Mammalian cells have an absolute requirement of oxygen and nutrients for their survival and are usually located within short proximity of blood vessels. Due to their high growth rate, rumors overgrow their vascular supply and are usually exposed to a hypoxic microenvironment. Hypoxia acts as a selective factor for mutations that increase survival and enhance metastatic capabilities. Furthermore, it increases the resistance of tumor cells to radiation and chemotherapeutic agents. Most of the adaptive responses of tumor cells to hypoxia are mediated by the transcriptional complex HIF-1, a master regulator of hypoxic-gene expression. These HIF-regulated genes include those that control angiogenesis, energy metabolism, and tumor invasiveness. The HEF-1 complex is composed by two sub-units: HIFIP that is constitutively expressed, and HIF-1alpha, whose levels and activity depend on oxygen concentration. Oxygen control of HEF1alpha stability depends on hydroxylation reactions and interaction with the VHL protein, which acts as an ubiquitin-ligase. Similarly, oxygen dependent hydroxylation determines the interaction of HIF1alpha with p300, its transcriptional co-activator. Notably, HIF-complexes are regulated not only by hypoxia but also by non-hypoxic signals like oncogenic mutations, cytokines and growth factor stimulations, suggesting a more ample role of HIF-1 in cell functions. Although the mechanisms by which these non-hypoxic signals control HIF-1 are not completely clear, current knowledge and our preliminary work indicate that a complex array of post-transcriptional modifications, including phosphorylation and acetylation determine the final activity of the HIF-1 complex, hi particular, acetylation appears to regulate both the stability of HIFla protein and its interactions with p300. It is the purpose of this proposal to characterize the role and mechanisms of action of the acetyl-transferases and deacetylases enzymes that act on HIF-1alpha and the HIF1alpha-p300 complex. Furthermore, we plan to investigate the possible role of the Von Hippel Lindau (VHL) protein in these effects. Deacetylase inhibitors are currently being tested as therapeutic agents in cancer therapy and the studies proposed herein will facilitate the understanding of its effects and help in the development of target-oriented inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA089212-05
Application #
6979165
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Macleod, Carol L
Project Start
2001-02-01
Project End
2010-05-31
Budget Start
2005-08-29
Budget End
2006-05-31
Support Year
5
Fiscal Year
2005
Total Cost
$265,200
Indirect Cost
Name
Thomas Jefferson University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Bartrons, Ramon; Caro, Jaime (2007) Hypoxia, glucose metabolism and the Warburg's effect. J Bioenerg Biomembr 39:223-9
Kong, Xianguo; Alvarez-Castelao, Beatriz; Lin, Zhao et al. (2007) Constitutive/hypoxic degradation of HIF-alpha proteins by the proteasome is independent of von Hippel Lindau protein ubiquitylation and the transactivation activity of the protein. J Biol Chem 282:15498-505
Kong, Xianguo; Lin, Zhao; Caro, Jaime (2006) Immunophilin-ligands FK506 and CsA inhibit HIF1alpha expression by a VHL- and ubiquitin-independent mechanism. FEBS Lett 580:6182-6
Kong, Xianguo; Lin, Zhao; Liang, Dongming et al. (2006) Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. Mol Cell Biol 26:2019-28
Sang, Nianli; Stiehl, Daniel P; Bohensky, Jolene et al. (2003) MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem 278:14013-9
Minchenko, Oleksandr; Opentanova, Iryna; Caro, Jaime (2003) Hypoxic regulation of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene family (PFKFB-1-4) expression in vivo. FEBS Lett 554:264-70
Minchenko, Alexander; Leshchinsky, Irene; Opentanova, Irina et al. (2002) Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect. J Biol Chem 277:6183-7
Sang, Nianli; Caro, Jaime; Giordano, Antonio (2002) Adenoviral E1A: everlasting tool, versatile applications, continuous contributions and new hypotheses. Front Biosci 7:d407-13
Sang, Nianli; Fang, Jie; Srinivas, Vickram et al. (2002) Carboxyl-terminal transactivation activity of hypoxia-inducible factor 1 alpha is governed by a von Hippel-Lindau protein-independent, hydroxylation-regulated association with p300/CBP. Mol Cell Biol 22:2984-92
Srinivas, V; Leshchinsky, I; Sang, N et al. (2001) Oxygen sensing and HIF-1 activation does not require an active mitochondrial respiratory chain electron-transfer pathway. J Biol Chem 276:21995-8

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