Bone morphogenetic proteins (BMPs) regulate
cell differentiation, proliferation, and
apoptosis through a canonical SMAD
signaling cascade. Absence of BMP signaling causes the formation of
intestinal juvenile
polyps in the colon cancer-prone
syndrome familial
juvenile polyposis. As sporadic
colon cancers appear to have intact BMP signaling, we evaluated if K-RAS,
driving a
mitogenic pathway frequently activated in
colon cancer, negatively affects BMP growth suppression. We treated non-tumorigenic but activated RAS/ERK FET cells with
BMP2, and in combination with
pharmacological or
genetic inhibition of RAS/ERK, examined BMP-SMAD signaling,
transcriptional activity, and
cell growth, and also assessed p21(WAF1)
mRNA,
transcriptional activation, and protein levels.
BMP2 increased nuclear phospho-SMAD1 2-fold, which increased another 2-3 fold when RAS/ERK was inhibited.
BMP2 increased BMP-specific SMAD
transcriptional activity 2-fold over control and decreased
cell growth, but inhibition of RAS/ERK further enhanced BMP-specific
transcriptional activity by an additional 1.5-2 fold and enhanced growth suppression by 20%. BMP-induced growth suppression is mediated in part by p21(WAF1), not by
transcriptional upregulation but by improved p21 protein stability, which is inhibited by RAS/ERK. In
colon cancer cells, BMP-SMAD signaling and growth suppression is facilitated by p21(WAF1) but modulated by
oncogenic K-RAS to reduce the growth suppression directed by this pathway.
