTEN are required to regulate Rb/E2F-associated apoptotic signal transduction. Furthermore, our findings suggest PTP-1B, SHP-2, and PTEN can contribute to tumor suppression through an Rb/E2F-associated mechanism. Citation Format: Liza D. Morales, Mario Capetillo, Edgar Casillas Pavon, Jun W. Shin, Alexander Garcia, Jonathan H. Lieman, Dae J. Kim. Protein tyrosine phosphatases PTP-1B, SHP-2 and PTEN facilitate Rb/E2F-associated apoptotic signaling. [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 1353. doi:10.1158/1538-7445.AM2014-1353