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：
8660931
负责人：
MONG-HONG LEE
金额：
$ 1.29万
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 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660931
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 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 public health relevance 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.

描述（由申请人提供）：一种受体酪氨酸激酶癌基因HER2（ERBB2）促进癌细胞的细胞生长和转化。 HER2在乳腺癌中的强烈表达与预后不良有关。同样，显示p27蛋白的表达降低与癌症发育和存活率差有关。研究表明，HER2的过表达与P27的下调相关。尽管建立了HER2激活与低p27表达之间的联系，但我们对HER2下游信号途径如何调节p27降解，这些途径的作用以及其法规如此重要的原因仍然难以捉摸。该提案的目的是阐明哺乳动物组成型光生生成的分子机制9信号体（COP9）亚基6（CSN6）介导的p27降解，并将其作为HER2/AKT信号的信号靶标说明涉及降解P27的信号。 COP9信号体最初是从植物（拟南芥）突变体中鉴定出来的，这些突变体模仿了在黑暗中生长的光引起的幼苗发育。哺乳动物细胞也具有COP9信号体，但是生物学功能在很大程度上未知。我们提出了三个具体目标：（1）确定HER2-AKT信号在调节CSN6和肿瘤性中的作用。（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途径调节p27降解的分子机制，我们将使用AKT（AKT，HER2下游激酶）研究CSN6的分子法规，并定义CSN6作为P27降解的调节剂的功能。我们已经产生了针对CSN6基因的靶向破坏的小鼠，并计划研究CSN6介导的P27调节体内。但是，CSN6敲除小鼠是胚胎致死的。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，对P27的功能如何调节的理解将提供有关P27调节化合物层的重要见解，并有助于开发癌症治疗干预措施，而P27被解释了P27 。

项目成果

期刊论文数量（39）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

COP9 signalosome subunit 6 (CSN6) regulates E6AP/UBE3A in cervical cancer.

DOI：
10.18632/oncotarget.4731
发表时间：
2015-09-29
期刊：
Oncotarget
影响因子：
0
作者：
Gao S;Fang L;Phan LM;Qdaisat A;Yeung SC;Lee MH
通讯作者：
Lee MH

Aurora-B kinase inhibitors for cancer chemotherapy.

DOI：
10.2174/138955708786786480
发表时间：
2008-11
期刊：
Mini reviews in medicinal chemistry
影响因子：
0
作者：
S. Yeung;C. Gully;Mong-Hong Lee
通讯作者：
S. Yeung;C. Gully;Mong-Hong Lee

14-3-3sigma exerts tumor-suppressor activity mediated by regulation of COP1 stability.

DOI：
10.1158/0008-5472.can-10-2518
发表时间：
2011-02-01
期刊：
Cancer research
影响因子：
11.2
作者：
Su CH;Zhao R;Zhang F;Qu C;Chen B;Feng YH;Phan L;Chen J;Wang H;Wang H;Yeung SC;Lee MH
通讯作者：
Lee MH

Nuclear export regulation of COP1 by 14-3-3σ in response to DNA damage.