Section: Research

Stephen Jones, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Cancer Biology
   Cell Biology

Other Affiliation(s):
   Interdisciplinary Graduate Program

Genes In Development and Tumorigenesis

Failure to properly regulate cell differentiation and proliferation can lead to aberrant development and/or cancer. Our laboratory creates genetically-modified mice to investigate the regulatory pathways governing normal cell growth and development, and to examine how alteration of these pathways leads to tumorigenesis. The use of genetically-defined mice and of cells derived from these mice permits analysis of the growth regulatory properties of genes to be performed in minimally-perturbed experimental systems. We are presently focusing our attention on the proto-oncogenes Mdm2 and Wnt5a.

The Mdm2 gene is amplified to high copy numbers in approximately one-third of all human sarcomas, and is overexpressed in a wide range of human cancers. The Mdm2 protein forms a complex with the p53 tumor suppressor protein, and work from our laboratory utilizing Mdm2-deficient mice and cells derived from these mice has demonstrated that Mdm2 plays a critical role in regulation of normal cell growth and development, primarily by binding to p53 and targeting p53 for proteosome degradation. Transgenic mice which overexpress Mdm2 undergo tumor formation, and the spectrum of tumor types present in these mice indicates that a p53-independent pathway to tumorigenesis is invoked by Mdm2 when Mdm2 is overexpressed. We are currently performing experiments to elucidate this mechanistic pathway to tumorigenesis.

Wnt5a is a member of the Wnt family of secreted glycoproteins which function as paracrine or autocrine signals to regulate growth control and tissue patterning. We have created mice deficient for Wnt5a in order to investigate the role of Wnt5a in development. Analysis of these mice indicates that Wnt5a is required for proper formation of the posterior axis and of other structures derived from the mesodermal precursors originating in the caudal portion of the embryo. These findings highlight the importance of Wnt5a in proper gastrulation. In addition, we have found that mice heterozygous for functional Wnt5a are susceptible to lymphoma. Characterization of the role of Wnt5a in control of cell proliferation is presently ongoing.

Office: S3-123
Phone: 508-856-7500
E-mail: Stephen.Jones@umassmed.edu
Keywords: Oncogenes/tumor suppressors, Cancer, Cell Cycle, Mouse Genetics, Mouse Models

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