Ets Transcription Factors in Development and Cancer

Burnham Institute For Medical Research, La Jolla CA

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Abstract

DESCRIPTION: (Adapted from the investigator's abstract) Ets2 is a transcription factor which transduces signals from growth factor receptors and oncogenes to alter gene expression. It contains a conserved DNA binding domain that defines the large family of Ets transcription factors and an N-terminal domain that is the target of MAP kinase activation. Ets2 is essential for development because Ets2 deficient embryos die before E8.5 due to defective trophoblast extraembryonic tissues. Adult mice which are rescued from early lethality have defects in hair follicle morphogenesis and function. In addition, decreasing the dosage of Ets2 by half can limit the development of transgenic mouse mammary tumors caused by oncogene stimulation of both MAP kinase and PI3 kinase pathways. Transformed characteristics of human prostate cancer cells can be reversed by the forced expression of derivatives of Ets2. We propose to continue the study of the Ets2 gene by generating two additional targeted mutations of Ets2 to conditionally inactive the gene by regulated Cre recombinase expression and to reveal the cell types which express Ets2 in complex tissues such as hair follicles, placenta, and mammary gland. These genetic tools will be used to understand the importance of Ets2 in: 1. trophoblast stem cell differentiation, 2. normal epidermal and mammary gland development; and 3. ErbB2 induced mammary tumors and epidermal neoplasms. These studies will provide important information on the role of Ets transcription factors during development and carcinogenesis and may lead to a strategy of intervention applicable to cancers caused by multiple types of non-nuclear oncogenes.