This K22 career transition award will support the development of the candidate, Runzhao Li, as an independent investigator. Dr. Li is a physician with extensive cancer-related basic science training. The candidate has received a tenure track academic appointment in the Department of Pathology and Laboratory Medicine at the Medical University of South Carolina, and is pursuing an academic research career in basic cancer research with a long-term goal of studying the role of epithelial-to-mesenchymal transition (EMT) in tumor invasion and metastasis. EMT is an essential process for both embryonic development and tumor invasiveness and metastases. ETS1, an Ets transcription factor, has been shown to play a role in tumor metastases and EMT. However, little is known about how ETS1 activity is regulated during EMT. The candidate has identified and cloned several novel genes that modulate ETS1 function using genetic screens. This award focuses on one of these interacting proteins, EAPII, a negative modulator of ETS1 transcriptional activity and a potential component of signaling pathways that mediate extracellular signaling to ETS1. The short term goal of this award is to elucidate the role of EAPII in the modulation of ETS1-mediated EMT. The candidate has shown that EAPII expression inhibits cell migration, a critical step of EMT, in epithelial cancer cells. EAPII is a phosphoprotein and its phosphorylation is modulated by the EMT-inducing factor HGF. The candidate further demonstrated that PTEN, a tumor suppressor that has been shown to negatively modulate migration, directly interacts with EAPII.
Three specific aims are designed to test the central hypothesis that EAPII negatively modulates ETS1-mediated EMT through its involvement in a PTEN-EAPII-ETS1 signal transduction cascade.
Aim 1 is to define the mechanism whereby EAPII modulates ETS1 function.
Aim 2 is to elucidate the biochemical relationship between PTEN and EAPII.
And Aim 3 will determine the role of EAPII in animal models of tumorigenesis and metastasis by EAPII overexpression and by siRNA knock-down.
| Li, Chunyang; Sun, Shi-Yong; Khuri, Fadlo R et al. (2011) Pleiotropic functions of EAPII/TTRAP/TDP2: cancer development, chemoresistance and beyond. Cell Cycle 10:3274-83 |
| Li, C; Fan, S; Owonikoko, T K et al. (2011) Oncogenic role of EAPII in lung cancer development and its activation of the MAPK-ERK pathway. Oncogene 30:3802-12 |
| Higuchi, Tsukasa; Bartel, Frank O; Masuya, Masahiro et al. (2007) Thymomegaly, microsplenia, and defective homeostatic proliferation of peripheral lymphocytes in p51-Ets1 isoform-specific null mice. Mol Cell Biol 27:3353-66 |
| Adereth, Yair; Dammai, Vincent; Kose, Nurgun et al. (2005) RNA-dependent integrin alpha3 protein localization regulated by the Muscleblind-like protein MLP1. Nat Cell Biol 7:1240-7 |
| Pei, Huiping; Li, Chunyang; Adereth, Yair et al. (2005) Caspase-1 is a direct target gene of ETS1 and plays a role in ETS1-induced apoptosis. Cancer Res 65:7205-13 |
