The overall goal of this research program is to understand the process of signal transduction by the pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin 1 (IL-1). The potent biological actions of these cytokines have been studied in detail. However, an understanding of the molecular basis of signal transduction has remained elusive. The long- term goal of this research is to define physiologically relevant signaling mechanisms employed by these cytokines. Recently, we identified a protein kinase that is markedly activated by treatment of cells with TNF or IL-1. This protein kinase, JNK, binds and phosphorylates the amino-terminal activation domain of the transcription factor c-Jun. The phosphorylation of c-Jun by JNK causes increased transcriptional activity and accounts, in part, for cytokine-stimulated gene expression mediated by AP-1. The mechanism of JNK activation by cytokines is mediated by dual phosphorylation on Thr and Tyr. A specific focus of this proposal is to define the functional significance and mechanism of activation of this protein kinase signal transduction pathway. Achievement of the goals of this proposal will increase understanding of signal transduction by cytokine receptors. This information represents a basis for the design of novel therapeutic strategies for the treatment of: 1) inflammation; and 2) proliferative diseases such as psoriasis and cancer.
The Specific Aims of this proposal are to examine: 1. The JNK protein kinase cascade. 2. The activation of the JNK pathway by cytokine receptors. 3. The interaction of JNK with other proteins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA065861-04
Application #
2700589
Study Section
Biochemistry Study Section (BIO)
Program Officer
Mccarthy, Susan A
Project Start
1995-07-01
Project End
2000-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biochemistry
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Lu, Huimin; Wang, Tao; Li, Jing et al. (2016) ?v?6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor. Cancer Res 76:5163-74
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Goel, Hira Lal; Sayeed, Aejaz; Breen, Michael et al. (2013) ?1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1. J Cell Physiol 228:1601-9
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Cellurale, Cristina; Sabio, Guadalupe; Kennedy, Norman J et al. (2011) Requirement of c-Jun NH(2)-terminal kinase for Ras-initiated tumor formation. Mol Cell Biol 31:1565-76
Liu, Wei; Zi, Min; Chi, Hongbo et al. (2011) Deprivation of MKK7 in cardiomyocytes provokes heart failure in mice when exposed to pressure overload. J Mol Cell Cardiol 50:702-11
Zou, Weiguo; Greenblatt, Matthew B; Shim, Jae-Hyuck et al. (2011) MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice. J Clin Invest 121:4383-92
Kant, Shashi; Swat, Wojciech; Zhang, Sheng et al. (2011) TNF-stimulated MAP kinase activation mediated by a Rho family GTPase signaling pathway. Genes Dev 25:2069-78

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