Journal
CELLULAR SIGNALLING
Volume 19, Issue 7, Pages 1465-1472Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2007.01.017
Keywords
bone morphogenetic protein; RAS; ERK; TGF beta; colorectal cancer
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Funding
- NCI NIH HHS [R01 CA090231-05, CA 90231, R01 CA090231] Funding Source: Medline
- NHLBI NIH HHS [T32 HL 07212, T32 HL007212] Funding Source: Medline
- NIDDK NIH HHS [K08 DK074019, DK 067287, R01 DK067287-01A2, R24 DK080506-01, R01 DK067287, R24 DK080506, DK 074019] Funding Source: Medline
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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-STAD signaling, transcriptional activity, and cell growth, and also assessed p(21WAF1) 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 p(21WAF1), 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 p(21WAF1) but modulated by oncogenic K-RAS to reduce the growth suppression directed by this pathway. (c) 2007 Elsevier Inc. All rights reserved.
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