Abstract

The interaction of an anticancer agent with its primary target represents only the first step in the drug's mechanism of action. Knowledge of the apoptotic signaling mechanisms subsequently induced is of critical importance if advances are to be made in improving the effectiveness of these agents. The overall goal of our research is to improve cancer chemotherapy by understanding the nature and regulation of these apoptotic signaling pathways. Specifically, we are interested in defining the role of the stress-activated, c-Jun NH2-terminal protein kinase (JNK) in the mechanism of action of antimitotic anticancer drugs, particularly vinblastine.
In Specific Aim 1 we will specifically inhibit JNK signaling to c-Jun/AP-1 and examine the effects of AP-1 inhibition on vinblastine-induced apoptosis and on gene expression in order to identify putative AP-1 target genes.
Specific Aim 2 will test the relevant AP-1 target genes as intermediates in vinblastine-induced apoptosis, using a combination of molecular and cellular approaches. Completion of this aim will provide experimental verification of the role of the candidate genes identified, and a better understanding of the mechanisms of apoptotic signaling by vinblastine-activated JNK/AP-1.
Specific Aim 3 will utilize chromatin immunoprecipitation to demonstrate recruitment of c-Jun to the regulatory regions of the relevant AP-1 target genes, and to identify novel regulatory partners that may cooperate with c-Jun.
Specific Aim 4 will utilizec-jun-/- immortalized fibroblasts as a unique model system to further explore the role of c-Jun in the cellular response to vinblastine. This research will provide molecular insight into the role of JNKJc-Jun in vinblastine-induced apoptosis, and contribute to our basic understanding of the mechanism of action of this and related agents. In turn, this research may suggest novel approaches to alter the threshold for cell death to make these drugs more effective, lessening toxicity and improving specificity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075577-06
Application #
6652104
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
1998-04-01
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
6
Fiscal Year
2003
Total Cost
$213,000
Indirect Cost

  Institution

Name
University of Arkansas for Medical Sciences
Department
Biochemistry
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205

  Publications

Bateman, T David; Joshi, Aarti L; Moon, Kwangyul et al. (2009) Synthesis and anticancer activity of sclerophytin-inspired hydroisobenzofurans. Bioorg Med Chem Lett 19:6898-901
Upreti, Meenakshi; Chu, Rong; Galitovskaya, Elena et al. (2008) Key role for Bak activation and Bak-Bax interaction in the apoptotic response to vinblastine. Mol Cancer Ther 7:2224-32
Kolomeichuk, Sergey N; Terrano, David T; Lyle, Christopher S et al. (2008) Distinct signaling pathways of microtubule inhibitors--vinblastine and Taxol induce JNK-dependent cell death but through AP-1-dependent and AP-1-independent mechanisms, respectively. FEBS J 275:1889-99
Duan, Lingling; Sterba, Kristen; Kolomeichuk, Sergey et al. (2007) Inducible overexpression of c-Jun in MCF7 cells causes resistance to vinblastine via inhibition of drug-induced apoptosis and senescence at a step subsequent to mitotic arrest. Biochem Pharmacol 73:481-90
Upreti, Meenakshi; Lyle, Christopher S; Skaug, Brian et al. (2006) Vinblastine-induced apoptosis is mediated by discrete alterations in subcellular location, oligomeric structure, and activation status of specific Bcl-2 family members. J Biol Chem 281:15941-50
Zharov, Vladimir P; Galitovskiy, Valentin; Lyle, Christopher S et al. (2006) Superhigh-sensitivity photothermal monitoring of individual cell response to antitumor drug. J Biomed Opt 11:064034
Kurten, Richard C; Chowdhury, Parag; Sanders Jr, Ronald C et al. (2005) Coordinating epidermal growth factor-induced motility promotes efficient wound closure. Am J Physiol Cell Physiol 288:C109-21
Obey, Toria B; Lyle, Christopher S; Chambers, Timothy C (2005) Role of c-Jun in cellular sensitivity to the microtubule inhibitor vinblastine. Biochem Biophys Res Commun 335:1179-84
Du, Lihua; Lyle, Christopher S; Chambers, Timothy C (2005) Characterization of vinblastine-induced Bcl-xL and Bcl-2 phosphorylation: evidence for a novel protein kinase and a coordinated phosphorylation/dephosphorylation cycle associated with apoptosis induction. Oncogene 24:107-17
Bene, Anca; Kurten, Richard C; Chambers, Timothy C (2004) Subcellular localization as a limiting factor for utilization of decoy oligonucleotides. Nucleic Acids Res 32:e142

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