Caveolin-1, which was first identified as a ~22-kDa, tyrosine-phosphorylated protein in Rous sarcoma virus-transformed cells , was later found to be an essential constituent of caveolae [17-19]. The caveolar membrane system mediates certain transport processes, including transcytosis, potocytosis, and clathrin-inde-pendent endocytosis . Caveolin-1 binds sphingolipids and cholesterol - lipids that are characteristic constituents of lipid rafts . Caveolin-1 and caveolae are also involved in mediating cellular cholesterol efflux [19,21].
Caveolin-1 is a member of a gene family that also comprises caveolin-2 and caveolin-3. Caveolin-2 is co-expressed with caveolin-1 in many cell types, including mesenchymal, endothelial, epithelial, neuronal, and glial cells [22,23]. Together, caveolin-1 and caveolin-2 form hetero-oligomeric assemblies that constitute the filamentous caveolar coat [23,24]. Caveolin-3 is selectively expressed in skeletal and heart muscle cells, where it appears to substitute functionally for caveolin-1 .
Caveolin-1 interacts with numerous proteins via a caveolin "scaffolding" domain (CSD) that binds short-sequence motifs that are rich in aromatic amino acids [1,26,27]. The ability of caveolin-1 to interact with many raft-localized signaling proteins has indicated that it participates in signal transduction, and that its expression may have a profound effect on cell function and fate. Indeed, the expression of caveolin-1 is altered dynamically under different physiological conditions, clearly implicating it as a regulator of cell growth and survival.
The induction of differentiation up-regulates caveolin-1 in various cell types [3,28-32]. Up-regulation of caveolin-1 is also observed upon acquisition of cell senescence [33,34]. In contrast, caveolin-1 is down-regulated upon transformation of fibroblasts by oncogenes such as Bcr-Abl, v-Abl, H-Ras, Polyoma virus middle T and Crk1 , or Neu-T, c-Src-Y52F and Myc . These data accorded well with the many growth-inhibitory effects of caveolin-1 (for reviews, see [5,6]) and its human chromosomal location near a locus (7q31.1/D7S522) that is deleted in several forms of cancers [37,38]. In addition, genetic knockout of caveolin-1 leads to hyperplasia of pulmonary endothelial cells and mammary gland epithelial cells [39,40] and results in increased sensitivity to oncogenic and carcinogenic stimuli [41,42]. Together, these data have led to the suggestion that caveolin-1 may act as a tumor-suppressor protein .
However, as discussed below, this simple hypothesis is unable to explain the complex pattern of caveolin-1 expression in human tumors and the full range of its actions in cancer cells.
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