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Galbiati Lab

Most cells cannot 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 stress-induced 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.

 

Our laboratory was the first to demonstrate that caveolin-1 plays a pivotal role in oxidative stress-induced premature senescence. We found that oxidative stress upregulates caveolin-1 protein expression through the p38 MAPK/Sp1-mediated activation of the caveolin-1 gene promoter. We also demonstrated that upregulation of caveolin-1 protein expression promotes premature senescence through activation of the p53/p21Waf1/Cip1 pathway by acting as a regulator of Mdm2, PP2A-C, TrxR1 and Nrf2. Moreover, we found that caveolin-1-mediated premature senescence regulates cell transformation and contributes to cigarette smoke-induced pulmonary emphysema, directly linking caveolin-1’s function to age-related diseases.

 

Taken together, our findings indicate that caveolin-1 plays a central role in the signaling events that lead to cellular senescence. Our current main research interest is the identification, at the molecular level, of novel signaling pathways that link caveolin-1 to oxidative stress-induced premature senescence and the characterization of their relevance to aging and age-related diseases using both cellular and animal models. These investigations will provide novel insights into the cellular and molecular mechanisms underlying aging and cancerous cell transformation and will identify novel molecular targets that can be exploited for the development of alternative therapeutic options in the context of age-related diseases, including cancer.

 

Ferruccio Galbiati, PhD

Most cells cannot 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 provide a better understanding of 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.
 
Our laboratory was the first to demonstrate that caveolin-1 plays a pivotal role in oxidative stress-induced premature senescence. We found that oxidative stress upregulates caveolin-1 protein expression through the p38 MAPK/Sp1-mediated activation of the caveolin-1 gene promoter. We also demonstrated that caveolin-1 promotes premature senescence through activation of the p53/p21Waf1/Cip1 pathway by acting as a regulator of Mdm2, PP2A-C, TrxR1, Nrf2 and Sirt1. More recently, we have shown that caveolin-1 promotes oncogene-induced senescence in cells and a mouse model of lung cancer.
 
Taken together, our findings indicate that caveolin-1 plays a central role in the signaling events that lead to cellular senescence. Our current main research interest is the identification, at the molecular level, of novel signaling pathways that link caveolin-1 to premature senescence and their relevance to aging and age-related diseases, such as cancer, using both cellular and animal models. These investigations will provide novel insights into cellular and molecular mechanisms underlying aging and cancerous cell transformation and will identify novel molecular targets that can be exploited for the development of alternative therapeutic options toward age-related diseases, including cancer.

 

 

 

 

 

 

Daniela Volonte, PhD

Tumor development is initiated by a multiplicity of genetic abnormalities. Tumor cells need to escape barriers that limit uncontrolled cell proliferation. One of these barriers is represented by cellular senescence. Cancer cells need to overcome this obstacle to produce a clinically relevant tumor mass. For these reasons, cellular senescence represents a natural tumor suppressor mechanism. Thus, molecules that regulate cellular senescence are potential therapeutic targets for the treatment of cancer and the fight against aging.

Caveolae are invaginations of the plasma membrane enriched in cholesterol. Caveolin-1, the structural protein component of caveolar membranes, acts as a scaffolding protein to concentrate and functionally regulate signaling molecules.

 

In recent years, several independent lines of evidence have emerged suggesting that caveolin-1 may function as a "tumor suppressor protein" in mammalian cells. For example, caveolin-1 protein expression has been shown to be absent in several transformed cell lines derived from human mammary carcinomas, including MCF-7. In addition, caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes, such as v-Abl and H-ras (G12V); caveolae are absent from these cell lines. In addition, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (D7S522; 7q31.1), a known fragile site (FRA7G) that is deleted in many types of cancer.

