Role of C/EBPs in Squamous Differentiation and Neoplasia

描述(申请人提供)：分层鳞状分化是一种 涉及角质形成细胞精确时间调控的复杂过程 分化特异性基因以及角质形成细胞的生长、存活和 程序性细胞死亡。这一高度协调的过程最终导致了 不能存活的鳞片，提供必不可少的皮肤屏障功能 终生如此。在分子水平上，层状鳞片的形成过程 差异化的特点是高度协调的顺序程序 基因表达的变化。碱性亮氨酸拉链(BZIP)转录 因子C/EBPA和C/EBPB在特定的基因中大量表达 表皮角质形成细胞。我们假设C/EBPA和C/EBPB具有特定的 在表皮内发挥作用，调节不同基因的表达 参与角质形成细胞的生长、分化和细胞存活。我们进一步 假设C/EBPA和C/EBPB在维持表皮中起关键作用 动态平衡和功能紊乱导致肿瘤的发生 进程。我们认为C/EBPA和C/EBPB可以作为肿瘤修饰基因发挥作用 改变致癌的易感性。具体地说，我们建议损失 C/EBPA功能使角质形成细胞摆脱负生长抑制 由C/EBPA(即肿瘤抑制因子)施加，而C/EBPB是关键的介质 致癌RAS诱导的肿瘤发生。因为30%的人类肿瘤 含有活化的RAS癌基因，阐明C/EBPB在调控中的作用 星形转化细胞的生长或存活对于理解 在很大一部分人类癌症的基础上的致癌途径。C/EBPB 从而为开发抗肿瘤药物提供了一个有吸引力的靶点。进一步 C/EBPA的特性将为细胞周期调控提供新的视角 在鳞状上皮中的作用以及功能丧失可能如何导致 肿瘤过程。

DESCRIPTION (provided by applicant): Stratified squamous differentiation is a complex process involving the precise temporal regulation of keratinocyte differentiation-specific genes as well as keratinocyte growth, survival and programmed cell death. This highly coordinated process ultimately results in a nonviable squame which provides the barrier function of skin that is essential for life. At the molecular level the process of stratified squamous differentiation is characterized by a highly coordinated program of sequential changes in gene expression. The basic leucine zipper (bZIP) transcription factors, C/EBPa and C/EBPB, are abundantly expressed within specific keratinocytes of epidermis. We hypothesize that C/EBPa and C/EBPB have specific functions within the epidermis and regulate the expression of distinct genes involved in keratinocyte growth, differentiation and cell survival. We further hypothesize that C/EBPa and C/EBPB are critical in maintaining epidermal homeostasis and disruption of their function contributes to the neoplastic process. We propose C/EBPa and C/EBPB can function as tumor modifier genes that alter susceptibility to carcinogenesis. Specifically, we suggest that the loss of C/EBPa function releases keratinocytes from the negative growth restraint imposed by C/EBPa (i.e. tumor suppressor) while C/EBPB is a critical mediator of oncogenic Ras-induced tumorigenesis. Since 30 percent of all human tumors contain activated Ras oncogenes, elucidating the role of C/EBPB in regulating growth or survival of Rastransformed cells is critical for understanding the tumorigenic pathways that underlie a large proportion of human cancers. C/EBPB may thus provide an attractive target for developing anti-tumor drugs. Further characterization of C/EBPa will provide new insight into cell cycle regulation in squamous epithelium and how the loss of function may contribute to the neoplastic process.