Galbiati F, Volonte D, Engelman J A, Watanabe G, Burk R, Pestell R G, Lisanti M P
The Albert Einstein Cancer Center, Microbiology and Immunology, and Epidemiology and Social Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
EMBO J. 1998 Nov 16;17(22):6633-48. doi: 10.1093/emboj/17.22.6633.
Caveolin-1 is a principal component of caveolae membranes in vivo. Caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes. Interestingly, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (7q31.1). However, it remains unknown whether downregulation of caveolin-1 is sufficient to mediate cell transformation or tumorigenicity. Here, we employ an antisense approach to derive stable NIH 3T3 cell lines that express dramatically reduced levels of caveolin-1 but contain normal amounts of caveolin-2. NIH 3T3 cells harboring antisense caveolin-1 exhibit anchorage-independent growth, form tumors in immunodeficient mice and show hyperactivation of the p42/44 MAP kinase cascade. Importantly, transformation induced by caveolin-1 downregulation is reversed when caveolin-1 protein levels are restored to normal by loss of the caveolin-1 antisense vector. In addition, we show that in normal NIH 3T3 cells, caveolin-1 expression levels are tightly regulated by specific growth factor stimuli and cell density. Our results suggest that upregulation of caveolin-1 may be important in mediating contact inhibition and negatively regulating the activation state of the p42/44 MAP kinase cascade.
小窝蛋白-1是体内小窝膜的主要成分。在被激活的癌基因诱导的细胞转化过程中，小窝蛋白-1的mRNA和蛋白表达缺失或降低。有趣的是，人类小窝蛋白-1基因定位于一个疑似肿瘤抑制基因座（7q31.1）。然而，小窝蛋白-1的下调是否足以介导细胞转化或致瘤性仍不清楚。在此，我们采用反义技术构建稳定的NIH 3T3细胞系，这些细胞系中小窝蛋白-1的表达水平显著降低，但小窝蛋白-2的含量正常。携带反义小窝蛋白-1的NIH 3T3细胞表现出不依赖贴壁生长，在免疫缺陷小鼠中形成肿瘤，并显示p42/44丝裂原活化蛋白激酶级联的过度激活。重要的是，当通过去除小窝蛋白-1反义载体使小窝蛋白-1蛋白水平恢复正常时，小窝蛋白-1下调诱导的转化被逆转。此外，我们表明在正常的NIH 3T3细胞中，小窝蛋白-1的表达水平受到特定生长因子刺激和细胞密度的严格调控。我们的结果表明，小窝蛋白-1的上调在介导接触抑制和负向调节p42/44丝裂原活化蛋白激酶级联的激活状态方面可能很重要。
