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  • The EMBO Journal (1998) 17, 6633 - 6648
  • doi:10.1093/emboj/17.22.6633

Targeted downregulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade

Ferruccio Galbiati1,2, Daniela Volonté1,2, Jeffrey A. Engelman1,2, Genichi Watanabe1,3, Robert Burk1,4, Richard G. Pestell1,3 and Michael P. Lisanti1,2

  1. The Albert Einstein Cancer Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA
  2. Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
  3. Departments of Developmental and Molecular Biology and Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
  4. Departments of Pediatrics, Microbiology and Immunology, and Epidemiology and Social Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA

Correspondence to:

Michael P. Lisanti, E-mail: lisanti@aecom.yu.edu

Received 13 May 1998; Accepted 14 September 1998; Revised 17 August 1998

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.

  • Keywords:

    • caveolae,
    • caveolin-1,
    • contact inhibition,
    • Ras-p42,
    • 44 MAP kinase cascade,
    • tumor suppressor activity