POLYAMINES AND EPITHELIAL TUMORIGENESIS

描述：鸟氨酸脱羧酶(ODC)是在 使用TPA治疗，但在使用其他药物治疗后不使用 增生性/非促进剂。在某些肿瘤中，ODC也升高。 ODC水平升高会导致多胺含量升高。转谷氨酰胺酶(TG) 将多胺与各种蛋白质联系起来，这可能是分化的中介 表皮细胞。在这款R01中，它在许多方面似乎是一个 关于R29(1990-95年)的延续，首席调查员希望 研究ODC表达和多胺是否能与ras协同作用 导致表皮肿瘤和/或影响角质形成细胞的分化。(1) 将含有odc基因的逆转录病毒载体导入几个细胞。 类型，这些类型被评估为在SC之后导致肿瘤的能力 注射。BK-1细胞不含激活的c-ras，没有肿瘤， 而含有活化c-ras的SP-1和308细胞则产生肿瘤。全 3例显示ODC和多胺升高。这表明提升的ODC 光是表达本身就可以起到至少部分促进作用。(2)ODC 过表达影响DNA合成、生长、分化和甘油三酯 水平(一般写的--细胞类型不清楚？)(3)转基因小鼠 由角蛋白[K6]启动子驱动的ODC基因表达产生。 他们出生时体重较低，2个月大时就会脱发。一个 异常真皮形成大的充满角蛋白的良性滤泡囊肿 在正常的表皮下。年龄较大的小鼠会患上良性角质癌。 可以通过使用ODC特异性抑制剂来预防脱发， DFMO，从出生起就一直如此。具体目标有三个：(1)能否实现ODC 过度表达与v-ras协同增强肿瘤形成潜能 BK-1细胞？(2)ODC转基因小鼠将与 携带活化v-ras基因的转基因小鼠(TG.AC)。小鼠会不会同时包含这两种东西 转基因会发展成表皮肿瘤？(3)不适当的ODC活性 影响正常角质形成细胞和启动角质形成细胞的分化 评估过了。

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.