Regulation of Keratinocyte Survival and Death

角质形成细胞存活和死亡的调节

• 批准号: 7025817
• 负责人: ULRICH RODECK
• 金额: $ 27.04万
• 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 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7025817
• 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（由申请人提供）：通过表皮的异常信号传导 表皮生长因子受体（EGFR/erbB 1）是一种常见的表皮生长因子受体， 恶性肿瘤然而，人们对这一现象的多重影响中， EGFR的激活对恶性表型至关重要。前一 申请人已分配给EGFR一个新的角色，以支持 不依赖贴壁的上皮细胞存活。在众多的功能中， EGFR这种效应被认为是发展的限速因素， 晚期上皮恶性肿瘤，因为它可能会损害建立 转移性病变本申请的总体目标是定义分子 EGFR激活控制锚定非依赖性的机制和途径 上皮细胞存活。申请人的初步结果表明， 不依赖于基质的EGFR依赖的MEK/MAPK信号传导是至关重要的， 这一过程所需的。进一步的初步结果表明，（i）EGFR 活化维持悬浮角质形成细胞的MAPK活化，至少在 部分，通过抑制MAPK磷酸酶;（ii）翻译后修饰 通过MAPK的凋亡调节剂可能有助于角质形成细胞 （iii）MAPK依赖性对转录的影响， 凋亡调节剂进一步增强存活表型。这些初步 结果提供了三个具体目标的基础，重点是EGFR依赖的 MAPK活性的调节和持续MAPK的分子后果 因为它们与角质形成细胞存活有关。待检验的假设 （1）EGFR活化是抑制MAPK磷酸酶所必需的，因此 能够在悬浮培养中持续MAPK信号传导;（2）MAPK依赖性 Rsks的激活有助于Bcl-2的翻译后修饰 （3）EGFR依赖性MAPK 在悬浮培养中的活化通过维持 抗凋亡基因的转录。拟议的研究与以下方面有关： 生理状态和病理状态，其中上皮细胞需要 在缺乏最佳基质相互作用的情况下存活， 愈合至瘤形成。此外，它们还将提供有关以下方面的宝贵信息： EGFR依赖性细胞凋亡易感性的控制，因为它与靶向有关 EGFR在上皮癌中的作用。

项目成果

Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage.

• 发表时间: 2003
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: C. Kari;T. Chan;Marlene Rocha de Quadros;U. Rodeck

Nuclear factor kappaB inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos.

• DOI: 10.1158/1535-7163.mct-09-0198
• 发表时间: 2009-09
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Daroczi B;Kari G;Ren Q;Dicker AP;Rodeck U
• 通讯作者: Rodeck U

Interaction with LC8 is required for Pak1 nuclear import and is indispensable for zebrafish development.

• DOI: 10.1371/journal.pone.0006025
• 发表时间: 2009-06-26
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lightcap CM;Kari G;Arias-Romero LE;Chernoff J;Rodeck U;Williams JC
• 通讯作者: Williams JC

Antisense inhibition of cyclin D1 expression is equivalent to flavopiridol for radiosensitization of zebrafish embryos.

细胞周期蛋白 D1 表达的反义抑制作用相当于黄吡醇对斑马鱼胚胎的放射增敏作用。

• DOI: 10.1016/j.ijrobp.2006.05.040
• 发表时间: 2006
• 期刊: International journal of radiation oncology, biology, physics
• 作者: McAleer,MaryFrances;Duffy,KevinT;Davidson,WilliamR;Kari,Gabor;Dicker,AdamP;Rodeck,Ulrich;Wickstrom,Eric
• 通讯作者: Wickstrom,Eric