The goal of this proposal is to elucidate the roles of cyclin-dependent kinase inhibitor p27 in cancer and its regulation by oncogenic signals. p27 is a new class of tumor suppressor and is haplo-insufficient in tumor suppression. Decreased expression of the p27 protein was shown to correlate with cancer development and poor survival rates, and is an important marker of cancer progression. Overexpression of HER2, a proto-oncogene, was reported to correlate with poor survival rates in cancer patients. Many cancers affected by HER2 overexpression, including breast, colon, gastric, lung, and ovarian cancers, are the cancers with decreased p27 expression. Little is known about the possible link between HER2 overexpression and low p27 expression in cancers. Based on the low level expression pattern of p27 in HER2-overexpressing breast cancer samples and cancer cell lines, we hypothesize that a link between these two important prognostic markers exists. Our studies showed that HER2 oncogenic signals cause enhanced ubiquitin-mediated p27 degradation and can lead to nuclear exporting of Jab1/p27 complex. Also, we showed that p27 expression in HER2-overexpressing mouse-derived tumors reduces the tumor volumes in a mouse model. To further understand the molecular mechanism of the regulation between these two important prognostic markers, we will determine the mechanism of HER2-mediated p27 degradation by characterizing the molecular regulation of Jabi, a p27 exporter, and SCF-SKP2 ubiquitin ligase complex in response to HER2 activity. Finally, we will explore the tumor expression activity of p27 to find an optimal therapeutic strategy for HER2-overexpressing breast cancers. We expect that these studies will greatly enrich our understanding of HER2-mediated p27 degradation in cancer and will help develop p27 as a novel therapeutic agent for HER2-associated cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089266-02
Application #
6604915
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mietz, Judy
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$267,000
Indirect Cost
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
Phan, Liem; Chou, Ping-Chieh; Velazquez-Torres, Guermarie et al. (2015) The cell cycle regulator 14-3-3? opposes and reverses cancer metabolic reprogramming. Nat Commun 6:7530
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
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
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
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
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
Shin, Jihyun; Phan, Liem; Chen, Jian et al. (2015) CSN6 positively regulates c-Jun in a MEKK1-dependent manner. Cell Cycle 14:3079-87
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
PĂ©rez, Cynthia M; Ortiz, Ana P; Fuentes-Mattei, Enrique et al. (2014) High prevalence of cardiometabolic risk factors in Hispanic adolescents: correlations with adipocytokines and markers of inflammation. J Immigr Minor Health 16:865-73

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