Regulation of cyclin-dependent kinase inhibitor p27 in cancer

细胞周期蛋白依赖性激酶抑制剂 p27 在癌症中的调节

基本信息

批准号：
8322888
负责人：
MONG-HONG LEE
金额：
$ 4.12万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8322888
关键词：
Address Affect Alleles Arabidopsis Binding Biological Models Biological Process Breast Cancer Patient Cell Cycle Regulation Cells Clinical Cyclin-Dependent Kinase Inhibitor Data Development Down-Regulation ERBB2 gene Embryo Gene Targeting Genes Goals Health Human Knockout Mice Light Link Malignant Neoplasms Mammalian Cell Mammary Tumorigenesis Mammary gland Measures Mediating Molecular Mouse Mammary Tumor Virus Mus Nuclear Export Oncogenic Pathway interactions Phosphorylation Phosphotransferases Physiological Plants Process Prognostic Factor Proto-Oncogenes Regulation Role Sampling Seedling Signal Pathway Signal Transduction Survival Rate Therapeutic Intervention Transgenic Mice Tumorigenicity Tyrosine-Kinase Oncogenes Work base cancer cell cancer therapy cell growth cell transformation cyclin-dependent kinase inhibitor 1B improved in vivo insight interest malignant breast neoplasm mammary gland development mutant novel outcome forecast overexpression receptor tumor tumor progression tumorigenesis ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): HER2 (ErbB2), a receptor tyrosine kinase oncogene, promotes cell growth and transformation of cancer cells. Strong expression of HER2 in breast cancer has been associated with poor prognosis. Also, decreased expression of the p27 protein was shown to correlate with cancer development and poor survival rates. Studies have shown that HER2 overexpression correlates with p27 downregulation. While link between HER2 activation and low p27 expression in cancers is established, our understanding of how precisely HER2 downstream signal pathways regulate p27 degradation, what these pathways do, and why their regulations are so important, remains elusive. The goal of this proposal is to elucidate the molecular mechanism of mammalian constitutive photomorphogenesis 9 signalosome (COP9) subunit 6 (CSN6)-mediated p27 degradation and to illustrate it as a signal target of HER2/Akt signals involved in degrading p27. The COP9 signalosome was originally identified from plant (Arabidopsis) mutants that mimic light-induced seedling development when grown in the dark. Mammalian cells have COP9 signalosome too, but the biological functions are largely unknown. We propose three Specific aims: (1) To determine the role of HER2-Akt signaling in regulating CSN6 and tumorigenicity. (2) To determine CSN6's role in regulating p27 function. (3) To determine the contribution of CSN6 in development and ErbB2-mediated mammary tumorigenesis. To further understand the molecular mechanism by which HER2- Akt-CSN6 pathway regulates p27 degradation, we will investigate the molecular regulations of CSN6 with Akt, a HER2 downstream kinase, and define the functions of CSN6 as a regulator of p27 degradation. We have generated mice carrying targeted disruption of the CSN6 gene with a plan to study CSN6-mediated p27 regulation in vivo. However, CSN6 knockout mice are embryonic lethal. We will generate CSN6 conditional knockout mice to determine the influence of CSN6 on the p27 degradation and on the development of mammary gland. Finally, we will use the MMTV-ErbB2 transgenic mouse as a model system to study the role of CSN6 in ErbB2 regulated cancer. Given the pivotal role of ErbB2-regulated p27 degradation in tumorigenesis, an understanding of how the function of p27 is regulated will provide important insight about the compound layers of p27 regulation and will help in the development of therapeutic interventions for cancer in which p27 is deregulated. PUBLIC HEALTH RELEVANCE: To further understand the molecular mechanism by which HER2-Akt-CSN6 pathway regulates p27 degradation, we will investigate the molecular regulations of CSN6 with Akt, a HER2 downstream kinase, and define the functions of CSN6 as a regulator of p27 degradation. Given the pivotal role of ErbB2-regulated p27 degradation in tumorigenesis, understanding novel mechanisms regulating p27 will provide important insight about the compound layers of p27 regulation and will help in the development of therapeutic interventions for cancer in which p27 is deregulated.

描述（申请人提供）：HER2（ErbB2），一种受体酪氨酸激酶癌基因，促进细胞生长和癌细胞转化。乳腺癌中 HER2 的强表达与不良预后相关。此外，p27 蛋白表达的降低与癌症的发展和较差的生存率相关。研究表明 HER2 过度表达与 p27 下调相关。虽然癌症中 HER2 激活与 p27 低表达之间的联系已被确立，但我们对 HER2 下游信号通路如何精确调节 p27 降解、这些通路的作用以及它们的调节为何如此重要的理解仍然难以捉摸。该提案的目标是阐明哺乳动物组成型光形态发生 9 信号体 (COP9) 亚基 6 (CSN6) 介导的 p27 降解的分子机制，并说明其作为参与降解 p27 的 HER2/Akt 信号的信号靶点。 COP9 信号体最初是从植物（拟南芥）突变体中发现的，该突变体在黑暗中生长时模拟光诱导的幼苗发育。哺乳动物细胞也有 COP9 信号体，但其生物学功能很大程度上未知。我们提出了三个具体目标：（1）确定 HER2-Akt 信号传导在调节 CSN6 和致瘤性中的作用。 (2)确定CSN6在调节p27功能中的作用。 (3)确定CSN6在发育和ErbB2介导的乳腺肿瘤发生中的贡献。为了进一步了解HER2-Akt-CSN6通路调控p27降解的分子机制，我们将研究HER2下游激酶Akt对CSN6的分子调控，并明确CSN6作为p27降解调节因子的功能。我们已经培育出了携带 CSN6 基因靶向破坏的小鼠，并计划在体内研究 CSN6 介导的 p27 调节。然而，CSN6 基因敲除小鼠的胚胎是致命的。我们将生成CSN6条件敲除小鼠，以确定CSN6对p27降解和乳腺发育的影响。最后，我们将使用MMTV-ErbB2转基因小鼠作为模型系统来研究CSN6在ErbB2调节的癌症中的作用。鉴于 ErbB2 调节的 p27 降解在肿瘤发生中的关键作用，了解 p27 功能如何调节将提供有关 p27 调节复合层的重要见解，并将有助于开发 p27 失调的癌症治疗干预措施。公共健康相关性：为了进一步了解 HER2-Akt-CSN6 通路调节 p27 降解的分子机制，我们将研究 CSN6 与 HER2 下游激酶 Akt 的分子调节作用，并定义 CSN6 作为 p27 降解调节剂的功能。鉴于 ErbB2 调节的 p27 降解在肿瘤发生中的关键作用，了解调节 p27 的新机制将提供有关 p27 调节复合层的重要见解，并将有助于开发针对 p27 失调的癌症的治疗干预措施。