Caveolin-1, cellular senescence and pulmonary emphysema

Abstract

Caveolae are vesicular invaginations of the plasma membrane. Caveolin-1 is the structural protein component of caveolae. Caveolin-1 participates in signal transduction processes by acting as a scaffolding protein that concentrates, organizes and functional regulates signaling molecules within caveolar membranes. Cigarette smoke, a source of oxidants, is an environmental hazard that causes pulmonary emphysema. Recently, we reported that the development of cigarette smoking-induced pulmonary emphysema was inhibited in caveolin-1 null mice, which do not express caveolin-1. We demonstrated that lack of caveolin-1 expression in lung fibroblasts dramatically inhibited premature senescence induced by oxidants contained in cigarette smoke. Mechanistically, we uncovered that premature senescence of lung fibroblasts induced by oxidative stress occurred through activation of an ataxia telangiectasia-mutated (ATM)/p53-depedent pathway following sequestration of the catalytic subunit of protein phosphatase 2A (PP2A-C), an inhibitor of ATM, by caveolin-1 into caveolar membranes. We propose caveolin-1 as a key player of a novel signaling pathway that links cigarette smoke to premature senescence of lung fibroblasts and development of pulmonary emphysema.

Keywords: Caveolin; oxidative stress; p53; premature senescence.

Figure 1.. Schematic diagram summarizing the caveolin-1-dependent activation of the p53/p21 ^Waf1/Cip1/senescence pathway after oxidative stress.

In resting cells, PP2A-C-dependent inhibition of ATM prevents the activation of p53. In addition, p53 is directly inhibited by binding to Mdm2. Oxidative stress promotes the sequestration of PP2A-C and Mdm2 by caveolin-1 leading to activation of p53 and its downstream target p21^Waf1/Cip1, and induction of premature senescence. Activation of the p53/p21^Waf1/Cip1/senescence pathway after oxidative stress is inhibited in cells lacking caveolin-1 expression. We suggest that activation of this pathway in lung fibroblasts by oxidants contained in cigarette smoke contributes to the development of pulmonary emphysema. Adapted from [33].