Targeted downregulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade.
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.
Galbiati
F
F
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.
Volonte
D
D
Engelman
J A
JA
Watanabe
G
G
Burk
R
R
Pestell
R G
RG
Lisanti
M P
MP
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D051242:Caveolin 1; D051243:Caveolin 2; D022461:Caveolins; D002471:Cell Transformation, Neoplastic; D002897:Chromosomes, Human, Pair 7; D016895:Culture Media, Serum-Free; D016373:DNA, Antisense; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D009374:Neoplasms, Experimental / Q000235:genetics; D015345:Oligonucleotide Probes; D012333:RNA, Messenger / Q000235:genetics
C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D051243:Caveolin 2; D022461:Caveolins; D016895:Culture Media, Serum-Free; D016373:DNA, Antisense; D008565:Membrane Proteins; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D017871:Calcium-Calmodulin-Dependent Protein Kinases