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Disease-oriented Research

Cell Migration and Cancer Metastasis

Uncontrolled migration of cells is associated with a host of human diseases, notably metastatic cancer. It has been shown that the Rho family of small GTPases, including RhoA, Rac1 and Cdc42, plays a pivotal role in cell migration by orchestrating the necessary cytoskeletal changes. To initiate directional cell movement, Rho GTPases require activation in a spatiotemporal manner. How the Rho GTPases are activated in a spatially-confined manner to initiate cell migration in response to extracellular stimulus is poorly understood. We found that Deleted in Liver Cancer 1 (DLC1) plays an important role in EGF/PDGF-driven epithelial cell migration by regulating the spatiotemporal activation of RhoA. The spatiotemporal activation of RhoA and Rac1 is also controlled by the dynamic phosphorylation of additional motility regulatory proteins that include the Tensin family and related proteins. We are carrying out studies to define the underlying mechanism of directional cell migration using a combination of biochemical, cell biology and proteomic approaches. These studies are, in turn, suggesting novel strategies of intervention for metastatic epithelial cancers.

DNA Repair, p53 and Drug Resistance

The effectiveness of chemotherapy is dependent on the apoptosis of cancer cells under cytotoxic stress, a process in which the tumor suppressor p53 plays an important role. Deletion or mutation of p53 often confers chemoresistance whereas expression of p53 is associated with chemosensitivity. The cellular level of p53 is controlled by Numb, a protein often down-regulated in breast cancer. Numb forms a complex with p53 and the E3 ligase HDM2, and thereby protecting p53 from HDM2-mediated ubiquitination and subsequent degradation. Loss of Numb in breast tumors leads to decreased p53 activity, increased activation of the oncogene Notch, and chemoresistance. We have recently shown that Numb is lysine methylated by the methyltransferase Set8 and that methylated Numb no longer binds to p53 and that methylated Numb no longer binds to p53 and protects it from degradation. We propose that the Set8-Numb-p53/Notch signaling pathway plays a critical role in sensitizing breast cancer cells to chemotherapy-induced apoptosis and that it represents an attractive therapeutic target. Studies are undertaken in the lab to characterize inhibitors that target the Set8-Numb-p53 signaling pathway and to identify additional signaling pathways, such as those involved in DNA damage repair (DDR) and kinase network-rewiring that convey therapeutic resistance.