Role of C/EBPs in Squamous Differentiation and Neoplasia

描述（由申请人提供）：分层鳞状分化是一种 涉及角质形成细胞的精确时间调节的复杂过程 分化特异性基因以及角质形成细胞生长、存活和 程序性细胞死亡这一高度协调的过程最终导致 无活力的鳞片，提供皮肤的屏障功能， 终身在分子水平上， 分化的特点是高度协调的程序顺序 基因表达的变化。碱性亮氨酸拉链（bZIP）转录 C/EBPa和C/EBPB因子在特定的细胞内大量表达， 表皮角质形成细胞。我们假设C/EBPa和C/EBPB具有特异性， 在表皮内起作用，并调节不同基因的表达 参与角质形成细胞生长、分化和细胞存活。我们进一步 假设C/EBPa和C/EBPB在维持表皮 体内平衡和功能的破坏有助于肿瘤的发生。 过程我们提出C/EBPa和C/EBPB可以作为肿瘤修饰基因， 改变对致癌作用的敏感性。具体来说，我们认为， C/EBPa功能的降低使角质形成细胞从负生长抑制中释放出来 C/EBPa（即肿瘤抑制因子）施加，而C/EBPB是关键介质 致癌Ras诱导的肿瘤发生。因为30%的人类肿瘤 含有激活的Ras癌基因，阐明了C/EBPB在调节 Rastransformed细胞的生长或存活对于理解 肿瘤发生途径是大部分人类癌症的基础。C/EBPB 因此可能为开发抗肿瘤药物提供有吸引力的靶点。进一步 C/EBPa的表征将为细胞周期调控提供新的见解 以及功能丧失如何导致 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.