One of the manifestations of aging is the accumulation of damage at both cellular and organism levels. This damage is initiated by endogenous and exogenous stimuli, including oxidative stress. Interestingly, reactive oxygen species have been shown to promote premature cellular senescence in culture, which is believed to have an important role in the more complicated ageing process. Caveolin-1 is the structural component of caveolae and is used by the cell to compartmentalize and functionally regulate signaling molecules. We have recently demonstrated that over-expression of caveolin-1 is sufficient to arrest mouse embryonic fibroblasts in the G0/G1 phase of the cell cycle and induce premature cellular senescence. However, whether caveolin-1 is a central figure in promoting cellular senescence remains unknown. In this proposal, we plan to test the hypothesis that caveolin-1 represents a key player in oxidative stress-induced premature senescence (SIPS). The three long-term objectives of this proposal are: 1. To characterize the caveolin-1 promoter response to oxidative stress. 2. To investigate modulation of the p53 pathway by caveolin-1 in SIPS. 3. To identify signaling molecules that are enriched into caveolar membranes after oxidative stress. In order to characterize the caveolin-1 promoter response to oxidative stress, we propose to identify the transcription factors that stimulate caveolin-1 gene expression during the cellular response to oxidative stress. To investigate modulation of the p53 pathway by caveolin-1 we will test the hypothesis that caveolin-1 activates p53 by sequestering Mdm-2 into caveolar membranes. To identify signaling molecules that are enriched into caveolar membranes after oxidative stress, we plan to use a proteomic-based approach to clone and characterize signaling molecules that move into caveolae upon oxidant stimulation. Understanding the signal transduction machinery involved in oxidative stress-induced premature senescence will provide new insights into the free radical theory of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG022548-04
Application #
7364641
Study Section
Special Emphasis Panel (ZRG1-CMAD (01))
Program Officer
Velazquez, Jose M
Project Start
2005-01-01
Project End
2009-12-31
Budget Start
2008-02-15
Budget End
2008-12-31
Support Year
4
Fiscal Year
2008
Total Cost
$244,462
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zou, Huafei; Volonte, Daniela; Galbiati, Ferruccio (2012) Interaction of caveolin-1 with Ku70 inhibits Bax-mediated apoptosis. PLoS One 7:e39379
Volonte, Daniela; Galbiati, Ferruccio (2011) Polymerase I and transcript release factor (PTRF)/cavin-1 is a novel regulator of stress-induced premature senescence. J Biol Chem 286:28657-61
Hezel, Michael; de Groat, William C; Galbiati, Ferruccio (2010) Caveolin-3 promotes nicotinic acetylcholine receptor clustering and regulates neuromuscular junction activity. Mol Biol Cell 21:302-10
Bartholomew, Janine N; Galbiati, Ferruccio (2010) Mapping of oxidative stress response elements of the caveolin-1 promoter. Methods Mol Biol 594:409-23
Volonte, Daniela; Galbiati, Ferruccio (2009) Inhibition of thioredoxin reductase 1 by caveolin 1 promotes stress-induced premature senescence. EMBO Rep 10:1334-40
Volonte, Daniela; Kahkonen, Beth; Shapiro, Steven et al. (2009) Caveolin-1 expression is required for the development of pulmonary emphysema through activation of the ATM-p53-p21 pathway. J Biol Chem 284:5462-6
Bartholomew, Janine N; Volonte, Daniela; Galbiati, Ferruccio (2009) Caveolin-1 regulates the antagonistic pleiotropic properties of cellular senescence through a novel Mdm2/p53-mediated pathway. Cancer Res 69:2878-86
Volonte, Daniela; Galbiati, Ferruccio (2009) Caveolin-1, cellular senescence and pulmonary emphysema. Aging (Albany NY) 1:831-5
Dasari, Arvind; Bartholomew, Janine N; Volonte, Daniela et al. (2006) Oxidative stress induces premature senescence by stimulating caveolin-1 gene transcription through p38 mitogen-activated protein kinase/Sp1-mediated activation of two GC-rich promoter elements. Cancer Res 66:10805-14