Emerging data reveals that cellular senescence in vivo is due to stress-induced premature senescence (SIPS). SIPS is involved in organismal aging, under both pathological and normal conditions, with studies showing that senescent cells have negative effects on overall organism homeostasis. Psoralen photoactivation (PUVA), a common free radical-producing treatment for many skin inflammation ailments, is known to promote premature senescence of dermal fibroblasts and aging of the skin. However, the molecular mechanism underlying PUVA-induced senescence/aging remains largely unknown. The long term objective of this study is to determine cellular mechanisms that may be involved in stress induced premature senescence in vivo. Specifically, this proposal is interested in determining the role of caveolin-1 during PUVA-induced SIPS. ? ? This proposal investigates the hypothesis that caveolin-1 expression is required for PUVA-induced SIPS of dermal fibroblasts in vitro and in vivo through activation of the p53 pathway after sequestration of MDM2 into caveolar membranes. The following specific aims are designed to explore this hypothesis: 1) Show that PUVA induces SIPS in dermal fibroblasts through sequestration of MDM2 into caveolae in vitro and 2) determine if in vivo PUVA-induced SIPS of dermal fibroblasts is dependent upon Cav-1. Research designs consist of deriving dermal fibroblasts from mice and treating with PUVA to induce SIPS. Using mutational analysis of MDM2, we plan to determine whether the protein's sequestration by Caveolin-1 is needed for SIPS. We will be using common biochemical techniques along with senescence associated beta galactosidase staining to assess SIPS. Additionally, we plan to treat mice with PUVA and examine their dermal layers for PUVA-induced SIPS. By using wildtype and Caveolin-1 knockout mice, it will be assessed whether Caveolin-1 is necessary for PUVA-induced SIPS. These data will elucidate molecular players related to both normal and pathogenic organismal aging. Additionally, because PUVA is known to increase likeliness of carcinogenesis while aging the skin, and senescent cells are believed to create an environment conducive for preneoplastic cell transformation, our investigations intend to propose caveolin-1 as a novel therapeutic target for the treatment/ prevention of aging and aging-related carcinogenesis. ? ? ?
| 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 |
