Research Interests
Our broad research interest centers on understanding the molecular basis of human carcinogenesis. Specifically, our research studies have dealt with three distinct aspects of Ras family oncogene proteins and on the discovery of novel oncogenes involved in specific human cancers. First, we are interested in deciphering the increasingly complex nature of signal transduction pathways that mediate the oncogenic actions of Ras. Ras is mutationally activated in 30% of all human cancers, with high frequencies seen in lung, colon, and pancreatic cancers. It has become quite apparent that Ras regulates a multitude of signaling pathways via its interaction with a surprisingly diverse spectrum of downstream effector targets, which include the Raf serine/threonine kinases. To date, at least a dozen distinct Ras effector targets have been identified. Whether the biology of Ras differs as a consequence of its interaction with different effectors is an important question that we are asking in our studies. How oncogenic Ras deregulates cell cycle control and promotes tumor cell invasion, metastasis, and angiogenesis is a major aspect of these studies. Our studies have focused on deregulated Ras signaling in breast, ovarian, lung, and pancreatic carcinomas, in melanomas, and in acute myelogenous leukemias.

Second, we now know that the three Ras proteins represent only a mere subset of a large superfamily of Ras-related proteins. Mammalian members of this family number more than 60, with more likely to be discovered. Since Ras-related proteins share strong sequence and biochemical similarities with Ras proteins, a logical question is whether the aberrant function of any other members of this superfamily are also oncogene proteins involved in cancer development. Much of our current interest has centered on members of the Rho family of Ras-related proteins, which function as regulators of a wide spectrum of cellular processes that include actin cytoskeletal organization, gene expression and cell cycle progression. Recent studies by us and others have revealed that quite a diverse collection of oncogene proteins (including Ras) cause transformation, in part, by deregulating the function of Rho family proteins. It is generally believed that Rho family proteins may serve as key players in promoting the invasive and malignant properties of tumor cells. How Rho proteins contribute to Ras transformation, and what signaling pathways connect Ras with Rho, are questions that we are pursuing in our studies.

Third, we are involved in drug discovery efforts to target Ras for cancer treatment. For example, we are engaged in studies to determine if farnesyltransferase inhibitors, which block Ras function by blocking its association with the plasma membrane, will be useful as anti-Ras and anti-cancer drugs. Other studies involve the ability of inhibitors of Ras signaling (e.g., Raf and MEK kinase inhibitors) to block the growth of Ras mutation positive human cancers. Finally, we have developed biological screens to search for novel oncogenes that are activated in a variety of human cancers, including carcinomas of the breast, colon, prostate and pancreas. We are using RNA isolated from tissues derived from these tumors to generate retrovirus cDNA expression libraries to screen for activated oncogenes using cell-based transformation assays. In summary, our studies span the broad range from gene discovery to drug discovery, with the long range goal of identifying better diagnostic and therapeutic approaches for cancer treatment.

Recent Accomplishments and Honors
Established the importance of aberrant Rho family GTPase activation and signaling in human oncogenesis.

Determined that Ras utilizes signaling pathways (e.g., Ral GEF and Tiam1), other than the ERK mitogen-activated protein kinase cascade, to mediate oncogenesis in human cells.

Determined that oncogenic Ras signaling is cell context dependent and that transformation of rodent versus human cells involves distinct signaling mechanisms.

Publications
Karnoub, A.E., Worthylake, D.K., Rossman, K.L., Pruitt, W.M., Campbell, S.L., Sondek, J., Der, C.J. (2001). Molecular basis for Rac1 recognition by guanine nucleotide exchange factors. Nat Struct Biol. 2001 Dec;8(12):1037-41.

Shields,J.M., Mehta,H., Pruitt,K., and Der,C.J. (2002). Opposing roles of the extracellular signal-regulated kinase and p38 mitogen-activated protein kinase cascades in Ras-mediated downregulation of tropomyosin. Mol. Cell Biol. 22, 2304-2317.

Hamad,N.M., Elconin,J.H., Karnoub,A.E., Bai,W., Rich,J.N., Abraham,R.T., Der,C.J., and Counter,C.M. (2002). Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16, 2045-2057.

Booden,M.A., Campbell,S.L., and Der,C.J. (2002). Critical but distinct roles for the pleckstrin homology and cysteine-rich domains as positive modulators of Vav2 signaling and transformation. Mol. Cell Biol. 22, 2487-2497.

Booden,M.A., Siderovski,D.P., and Der,C.J. (2002). Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. Mol. Cell Biol. 22, 4053-4061.

Lambert,J.M., Lambert,Q.T., Reuther,G.W., Malliri,A., Siderovski,D.P., Sondek,J., Collard,J.G., and Der,C.J. (2002). Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nat. Cell Biol. 4, 621-625.

Wennerberg, K., Forget, M.-A., Ellerbroek, S.M., Arthur, W.T., Burridge, K., Settleman, J., Der, C.J. and Hansen, S.H. (2003). Rnd proteins function as RhoA antagonists by activating p190 RhoGAP. Curr. Biol., 13, 1106-1115

E-mail: cjder@med.unc.edu
Telephone: (919) 966-5634
FAX: (919) 966-0162
Address: Lineberger Comprehensive Cancer Center, CB# 7295 Chapel Hill, NC
URL: cancer.med.unc.edu/derlab
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