Most cells can not divide indefinitely due to a process termed cellular senescence. Because cancer cells need to escape cellular senescence in order to proliferate and eventually form tumors, it is well accepted that cellular senescence is a powerful tumor suppressive mechanism. In addition, since several molecular changes that are observed in senescent cells occur in somatic cells during the aging process, investigating the molecular mechanisms underlying cellular senescence will also allow us to better understand the more complicated aging process. Thus, molecules that regulate cellular senescence represent potential therapeutic targets for the prevention/treatment of cancer as well as the fight against aging.

Our work is directed at unraveling the role of caveolin-1 as a novel mediator of cellular senescence. Caveolin-1 is the structural protein component of caveolae, invaginations of the plasma membrane involved in signal transduction. Caveolin-1 acts as a scaffolding protein to concentrate, organize, and functionally modulate signaling molecules within caveolar membranes.

Senescent human diploid fibroblasts express higher levels of caveolin-1, as compared to non-senescent cells. We showed that mouse embryonic fibroblasts derived from caveolin-1 overexpressing transgenic mice are arrested in the G0/G1 phase of the cell cycle and display a premature senescent phenotype. In addition, we demonstrated that oxidative stress induces premature senescence by stimulating caveolin-1 gene transcription through p38 MAPK/Sp1-mediated activation of two GC-rich promoter elements in fibroblasts and epithelial cells. Interestingly, oxidative stress-induced premature senescence (SIPS) does not occur in fibroblasts where caveolin-1 expression is reduced using an antisense mRNA-based approach. Moreover, oxidative stress does not induce premature senescence in caveolin-1-negative MCF-7 breast cancer cells and reintroduction of caveolin-1 in these cells restores IPS.

Taken together, these data indicate that caveolin-1 plays a central role in the signaling events that lead to cellular senescence. We are currently investigating, at the molecular level, the signaling pathways that link caveolin-1 function to oxidative stress-induced premature senescence. These investigations will contribute to elucidate the molecular mechanisms underlying aging and cancerous cell transformation.

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Important Publications

Hezel M, WC de Groat and F Galbiati. Caveolin-3 promotes nicotinic acetylcholine receptor clustering and regulates neuromuscular junction activity. Mol Biol Cell 21:302-310, 2010.

Volonte D and F Galbiati. Inhibition of thioredoxin reductase 1 by caveolin-1 promotes stress-induced premature senescence. EMBO Reports 10:1334-1340, 2009.

Bartholomew JN, D Volonte and F Galbiati. Caveolin-1 regulates the antagonistic pleiotropic properties of cellular senescence through a novel Mdm2/p53-mediated pathway. Cancer Research 69:2878-2886, 2009.

Volonte D, B Kahkonen, S Shapiro, Y Di and F Galbiati. Caveolin-1 expression is required for the development of pulmonary emphysema through activation of the ATM-p53-p21 pathway. J Biol Chem 284:5462-5466, 2009.

Volonte D, C McTiernan, M Drab, M Kasper and F Galbiati. Caveolin-1 and caveolin-3 form hetero-oligomeric complexes in atrial cardiac myocytes that are required for doxorubicin-induced apoptosis. Am J Physiol Heart Circ Physiol 294 (1):H392-401, 2008.

Dasari A, JN Bartholomew, D Volonte and F Galbiati. Oxidative stress induces premature senescence by stimulating caveolin-1 gene transcription through p38 MAPK/Sp1-mediated activation of two GC-rich promoter elements. Cancer Research 66(22):10805-10814, 2006.

Volonte D, Y Liu and F Galbiati. The modulation of caveolin-1 expression controls satellite cell activation during muscle repair. FASEB J 19(2):237-239, 2005.