Regulation of Keratinocyte Survival and Death

角质形成细胞存活和死亡的调节

• 批准号: 6625666
• 负责人: ULRICH RODECK
• 金额: $ 34.8万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6625666
• 关键词: BCL2 gene /protein; apoptosis; enzyme activity; epidermal growth factor; extracellular matrix; gene expression; growth factor receptors; human tissue; keratinocyte; microarray technology; mitogen activated protein kinase; phosphomonoesterases; posttranslational modifications; tissue /cell culture

DESCRIPTION (provided by applicant): Aberrant signaling through the epidermal growth factor receptor (EGFR/erbB 1) is frequently observed in epithelial malignancies. However, it is poorly understood which of the manifold effects of EGFR activation are critical to the malignant phenotype. During the previous grant cycle the applicants have assigned a novel role to the EGFR in support of anchorage-independent epithelial cell survival. Among the many functions of the EGFR this effect is considered to be rate-limiting to the development of advanced epithelial malignancies as it is likely to impair the establishment of metastatic lesions. The overall goal of this application is to define molecular mechanisms and pathways by which EGFR activation controls anchorage-independent epithelial cell survival. Preliminary results by the applicants demonstrate that matrix-independent, EGFR-dependent MEK/MAPK signaling is critically required for this process. Further preliminary results suggest that (i) EGFR activation sustains MAPK activation of suspended keratinocytes, at least in part, by suppressing MAPK phosphatases; (ii) posttranslational modifications of apoptosis regulators through MAPK are likely to contribute to keratinocyte survival in this setting; (iii) MAPK-dependent effects on transcription of apoptosis modifiers further enhances the survival phenotype. These preliminary results provide the basis for three specific aims focusing on EGFR-dependent regulation of MAPK activity and molecular consequences of sustained MAPK signaling as they relate to keratinocyte survival. The hypotheses to be tested are (1) EGFR activation is required to suppress MAPK phosphatases and thus enables sustained MAPK signaling in suspension culture; (2) MAPK-dependent activation of Rsks contributes to posttranslational modifications of Bcl-2 family members and thus supports cell survival; (3) EGFR-dependent MAPK activation in suspension culture further supports cell survival by maintaining transcription of anti-apoptotic genes. The proposed studies are relevant to physiological states and pathological conditions in which epithelial cells need to survive in the absence of optimal matrix interaction ranging from wound healing to neoplasia. Furthermore, they will provide valuable information about EGFR-dependent control of apoptosis susceptibility as it relates to targeting the EGFR in epithelial cancers.

描述(申请人提供)：通过表皮发出异常信号 生长因子受体(EGFR/erbB-1)在上皮细胞中广泛存在 恶性肿瘤。然而，人们还不太清楚的是， EGFR的激活是恶性表型的关键。在上一次 拨款周期申请者已为绿色外汇储备基金分配了一个新的角色，以支持 锚定非依赖性上皮细胞存活。在的众多功能中， EGFR这种影响被认为是对发展的速度限制 晚期上皮性恶性肿瘤，因为它可能损害建立 转移的病变。本应用程序的总体目标是定义分子 表皮生长因子受体激活控制支抗非依赖性的机制和途径 上皮细胞存活。申请者的初步结果表明 不依赖于基质、依赖于EGFR的MEK/MAPK信号是至关重要的 此过程所需的。进一步的初步结果表明：(I)EGFR 激活维持悬浮角质形成细胞的MAPK激活，至少在 部分通过抑制MAPK磷酸酶；(Ii)翻译后修饰 通过MAPK的细胞凋亡调节因子可能对角质形成细胞起作用 在这种环境下存活；(Iii)MAPK依赖对转录的影响 细胞凋亡修饰物进一步增强存活表型。这些初步的 这些结果为关注EGFR依赖的三个具体目标提供了基础 MAPK活性的调节及其持续性MAPK的分子后果 它们与角质形成细胞存活有关的信号。需要检验的假设 Are(1)需要EGFR的激活来抑制MAPK磷酸酶，从而 在悬浮培养中启用持续的MAPK信号；(2)MAPK依赖 RSKs的激活参与了Bcl2的翻译后修饰 家族成员，从而支持细胞存活；(3)EGFR依赖的MAPK 悬浮培养中的激活通过维持 抗细胞凋亡基因的转录。拟议的研究与以下方面有关 上皮细胞所需的生理状态和病理条件 在没有最佳基质相互作用的情况下生存 愈合为肿瘤。此外，它们还将提供有关以下方面的宝贵信息 EGFR依赖的细胞凋亡易感性调控与靶向相关 表皮生长因子受体在上皮性肿瘤中的表达。