Id proteins in UV-mediated keratinocyte apoptosis

紫外线介导的角质形成细胞凋亡中的 Id 蛋白

• 批准号: 7031025
• 负责人: DEAN ROSENTHAL
• 金额: $ 17.05万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-14 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031025
• 关键词: DNA binding protein; apoptosis; cell differentiation; gene expression; histology; human papillomavirus; immunocytochemistry; keratinocyte; laboratory mouse; microarray technology; neoplastic transformation; polymerase chain reaction; protein structure function; skin neoplasms; transcription factor; ultraviolet radiation; western blottings

DESCRIPTION (provided by applicant): The most common malignancy occurring in humans is skin cancer, with an incidence that approaches that of all other cancer subtypes combined. Both human papillomavirus (HPV) and ultraviolet (UV) irradiation are risk factors for this disease. Immortalization by HPV may be an early stage in carcinogenesis, while UV may induce subsequent events both by inducing further mutations, as well as selecting for tumorigenic cells. HPV-16 E6/7-immortalized human keratinocytes were exquisitely sensitive to UVB-induced apoptosis compared to either vector-transduced or early passage (p7) E6/7 cells. DNA microarray analysis showed that, out of 16,000 genes monitored, three members of the Id protein family exhibit significant changes following UVB exposure; each Id was differentially regulated by UV in primary versus immortalized cells. Id proteins play important roles in differentiation, apoptosis, and tumorigenesis in a variety of other cell types. The Specific Aims will therefore test the hypothesis that Id genes play a central role in modulating keratinocyte apoptosis and differentiation induced by acute UVB exposure both in cell culture and grafted human epidermis. Specific Aim I will examine the genetic elements that are responsible for the differential regulation of Id2 and Id3 in primary and immortalized HFK. Specific Aim II will delineate the roles of Id2 and Id3 in the regulation of apoptosis in human keratinocytes. The mechanism(s) of the gene- and cell-type specific response will be studied by investigating the factors that interact preferentially with Id2 and Id3. Specific Aim III will generate a grafted human epidermis derived from keratinocytes that overexpress Id2 or Id3 to examine both the short-term (differentiation and apoptosis) and long-term (transformation) responses to UVB or topical carcinogens.

描述（由申请人提供）：人类中最常见的恶性肿瘤是皮肤癌，其发生率接近所有其他癌症亚型的发病率。人乳头瘤病毒（HPV）和紫外线（UV）辐射都是该疾病的危险因素。 HPV的永生化可能是癌变的早期阶段，而紫外线可能通过诱导进一步的突变以及选择肿瘤细胞来诱导随后的事件。 HPV-16 E6/7剥离的人角质形成细胞对UVB诱导的凋亡非常敏感，与载体转导或早期通过或早期（P7）E6/7细胞相比。 DNA微阵列分析表明，在监测的16,000个基因中，ID蛋白家族的三个成员在UVB暴露后显示出显着变化。每个ID在原发性和永生细胞中通过紫外线差异调节。 ID蛋白在各种其他细胞类型中在分化，凋亡和肿瘤发生中起重要作用。因此，具体目的将检验以下假设：ID基因在调节角质形成细胞细胞凋亡和急性UVB诱导的分化和分化的假设中均在细胞培养和移植的人表皮中诱导的分化。 具体目的，我将检查负责在原发性和永生HFK中ID2和ID3差异调节的遗传因素。 特定的目标II将描述ID2和ID3在人角质形成细胞中凋亡调节中的作用。通过研究与ID2和ID3优先相互作用的因素，将研究基因和细胞类型特异性反应的机制。 特定的目标III将产生源自角质形成细胞的移植人类表皮，过表达ID2或ID3，以检查短期（分化和凋亡）以及对UVB或局部致癌物的长期（转化）反应。