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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA089266-09S1
Application #
8396586
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Ogunbiyi, Peter
Project Start
2000-12-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$54,948
Indirect Cost
$19,268
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Fang, Lekun; Lu, Weisi; Choi, Hyun Ho et al. (2015) ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development. Cancer Cell 28:183-97
Shin, Jihyun; Phan, Liem; Chen, Jian et al. (2015) CSN6 positively regulates c-Jun in a MEKK1-dependent manner. Cell Cycle 14:3079-87
Phan, Liem; Chou, Ping-Chieh; Velazquez-Torres, Guermarie et al. (2015) The cell cycle regulator 14-3-3σ opposes and reverses cancer metabolic reprogramming. Nat Commun 6:7530
Choi, Hyun Ho; Phan, Liem; Chou, Ping-Chieh et al. (2015) COP1 enhances ubiquitin-mediated degradation of p27Kip1 to promote cancer cell growth. Oncotarget 6:19721-34
Phan, Liem M; Fuentes-Mattei, Enrique; Wu, Weixin et al. (2015) Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma. Cancer Res 75:4131-42
Choi, Hyun Ho; Guma, Sergei; Fang, Lekun et al. (2015) Regulating the stability and localization of CDK inhibitor p27(Kip1) via CSN6-COP1 axis. Cell Cycle 14:2265-73
Choi, Hyun Ho; Su, Chun-Hui; Fang, Lekun et al. (2015) CSN6 deregulation impairs genome integrity in a COP1-dependent pathway. Oncotarget 6:11779-93
Fang, Lekun; Yang, Zihuan; Zhou, Junyi et al. (2015) Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer. Mol Cancer Ther 14:1476-87
Gao, Shujun; Fang, Lekun; Phan, Liem Minh et al. (2015) COP9 signalosome subunit 6 (CSN6) regulates E6AP/UBE3A in cervical cancer. Oncotarget 6:28026-41
Fuentes-Mattei, Enrique; Velazquez-Torres, Guermarie; Phan, Liem et al. (2014) Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer. J Natl Cancer Inst 106:

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