Current data indicates that the LIM protein network, including the LIM domain containing kinase (LIMK), the LIM-only (LMO) proteins, and LIM domain binding co-factors plays an important role in the development and metastasis of cancer. However, the manner in which these proteins function in cancer, their regulation by signal transduction, and their downstream effectors remain largely unknown. A known regulator of the LIM protein network is the ubiquitin ligase RLIM. We have demonstrated that RLIM regulates the activity of the LIM domain system through both targeted protein degradation (ubiquitination) and the recruitment of transcriptional co-repressor complexes. The purpose of this proposal is to investigate the role of RLIM in the development and metastasis of cancer, and to determine the mechanisms regulating RLIM activity in cancer. The project will attempt to address this question using three approaches: 1) determining the importance of RLIM activity in cell proliferation and metastasis of human cancer cells; 2) investigating the functional importance of RLIM phosphorylation by the MAPK and LIMK signaling pathways; and finally 3) to test the importance of RLIM, and RLIM phosphorylation, in vivo using the Zebrafish model system. ? ?
| Johnsen, Steven A; Güngör, Cenap; Prenzel, Tanja et al. (2009) Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer. Cancer Res 69:128-36 |
| Tursun, Baris; Schluter, Anne; Peters, Marvin A et al. (2005) The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones. Genes Dev 19:2307-19 |
