Processing of the NF-KB2 p100 precursor protein to generate p52, which is tightly controlled, is important for proper regulation of NF-KB function in cell growth and survival. Aberrantly persistent processing of p100 causes abnormal lymphocyte proliferation and transformation. Accordingly, enhanced p100 processing is associated with various human malignancies, particulary lymphomas/leukemia. Tax, an oncoprotein encoded by human T-cell leukemia virus type I (HTLV- I), the etiological agent of adult T-cell leukemia (ATL), is the first pathogenic inducer of p100 processing and responsible for overproduction of p52 in leukemic T cells transformed by HTLV-I. Thus, the long-term objective of this research project is to use HTLV-l/Tax as a model system to elucidate the molecular mechanism by which p100 processing is regulated and involved in tumorigenesis, for preventive and therapeutic purposes. The central hypothesis of this investigation is that deregulated processing of p100 contributes to tumorigenesis. The rationale for the proposed research is that, once the mechanisms by which p100 processing is deregulated under pathogenic conditions have been determined, this information can be used to specifically block p100 processing to prevent and treat lymphomas/leukemia including ATL, and other diseases associated with p100 processing. The objective of this proposal is to investigate the mechanisms of HTLV-l/Tax-induced p100 processing and its involvement in tumorigenesis.
The specific aims of this proposal are: (1) to characterize cellular factors regulating Tax-induced processing of p100; (2) to define the p-TrCP (an E3 ubiquitin ligase)-independent mechanism involved in pathogenic, but not physiological, processing of p100; (3) to determine the mechanism by which p100 processing regulates HTLV-l/Tax-induced cell transformation and tumorigenesis. The completion of the proposed studies may lead to new therapeutic strategies for p100 processing-associated human diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA116616-03
Application #
7494730
Study Section
Virology - B Study Section (VIRB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2006-07-01
Project End
2011-05-31
Budget Start
2007-09-20
Budget End
2008-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$53,726
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Wu, Xuewei; Qi, Jun; Bradner, James E et al. (2013) Bromodomain and extraterminal (BET) protein inhibition suppresses human T cell leukemia virus 1 (HTLV-1) Tax protein-mediated tumorigenesis by inhibiting nuclear factor ?B (NF-?B) signaling. J Biol Chem 288:36094-105
Arabi, Azadeh; Ullah, Karim; Branca, Rui M M et al. (2012) Proteomic screen reveals Fbw7 as a modulator of the NF-?B pathway. Nat Commun 3:976
Huang, B; Qu, Z; Ong, C W et al. (2012) RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor ýý. Oncogene 31:527-34
Xiao, Gutian (2012) NF-kappaB activation: Tax sumoylation is out, but what about Tax ubiquitination? Retrovirology 9:78
Fu, Jing; Qu, Zhaoxia; Yan, Pengrong et al. (2011) The tumor suppressor gene WWOX links the canonical and noncanonical NF-?B pathways in HTLV-I Tax-mediated tumorigenesis. Blood 117:1652-61
Xiao, Gutian; Fu, Jing (2011) NF-*B and cancer: a paradigm of Yin-Yang. Am J Cancer Res 1:192-221
Imanishi, Yorihisa; Hu, Bo; Xiao, Gutian et al. (2011) Angiopoietin-2, an angiogenic regulator, promotes initial growth and survival of breast cancer metastases to the lung through the integrin-linked kinase (ILK)-AKT-B cell lymphoma 2 (Bcl-2) pathway. J Biol Chem 286:29249-60
Qu, Zhaoxia; Xiao, Gutian (2011) Human T-cell lymphotropic virus: a model of NF-*B-associated tumorigenesis. Viruses 3:714-49
Qu, Zhaoxia; Fu, Jing; Yan, Pengrong et al. (2010) Epigenetic repression of PDZ-LIM domain-containing protein 2: implications for the biology and treatment of breast cancer. J Biol Chem 285:11786-92
Qu, Zhaoxia; Yan, Pengrong; Fu, Jing et al. (2010) DNA methylation-dependent repression of PDZ-LIM domain-containing protein 2 in colon cancer and its role as a potential therapeutic target. Cancer Res 70:1766-72

Showing the most recent 10 out of 19 publications