Research Interests

My research focus is to understand the roles of oncogenic steroid receptor coactivators and their molecular targets in the development and progression of cancer and to identify the molecular mechanisms underpinning their biological activities and functions.

Research Program

Steroid receptors coactivators (SRCs) play a critical role in normal physiological development and are shown to be bona fide oncogenes involved in various types of human cancer. Progression of cancer is a multistep process that requires changes of intrinsic cellular functions and interaction of cancerous cells with the microenvironment. To fully understand the mechanisms by which SRCs contribute to the development and progression of cancer, we identified several molecular targets of SRCs, including a pro-inflammatory cytokine macrophage migration inhibitory factor (MIF). Our current study showed that MIF is an oncogenic cytokine that promotes cell migration/invasion, epithelial-mesenchymal transition (EMT) and may coordinate energy metabolism in favor of proliferation and survival of cancer cells while under stress. The following directions have been undertaken to elucidate the molecular mechanisms by which MIF regulates tumorigenesis and to understand how MIF contributes to the aggressive phenotypes of cancer.

(a) Cellular membrane signaling pathways. MIF, by binding to cellular membrane receptor, may initiate signaling pathways required for the tumorigenic function of MIF. Work in this direction includes elucidation of pathways activated by MIF and investigations of how post-translational modifications regulate signals emanated from the cellular membrane are being transduced to the downstream targets.

(b) Nuclear targets of membrane signaling pathways. The consequence of membrane signalings often cumulates in the nucleus and manifests in the form of transcriptional activation/suppression of important genes. Identification of these genes will provide a better knowledge into the tumorigenic function of MIF signaling. Understanding how these genes are regulated by MIF signaling represents potential molecular targets for medical interventions.

(c) Biological validation. Activation and inhibition of MIF signaling will be carried out to functionally validate the role of MIF in cancer development and progression using cell culture and animal models.

Selected Publications

• Xu J., Wu R.C., O’Malley BW. Normal and cancer-related functions of the p160 steroid receptor coactivator (SRC) family. Nature Reviews Cancer. 9:615-630, 2009.
• Wu R.C., Feng Q., Lonard D.M. and O’Malley B.W. SRC-3 coactivator functional lifetime is regulated by a phospho-dependent ubiquitin time clock. Cell 129:1125-1140, 2007.
• Wu R.C., Smith C.L., O’Malley B.W. Transcriptional regulation by steroid receptor coactivator phosphorylation. Endocrine Reviews 26:393-399, 2005.
• Wu R.C., Qin J., Yi P., Wong J., Tsai S. Y., Tsai M.-J., and O’Malley B.W. Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic responses to multiple cellular signaling pathways. Mol. Cell. 15: 937-949, 2004.
• Wu R.C., Qin J., Hashimoto Y., Wong J., Xu J., Tsai S.Y., Tsai M.-J., O'Malley B.W. Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase. Mol. Cell. Biol. 10:3549-3561, 2002.