Bone morphogenetic protein (BMP), a member of the
transforming growth factor beta family, classically utilizes the SMAD
signaling pathway for its growth suppressive effects, and loss of this
signaling cascade may accelerate
cell growth. In the
colon cancer predisposition
syndrome Juvenile Polyposis, as well as in the late progression stages of nonsyndromic
colorectal cancers,
SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480
colon cancer cell line to examine BMPs effect on a potential target gene, PTEN, and how its expression might be regulated. Initial treatment of the SMAD4-null cells with BMP resulted in mild growth suppression, but with prolonged exposure to BMP, the cells become growth stimulatory, which coincided with observed decreases in transcription and translation of PTEN, and with corresponding increases in phospho-AKT protein levels. BMP-induced PTEN suppression was mediated via the RAS/ERK pathway, as
pharmacologic inhibition of RAS/ERK, or interference with protein function in the
cytosol by DN-RAS prevented BMP-induced growth promotion and changes in PTEN levels, as did treatment with noggin, a BMP ligand inhibitor. Thus, BMP downregulates PTEN via RAS/ERK in a SMAD4-null environment that contributes to
cell growth, and constitutes a SMAD4-independent but BMP-responsive
signaling pathway.
