Abstract

Deficiencies in blood supply in tumors lead to suboptimal concentrations ox oxygen, glucose, and other substances. Tumor hypoxia is a patho-physiological stress that contributes to clinically important phenomena such as resistance to radio-therapy. Preliminary data is presented that hypoxia and reoxygention stimulate expression of the c-jun pronto-oncogene and c-jun/AP1 transcriptional complexes. Studies are proposed to identify the stress-inducible biochemical pathways that activate c-jun expression and transform cells in response to hypoxia and reoxygenation. In addition, the physiologic consequences of this activation will be investigated, with a particular focus on activation of the tyrosine phosphatase gene, MKP-1, and activation of the matrix metalloproteinase gene MMP-2/GL-1. Genes such as these regulated by the c- jun/AP1 complexes may be part of a concerted response to injury or environmental stress associated with perturbations of cellular redox states.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073807-03
Application #
6173349
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
1998-07-15
Project End
2002-02-28
Budget Start
2000-07-01
Budget End
2002-02-28
Support Year
3
Fiscal Year
2000
Total Cost
$298,999
Indirect Cost

  Institution

Name
Sri International
Department
Type
DUNS #
City
Menlo Park
State
CA
Country
United States
Zip Code
94025

  Publications

Laderoute, Keith R; Calaoagan, Joy M; Chao, Wan-ru et al. (2014) 5'-AMP-activated protein kinase (AMPK) supports the growth of aggressive experimental human breast cancer tumors. J Biol Chem 289:22850-64
Jang, Taichang; Calaoagan, Joy M; Kwon, Eunice et al. (2011) 5'-AMP-activated protein kinase activity is elevated early during primary brain tumor development in the rat. Int J Cancer 128:2230-9
Laderoute, Keith R; Calaoagan, Joy M; Madrid, Peter B et al. (2010) SU11248 (sunitinib) directly inhibits the activity of mammalian 5'-AMP-activated protein kinase (AMPK). Cancer Biol Ther 10:68-76
Duellman, Sarah J; Calaoagan, Joy M; Sato, Barbara G et al. (2010) A novel steroidal inhibitor of estrogen-related receptor alpha (ERR alpha). Biochem Pharmacol 80:819-26
Machrouhi, Fouzia; Ouhamou, Nouara; Laderoute, Keith et al. (2010) The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity. Bioorg Med Chem Lett 20:6394-9
Laderoute, Keith R; Amin, Khalid; Calaoagan, Joy M et al. (2006) 5'-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol Cell Biol 26:5336-47
Murphy, Brian J; Sato, Barbara G; Dalton, Timothy P et al. (2005) The metal-responsive transcription factor-1 contributes to HIF-1 activation during hypoxic stress. Biochem Biophys Res Commun 337:860-7
Talcott, C; Eker, S; Knapp, M et al. (2004) Pathway logic modeling of protein functional domains in signal transduction. Pac Symp Biocomput :568-80
Laderoute, Keith R; Calaoagan, Joy M; Knapp, Merrill et al. (2004) Glucose utilization is essential for hypoxia-inducible factor 1 alpha-dependent phosphorylation of c-Jun. Mol Cell Biol 24:4128-37
Laderoute, Keith R; Calaoagan, Joy M; Gustafson-Brown, Cindy et al. (2002) The response of c-jun/AP-1 to chronic hypoxia is hypoxia-inducible factor 1 alpha dependent. Mol Cell Biol 22:2515-23

Showing the most recent 10 out of 16 publications