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The primary research interests in my laboratory are to study the fundamental mechanisms of tumorigenesis and normal mouse development. We are currently studying the role(s) of the mitogen activated protein kinase kinase kinase 8 gene (Map3k8, formally known as Tpl2) during these processes using a molecular genetic approach. Previous studies have shown that a mutation in the Map3k8 gene, which results in the expression of a truncated protein, causes the development of T-cell tumors in rats. Truncated MAP3K8 exhibits a seven-fold higher kinase activity and is three-fold more efficient than the wild-type protein in vitro at activating two signal transduction pathways important for controlling cellular responses to stress and growth factors. Transgenic mice expressing two different forms of the truncated protein developed either T-cell lymphoblastic lymphomas or thymomas. The time course of this tumor development suggested that mutations in other genes (i.e. proto-oncogenes, tumor suppressor genes) are required for the development of these tumors. To identify such genes that can cooperate with Map3k8 during tumor progression, we have infected Map3k8 transgenic mice with Moloney murine leukemia virus (MoMuLV). Virus-infected Map3k8 mice exhibit accelerated tumorigenesis, indicating that the virus is altering the expression of genes that cooperate with Map3k8 in T-cell tumor progression. We have cloned over 50 integration sites from T-cell lymphomas of MoMuLV-infected Map3k8 mice. Many of these sites correspond to the type of genes one would expect to be affected during tumorigenesis such as receptors, growth factors, kinases, and transcription factors. In addition, many of the integrations occurred in novel genes. We have found frequent integrations in Notch1 and in a novel gene of unknown function, suggesting that these genes play important roles in the progression of lymphoblastic lymphomas. Our future studies we will focus on determining the mechanism by which Map3k8 cooperates with these genes during tumor progression. We will also begin to characterize novel genes that we identify from our retroviral mutagenesis screen. We have also crossed our Map3k8 transgenic mice to other transgenic or knockout mice that are susceptible to tumorigenesis, and have identified additional genes that are able to cooperate with Map3k8 during tumorigenesis. We are currently attempting to understand the mechanisms by which Map3k8 is able to cooperate with the genes that we have identified to promote tumor progression. These studies should provide valuable insights into the biochemical mechanisms and the sequence of genetic events required for the progression of Map3k8-induced T-cell tumors, and presumably of other T-cell tumors. Our long-term goals are to develop mouse models to understand the genetics of T-cell tumorigenesis, and ultimately to use these models to devise new therapeutic strategies for treating human T-cell tumors. Ceci JD, Mills KA. Mouse chromosome 8. Mammalian Genome 8:S160-S179,1998. Ceci JD, Mills KA. Mouse chromosome 8. Mammalian Genome 10:948,1999. Quast M, Wei J, Ezell EL, Rady PL, Platt KA, Skinner HB, Campbell GA, Matalon K, Ceci JD, Tyring K, Nehls M, Szucs S, Matalon R. MRI/MRS of a mouse model for Canavan disease. Proc Intl Soc Mag Reson Med 8:1089, 2000. Szalai G, Xie D, Wassenich M, Veres M, Ceci JD, Dewey M, Felder MR. Tissue expression pattern and hormonal regulation of mouse alcohol dehydrogenase 1-containing (Adh1) minigenes and cosmids in transgenic mice. Gene 291:259-270, 2002.
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This site
published by
Donna Davis
for
the Sealy Center for Cancer Cell Biology. Last Revised: Jan. 18, 2006 |
