Caveolin-1 up-regulates IGF-I receptor gene transcription in breast cancer cells via Sp1- and p53-dependent pathways.
The insulin-like growth factor (IGF) system plays an important role in the biology of breast cancer. Most of the biological actions of IGF-I and IGF-II are mediated by the IGF-I receptor (IGF-IR), a membrane-bound heterotetramer with potent antiapoptotic and cell survival activities. Caveolin-1 (Cav-1) is one of the main components of caveolae, and it has been shown to interact with multiple signaling molecules. In view of the important roles of IGF-IR and Cav-1 in oncogenically transformed mammary gland cells, in the present study we addressed the potential regulation of IGF-IR gene expression by Cav-1. The results obtained showed that MCF7/Cav-1 cells, expressing the Cav-1 gene in a stable manner, contain significantly higher levels of IGF-IR protein and mRNA than native MCF7 cells. These elevated levels of expression are mediated at the level of transcription, as shown by the results of experiments showing that the activity of the proximal IGF-IR promoter was higher in Cav-1-expressing MCF7 cells than in untransfected MCF7 cells. Furthermore, in subcellular localization studies, intensive IGF-IR staining in membrane ruffles and projections in MCF7/Cav-1 cells were noted, in contrast to typical membrane staining in MCF7 cells. In addition, we demonstrated that transcriptional activation of the IGF-IR gene by Cav-1 requires an intact p53 signaling pathway, since Cav-1 was unable to elevate IGF-IR levels in p53-null cells. Finally, the effect of Cav-1 was associated with an elevation in the levels of Sp1, a zinc-finger protein with important roles in IGF-IR gene transactivation. In summary, we identified the IGF-IR gene as a downstream target for Cav-1 action in breast cancer cells.
Glait
Chen
C
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Tencer
Lilach
L
Ravid
Dana
D
Sarfstein
Rive
R
Liscovitch
Mordechai
M
Werner
Haim
H
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
C495540:CAV1 protein, human; D051242:Caveolin 1; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011994:Recombinant Proteins; D016329:Sp1 Transcription Factor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D017526:Receptor, IGF Type 1