Abstract |
Downregulation of the cellular retinol-binding protein-I (CRBP-I) occurs in breast and other human cancers, but its significance is not well understood. Recently, we showed that restoration of CRBP-I expression in transformed MTSV1-7 breast epithelial cells increased retinoic receptor activity, inhibited anoikis, promoted acinar differentiation and inhibited tumorigenicity, suggesting that CRBP-I suppresses tumor progression. However, the mechanism underlying these effects of CRBP-I was not elucidated. Here we demonstrate, using genetic and pharmacological approaches, that CRBP-I inhibits, in a retinoic acid receptor-dependent manner, the PI3K/Akt survival pathway. Inhibition of PI3K/Akt was necessary and sufficient to explain the antitumor effects of CRBP-I and was mediated by decreased p85 regulatory and p110 catalytic subunit heterodimerization. We present evidence consistent with the idea that this effect is due to CRBP-I inhibition of p85 phosphorylation at Y688. To our knowledge, this is the first demonstration of PI3K regulation at the level of p85-p110 heterodimerization. These findings lead us to hypothesize that CRBP-I downregulation in cancer promotes tumor progression through inhibition of retinoic acid receptor activity and derepression of PI3K/Akt signaling via a novel mechanism.
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Authors | Eduardo F Farias, Chistine Marzan, Rafael Mira-y-Lopez |
Journal | Oncogene
(Oncogene)
Vol. 24
Issue 9
Pg. 1598-606
(Feb 24 2005)
ISSN: 0950-9232 [Print] England |
PMID | 15608670
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Proto-Oncogene Proteins
- RBP1 protein, human
- Receptors, Retinoic Acid
- Recombinant Proteins
- Retinol-Binding Proteins
- Retinol-Binding Proteins, Cellular
- AKT1 protein, human
- Protein Serine-Threonine Kinases
- Proto-Oncogene Proteins c-akt
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Topics |
- Breast
- Breast Neoplasms
(genetics, pathology)
- Cell Differentiation
- Cell Line
- Cell Line, Transformed
- Dimerization
- Disease Progression
- Female
- Humans
- Phosphatidylinositol 3-Kinases
(metabolism)
- Protein Serine-Threonine Kinases
(metabolism)
- Proto-Oncogene Proteins
(metabolism)
- Proto-Oncogene Proteins c-akt
- Receptors, Retinoic Acid
(physiology)
- Recombinant Proteins
(metabolism)
- Retinol-Binding Proteins
(physiology)
- Retinol-Binding Proteins, Cellular
- Signal Transduction
(physiology)
- Transfection
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