The tumor suppressor p53 has multiple functions in cells, including an ability to induce cell cycle arrest in essentially all types of cells and to trigger apoptosis in some cellular contexts. One mechanism of p53- induced G1 arrest involves expression of p21 Waf1, which binds and inhibits active Cdk2/Cyclin complexes. However, recent evidence suggests the existence of an alternative p21Waf1-independent pathway through which p53 can suppress cell proliferation. We have discovered a novel pathway for p53-induced beta-Catenin degradation involving Siah and Ebi, a F-box protein which binds beta-Catenin (Matsuzawa & Reed. Mol Cell 7:915,2001). A series of protein interactions link genotoxic injury to destruction of b-Catenin, thus reducing activity of b-Catenin-binding Tcf/LEF transcription factors and potentially contributing to cell cycle arrest in a p53-dependent manner. The goal of this proposal is to test the hypothesis that this novel pathway for controlling beta-Catenin degradation is operative in vivo and that it plays an important role in genotoxic injury responses. Accordingly, knock-out mice have been generated which lack SIP, a protein we identified that bridges p53-inducible Siam to downstream proteins targeting beta-Catenin for ubiquitination and proteasome dependent degradation. Our goals are to study these mice and cells derived from them for addressing questions about the biological significance and molecular mechanisms of this pathway which links p53 to b-Catenin degradation. The results obtained could suggest new strategies for restoring tumor suppressive pathways lost in cancers that have suffered p53 inactivation.
| Yanagi, Teruki; Krajewska, Maryla; Matsuzawa, Shu-ichi et al. (2014) PCTAIRE1 phosphorylates p27 and regulates mitosis in cancer cells. Cancer Res 74:5795-807 |
| Nagano, Yoshito; Fukushima, Toru; Okemoto, Kazuo et al. (2011) Siah1/SIP regulates p27(kip1) stability and cell migration under metabolic stress. Cell Cycle 10:2592-602 |
| Fukushima, Toru; Zapata, Juan M; Singha, Netai C et al. (2006) Critical function for SIP, a ubiquitin E3 ligase component of the beta-catenin degradation pathway, for thymocyte development and G1 checkpoint. Immunity 24:29-39 |
