B-MYC REGULATION AND FUNCTION

点击翻译按钮获取中文摘要

Our long term goal is to determine the role of B-myc in the processes of cell growth, apoptosis and carcinogenesis. Our preliminary studies show that B-myc is expressed at relatively high levels in harmonally- controlled tissues. In contrast to c-Myc, B-myc is regionally expressed and dramatically downregulated by testosterone withdrawal in the epididymis. It also appears to be downregulated by estrogen in the uterus, while c-myc is up-regulated by estrogen. Interestingly, B-myc expression was not detected in a variety of tumorigenic cell lines or in a primary mouse prostate tumor, suggesting a role in tumor suppression. Further supporting a role for B-myc in growth inhibition and tumor suppression, overexpression of B-myc significantly inhibits cellular proliferation and antagnonizes the ability of c-Myc to stimulate cellular proliferation, but not apoptosis. Finally, with specific B-myc antibodies we have generated, we have identified and characterized the B-Myc protein in mouse tissue. Our hypothesis is that B-Myc is a highly-regulated myc family member which has a role in growth inhibition and tumor suppression, especially in hormonally-controlled tissues, as an antagonist of c-Myc and perhaps other growth stimulatory transcription factors. We will test this hypothesis in the following specific aims: 1) Examine the expression of B-myc in tumorigenic cells compared to normal cells. The loss of B-myc expresssion will be investigated in tumorigenic cell lines and in a transgenic prostate cancer model. The specific cell types expressing B-myc in vitro and in vivo will also be examined in normal cells and tissues; 2) Examine the hormonal and devlopmental regulation of B-myc expression in mice and rat tissues and determine if B-myc is regulated during growth, diferentiation or apoptosis in selected cell lines; 3) Examine the function of B-myc as a growth inhibitor and tumor suppressor by overexpression in selected cell lines and evaluate the effects of B-myc loss in vivo by generating a B-myc null mouse; and 4) Examine the mechanism of B-myc action. The interaction of B-Myc with critical c-Myc binding proteins will be investigated.