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）：人类最常见的恶性肿瘤是皮肤癌，其发病率接近所有其他癌症亚型的总和。人乳头瘤病毒（HPV）和紫外线（UV）照射都是这种疾病的危险因素。 HPV 引起的永生化可能是致癌的早期阶段，而紫外线可能通过诱导进一步突变以及选择致瘤细胞来诱导后续事件。与载体转导的或早期传代 (p7) E6/7 细胞相比，HPV-16 E6/7 永生化人角质形成细胞对 UVB 诱导的细胞凋亡极其敏感。 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 暴露后表现出显着变化；在原代细胞和永生化细胞中，每个 Id 都受到紫外线的差异调节。 Id 蛋白在多种其他细胞类型的分化、细胞凋亡和肿瘤发生中发挥重要作用。因此，具体目标将检验这样的假设：Id 基因在调节细胞培养物和移植的人表皮中由急性 UVB 暴露诱导的角质形成细胞凋亡和分化中发挥核心作用。 具体目标 I 将检查在原代和永生化 HFK 中负责 Id2 和 Id3 差异调节的遗传元件。 具体目标 II 将描述 Id2 和 Id3 在调节人角质形成细胞凋亡中的作用。将通过研究优先与 Id2 和 Id3 相互作用的因素来研究基因和细胞类型特异性反应的机制。 Specific Aim III 将生成源自过度表达 Id2 或 Id3 的角质形成细胞的移植人表皮，以检查对 UVB 或局部致癌物的短期（分化和细胞凋亡）和长期（转化）反应。