POLYAMINES AND EPITHELIAL TUMORIGENESIS

点击翻译按钮获取中文摘要

DESCRIPTION: Ornithine decarboxylase (ODC) is synthesized early after treatment with TPA, but not after treatment with other hyperplastic/non-promoting agents. ODC is also elevated in certain tumors. Elevated ODC levels lead to elevated polyamines. Transglutaminase (TG) links polyamines to various proteins, which may mediate the differentiation of epidermal cells. In this R01, which in many ways appears to be a continuation of an R29 (1990-95), the principal investigator wishes to investigate whether ODC expression and polyamines can cooperate with ras to cause epidermal tumors and/or affect differentiation of keratinocytes. (1) A retroviral vector containing the ODC gene was introduced into several cell types, which were assessed for the ability to cause tumors following sc injection. BK-1 cells, which contain no activated c-ras, gave no tumors, while SP-1 and 308 cells, which contain activated c-ras, gave tumors. All three showed elevated ODC and polyamines. This suggests that elevated ODC expression alone can be promoting at least partially. (2) ODC overexpression affected DNA synthesis, growth, differentiation, and TG levels (written generally--cell type unclear?). (3) Transgenic mice were generated with ODC gene expression driven from a keratin [K6 ]promoter. They have low birth weight and experience hair loss at 2 months. An abnormal dermis develops with large keratin-filled, benign, follicular cysts underneath a normal epidermis. Older mice develop benign keratocarcinomas. Hair loss can be prevented by administering the ODC specific inhibitor, DFMO, continuously from birth. There are 3 Specific Aims: (1) Can ODC overexpression cooperate with v-ras to enhance the tumor forming potential of BK-1 cells? (2) The ODC transgenic mice will be cross-bred with transgenic mice carrying activated v-ras (TG.AC). Will mice containing both transgenes develop epidermal tumors? (3) How inappropriate ODC activity affect differentiation of normal and initiated keratinocytes will be assessed.