In the previous grant period, we characterized the Jun activation domain-binding protein (JAB1), which interacts with and transactivates c-Jun and promotes cellular proliferation. JAB1 was also found as a key negative regulator that controls the activity of p27, a cyclin-dependent kinase inhibitor, by facilitating its relocalization from the nucleus to the cytoplasm and therefore promoting p27 degradation and cell cycle progression. Reduced p27 levels correlate with poor prognosis in a wide spectrum of human tumors and can accelerate tumorigenesis in mouse tissues. Additional data from our laboratory suggest that constitutive transcriptional activation of the Jab1 gene is responsible for JAB1 protein overexpression. Also, Jab1 gene amplification and protein overexpression are associated with low p27 levels and a poor prognosis in breast carcinoma patients. Emerging evidence has indicated that abnormal expression of Jab1 is implicated in the pathogenesis of a variety of cancers. Conversely, targeted silencing of JAB1 increases p27 protein levels, reinstates a G1 checkpoint, dramatically reduces the expression of many cell cycle genes, and induces cell cycle arrest and apoptosis in tumor cells. Although it is assumed that the phenotypes resulting from Jab1 silencing are due to p27 stabilization, this has not been proven. In addition, recent findings from a Jab1 knockout mouse study clearly demonstrated that p27 is elevated as p53 and cyclin E, in Jab-/- embryos resulting in impaired proliferation and accelerated apoptosis. Thus, providing evidence that JAB1 is a critical regulator of p27 degradation. We have mapped the domains within JAB1 that transactivate c-Jun and potentiate p27 degradation. Exactly how those separated activities of JAB1 (e.g. AP-1 co-activator and negative regulator of p27 cell cycle inhibitor) work together and contribute to breast tumorigenesis is not clear. In this second funding period, we propose to test the hypothesis that JAB1 is an important mediator of cell proliferation and that its aberrant expression is oncogenic and contributes to the progression of some breast carcinomas. With this continuation application, we propose to identify the oncogenic function of JAB1 by a series of molecular approaches. We will then evaluate whether JAB1 can represent an attractive target for therapeutic inhibition in breast cancer and investigate its role in resistance to treatment with Herceptin. Finally, we will characterize the control Jab1 expression in human breast carcinoma by identifying the transcriptional positive and negative regulators of Jab1, thus will indicate the upstream pathways responsible for its increased JAB1 levels in tumor cells and not in non-transformed cells. Our goals are to understand the effective transcriptional up-regulation of the Jab1 gene in breast tumors and to find a more effective therapeutic treatment for breast cancer. A more complete knowledge of JAB1's oncogenic function could be of therapeutic importance for other solid tumors with a similar phenotype. Upstream targets regulating JAB1 expression may be identified for use in future therapeutic paradigms.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090853-09
Application #
7755399
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2001-04-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
9
Fiscal Year
2010
Total Cost
$255,009
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Other Basic Sciences
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Pan, Y; Wang, S; Su, B et al. (2017) Stat3 contributes to cancer progression by regulating Jab1/Csn5 expression. Oncogene 36:1069-1079
Wang, S; Pan, Y; Zhang, R et al. (2016) Hsa-miR-24-3p increases nasopharyngeal carcinoma radiosensitivity by targeting both the 3'UTR and 5'UTR of Jab1/CSN5. Oncogene 35:6096-6108
Guo, Hui; Jing, Li; Cheng, Yangzi et al. (2016) Down-regulation of the cyclin-dependent kinase inhibitor p57 is mediated by Jab1/Csn5 in hepatocarcinogenesis. Hepatology 63:898-913
Atsaves, V; Zhang, R; Ruder, D et al. (2015) Constitutive control of AKT1 gene expression by JUNB/CJUN in ALK+ anaplastic large-cell lymphoma: a novel crosstalk mechanism. Leukemia 29:2162-72
Xu, Tao; Huang, Zeli; Deng, Yanming et al. (2015) Clinical implications of hepatitis B viral infection in Epstein-Barr virus-associated nasopharyngeal carcinoma. J Clin Virol 64:64-71
Xu, Tao; Su, Bojin; Wang, Chunhua et al. (2015) Molecular markers to assess short-term disease local recurrence in nasopharyngeal carcinoma. Oncol Rep 33:1418-26
Pan, Yunbao; Yang, Huiling; Claret, Francois X (2014) Emerging roles of Jab1/CSN5 in DNA damage response, DNA repair, and cancer. Cancer Biol Ther 15:256-62
Wang, Sumei; Zhang, Rong; Claret, Francois X et al. (2014) Involvement of microRNA-24 and DNA methylation in resistance of nasopharyngeal carcinoma to ionizing radiation. Mol Cancer Ther 13:3163-74
Vu, Thuy; Sliwkowski, Mark X; Claret, Francois X (2014) Personalized drug combinations to overcome trastuzumab resistance in HER2-positive breast cancer. Biochim Biophys Acta 1846:353-65

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