Oxidative stress is a known inducer of cellular senescence. We have shown that up-regulation of caveolin-1 is required for oxidative stress–induced cellular senescence in fibroblasts. To unravel the molecular mechanisms underlying oxidative stress-induced up-regulation of caveolin-1 in senescent cells, Dr. Volonte has shown that oxidants stimulate the activity of the caveolin-1 promoter reporter gene construct in fibroblasts. She has identified Sp1 binding to two GC-boxes as the core mechanism of oxidative stress–triggered caveolin-1 transactivation. In addition, through signaling studies she has shown p38 mitogen-activated protein kinase (MAPK) as the upstream regulator of Sp1-mediated activation of the caveolin-1 promoter following oxidative stress. For the first time Dr. Volonte has delineated the molecular mechanisms that modulate caveolin-1 gene transcription upon oxidative stress bringing new insights into the redox control of cellular senescence in both normal and cancer cells.

Thus, cellular senescence may represent one of the molecular mechanisms through which caveolin-1 acts as a tumor suppressor protein. Current efforts are aimed at identifying the signaling molecules which link caveolin-1’s function to cellular senescence.

Headshot of Ferruccio Galbiati, PhD
Ferruccio Galbiati, PhD
Professor & Vice Chair for Research

Headshot of Daniela Volonte, PhD
Daniela Volonte, PhD
Research Assistant Professor

Ferruccio Galbiati, PhD

Journal Articles

Jeffries EP, M Di Filippo and F Galbiati. Failure to reabsorb the primary cilium induces cellular senescence. FASEB J 33:4866-4882, 2019.
 
Volonte D, AR Vyas, C Chen, S Dacic, LP Stabile, BF Kurland, SR Abberbock, TF Burns, JM Herman, YP Di and  F Galbiati. Caveolin-1 promotes the tumor suppressor properties of oncogene-induced cellular senescence. J Biol Chem 293:1794-1809, 2018.
 

Volonte D, Zou H, Bartholomew JN, Liu Z, Morel PA and Galbiati F. Oxidative stress-induced inhibition of Sirt1 by caveolin-1 promotes p53-dependent premature senescence and stimulates the secretion of IL-6. J Biol Chem 290:4202-4214, 2015.

Volonte D, Z Liu, PM Musille, E Stoppani, N Wakabayashi, YP Di, MP Lisanti, TW Kensler and F Galbiati.  Inhibition of nuclear factor-erythroid 2-related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence.  Mol Biol Cell 24:1852-1862, 2013.
Zou H, D Volonte and F Galbiati.  Interaction of caveolin-1 with Ku70 inhibits Bax-mediated apoptosis.  PLoS One 7:e39379, 2012.
Volonte D and F Galbiati.  Polymerase I and transcript release factor (PTRF)/cavin-1 is a novel regulator of stress-induced premature senescence.  J Biol Chem 286:28657-28661, 2011.

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

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

Daniela Volonte, PhD

Journal Articles

Volonte D, Z Liu, PM Musille, E Stoppani, N Wakabayashi, YP Di, MP Lisanti, TW Kensler and F Galbiati.  Inhibition of nuclear factor-erythroid 2-related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence.  Mol Biol Cell 24:1852-1862, 2013.
Zou H, D Volonte and F Galbiati.  Interaction of caveolin-1 with Ku70 inhibits Bax-mediated apoptosis.  PLoS One 7:e39379, 2012.

Volonte D and F Galbiati. Polymerase I and transcript release factor (PTRF)/cavin-1, a novel regulator of stress-induced premature senescence. J Biol Chem 286:28657-28661, 2011.

Zou H, E Stoppani, D Volonte and F Galbiati.  Caveolin-1, cellular senescence and age-related diseases.  Mech Ageing Dev 132:533-542, 2011.
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 J, D Volonte and F Galbiati.  Caveolin-1 regulates the antagonistic pleitropic properties of cellular senescence through a novel Mdm2/P53-mediated pathway.  Cancer Research 69:2878-2886, 2009.
Volonte D, B Kahkonen, S Shapiro, Di YP 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.