Caveolin-1 is clearly found in caveolae on its inner surface in plasma membrane [17]. Also, caveolin-1 could exist in cytoplasm and the nucleus. It could function in signal transduction at the plasma membrane. Biochemical and morphological experiments have shown that a variety of lipid-modified signaling molecules are concentrated within plasma membrane microdomains, such as Src family tyrosine kinases, H-Ras and heterotrimeric G-proteins [21]. Our findings indicate that there is a great difference in caveolin-1 subcellular localization between BRCA1 +/+ MEFs and BRCA1 ?/? MEFs cells. BRCA1 +/+ MEFs
Epothilone A exhibited a typical plasma membrane pattern of expression; BRCA1 ?/? MEFs cells showed mainly a cytoplasmic distribution. Thus BRCA1 could lead to a redistribution of caveolin-1 from cytoplasm to plasma membrane. Because the invasive and metastatic abilities of BRCA1 +/+ MEFs cells are quite different from those of BRCA1 ?/? MEFs cells, caveolin-1 distribution might account for the altered invasive and metastatic abilities. The accumulation of caveolin-1 in plasma membranes could greatly contribute to the regulation of the invasive and metastatic abilities of mammalian cells. Indeed, Hunter et al. [22] had demonstrated that caveolin-1 plays vital roles in the endocytosis of E-cadherin. Accumulation of caveolin-1 in plasma membranes can result in the upregulation of E-cadherin expression, decrease β-catenin transcriptional activation, and reduce invasiveness in neoplastic cell. Because invasiveness is one of the common features of metastatic cells, the findings have important implications for metastases. On the other hand, several independent lines of evidence suggest that within caveolae, caveolin-1 plays a regulatory role in signaling, i.e., by functioning as an inhibitor of a variety of plasma membrane initiated signaling cascades. More specifically, caveolin-1 negatively regulates different mitogenic pathways either by preferentially interacting with signaling molecules in their inactive state or by actively repressing their signaling function. For example, caveolin-1 binding can functionally suppress the kinase activity of both Src family tyrosine kinases and receptor tyrosine kinases (like EGF-R). Caveolin-1 interacts preferentially with inactive H-Ras and negatively regulates many members of the p42/44 MAP kinase cascade in vivo, including MEK and ERK. In accordance with the idea that caveolin-1 functions as a negative regulator of signal transduction, recombinant expression of caveolin-1 in H-Ras-(G12V) and v-Abl-transformed NIH 3T3
cells abrogates their anchorage independent growth phenotype. We can draw the conclusion that BRCA1 might attenuate the invasive and metastatic abilities of mammalian cells probably through regulating the distribution of caveolin-1.
