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：
7622913
负责人：
MONG-HONG LEE
金额：
$ 27.57万
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：
2008
资助国家：
美国
起止时间：
2008-06-11 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7622913
关键词：
Address Affect Alleles Arabidopsis Binding Biological Models Biological Process Breast Cancer Patient Cell Cycle Regulation Cells Cyclin-Dependent Kinase Inhibitor Data Development Disruption Down-Regulation ERBB2 gene Embryo Gene Targeting Genes Goals Knockout Mice Malignant Neoplasms Mammalian Cell Mammary Tumorigenesis Mammary gland Measures Mediating Mediator of activation protein Molecular Mus Oncogenic Pathway interactions Phosphorylation Phosphotransferases Physiological Plants Process Prognostic Factor Protein Overexpression Proto-Oncogenes Purpose Receptor Protein-Tyrosine Kinases Regulation Role Sampling Seedling Signal Pathway Signal Transduction Survival Rate Therapeutic Intervention Transgenic Mice Tumor Suppressor Proteins Tumorigenicity Tyrosine-Kinase Oncogenes Work base cancer cell cancer therapy carcinogenesis cell growth cell motility cyclin-dependent kinase inhibitor 1B improved in vivo insight interest malignant breast neoplasm mutant novel outcome forecast p27 Cell Cycle Protein p27 Enzyme Inhibitor rho tumor tumor progression tumorigenesis ubiquitin ligase

项目摘要

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 has been shown to correlate with cancer development and poor survival rates. While studies have shown that HER2 overexpression correlates with p27 downregulation, our understanding of how the downstream signaling from HER2 regulates p27 degradation and functional significance of this regulation in carcinogenesis remains elusive. The goal of this proposal is to evaluate mammalian constitutive photomorphogenesis 9 signalosome (COP9) subunit 6 (CSN6) as a mediator of HER2/Akt signals regulating p27 degradation, and to elucidate the molecular mechanisms involved. 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, 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.

HER2（ERBB2）是一种受体酪氨酸激酶癌，促进细胞生长和癌细胞的转化。与预后不良有关。蛋白质已显示与癌症发展和生存不良相关虽然研究表明HER2的过表达与P27相关下调，我们对HER2下游信号的理解调节该法规的p27降解和功能含义癌变仍然难以捉摸。 Mamalian偶然的光形态发生9信号体（COP9）亚基6 （CSN6）作为调节P27降解的HER2/AKT信号的调解人，阐明涉及的分子机制。最初是从植物（拟南芥）突变体中鉴定出来的幼苗在黑暗中生长。信号体也是如此，但生物学功能是我们提出的三个具体目标：（1）确定HER2-AKT信号在调节中的作用 CSN6和肿瘤性。在调节P27中的作用（3）的功能。介导的乳房肿瘤发生。 HER2-AKT-CSN6途径调节p27降解的机制，我们将使用Akt（下游HER2）调查CSN6的分子法规激酶，并将CSN6的功能定义为p27降解的芳族已经产生了带有靶向破坏CSN6基因的小鼠在体内研究CSN6介导的P27调节。是胚胎致死的。确定CSN6对P27降解和乳腺的发育。转基因小鼠作为研究CSN6在ERBB2中的作用的模型系统鉴于ERBB2登记的P27降解的关键作用肿瘤发生，了解调节P27的新机制将提供关于P27法规的复合层的重要见解，将有助于开发对p27的癌症治疗性干预。