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Scripps Research Joint Appointments

Faculty, Kellogg School of Science and Technology

Research Focus

Signal transduction pathways mediating cellular responses to oncogenic mutations

The development of human cancer is a multi-step process involving activation of oncogenes and inactivation of tumor suppressor genes. While these oncogenic mutations contribute to the transformation of normal cells into tumoigenic cells, normal cells usually respond to these changes by triggering tumor-suppressing defense mechanisms such as apoptosis and premature senescence. As a result, tumor development requires additional mutations that compromise these anti-oncogenic responses. The research in our lab focuses on the signal transduction pathways that mediate the tumor-suppressing responses, and the genetic alterations in cancer cells that are responsible for abolishing these responses.

Signaling pathways mediating oncogene-induced senescence
Senescence is a stable proliferative arrest historically associated with the exhaustion of replicative potential of cells. Activated oncogenes, such as ras, can induce premature senescence in young cells, as a defense mechanism that restricts oncogenic transformation. Recent studies demonstrate that like apoptosis, oncogene-induced senescence is a bona fide tumor suppressing mechanism in vivo, which needs to be compromised during cancer development. However, the signaling pathways responsible for this important anti-tumorigenic response are poorly understood. Studies from our lab indicate that the stress-induced p38 MAPK pathway plays a major role in ras-induced senescence both in cell culture and in mouse cancer models, and that inactivation of this pathway leads to disruption senescence induction and accelerated cancer development in mice. The ability of p38 to mediate ras-induced senescence and tumor suppression is achieved through activation of the p53 tumor suppressor protein, via direct phosphorylation of p53 by both p38 and a p38 downstream protein kinase PRAK. These results have revealed a novel role of p38 in tumor suppression, besides its well-defined functions in inflammation and stress responses. Experiments are currently under way to search for additional signaling components that regulate senescence induction, and to determine whether the p38 pathway is disarmed during human cancer development. Results from these studies will provide insights into the mechanisms underlying the tumor-suppressing responses in a normal organism, and may lead to the development of novel cancer therapies targeting the senescence pathway.

The role of MDM2 in TGF-β resistance in cancer MDM2 is a proto-oncogene frequently overexpressed in cancers. The oncogenic activity of MDM2 is thought to be achieved primarily through inactivation of the p53 tumor suppressor. However, we have found that in epithelial cells, MDM2 confers resistance to a growth-inhibitory cytokine TGF-β through a p53-independent mechanism. Since a high percentage of human tumors have acquired resistance to TGFβ-induced growth inhibition, this finding suggests that the p53-independent activity of MDM2 plays an important role in cancer development. One of the interests of our lab is to delineate this p53-independent activity of MDM2.

Systematic identification of oncogenic alterations
Cancer development involves multiple genetic alterations, with each contributing to one or more cancer-associate phenotypes. Correlating an oncogenic phenotype with the genetic mutations that cause this phenotype is critical for understanding the mechanisms of tumorigenesis. We attempt to systematically search for genetic alterations that are responsible for a specific cancer phenotype by performing genetic screens in cell culture using recombinant retrovirus-based cDNA expression libraries and small interference RNA (siRNA) libraries. Our major interests include resistance to chemotherapeutic drugs and growth-inhibitory cytokines, cellular immortalization and metastasis.

Education

Ph.D., Biology, University of Iowa, 1995

Awards & Professional Activities

New Scholar Award, Ellison Medical Foundation.

Selected References

Sun P, Dong P, Dai K, Hannon GJ and Beach D, 1998. The p53-Independent Role of MDM2 in TGF-β Resistance in Tumors. Science 282:2270-2272.

Wang WJ, Chen X, Liao R, Deng Q, Zhou JJ, Huang S and Sun P, 2002. Sequential Activation of the MEK-Extracellular Signal-Regulated Kinase and MKK3/6-p38 Mitogen-Activated Protein Kinase Pathways Mediates Oncogenic ras-Induced Premature Senescence. Mol. Cell Biol. 22:3389-3403.

Deng Q, Li Y, Tedesco D, Liao R, Fuhrmann G and Sun P. 2005. The Ability of E1A to Rescue ras-induced Premature Senescence and Confer Transformation Relies on Inactivation of both p300/CBP and Rb Family Proteins. Cancer Res. 65:8298-307.

Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, Xie C, Chen J, Deng Q, Yamout M, Dong M, Frangou CG, Yates, JR III, Wright PE and Han J, 2007. PRAK Mediates a Novel Pathway Essential for Oncogenic ras-Induced Senescence and Tumor Suppression. Cell 128:295-308.

Links

Study Reveals New Function of Protein Kinase Pathway in Tumor Suppression