Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 302, Issue 10, Pages G1223-G1230Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00047.2011
Keywords
bone morphogenetic protein 4; GATA2; colon cancer; extracellular signal-regulated kinase; phosphatidylinositol 3-kinase
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Funding
- German Research Foundation (Deutsche Forschungsgemeinschaft)
- National Cancer Institute [CA-92594]
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Duerr EM, Mizukami Y, Moriichi K, Gala M, Jo WS, Kikuchi H, Xavier RJ, Chung DC. Oncogenic KRAS regulates BMP4 expression in colon cancer cell lines. Am J Physiol Gastrointest Liver Physiol 302: G1223-G1230, 2012. First published March 1, 2012; doi:10.1152/ajpgi.00047.2011.-Activating mutations in the KRAS oncogene are common in colorectal cancer. However, the complete spectrum of KRAS targets that mediate its tumorigenic effect has not yet been fully delineated. We identified bone morphogenetic protein 4 (Bmp4), a transforming growth factor-beta family member that regulates development and tissue homeostasis, as a new target of KRAS. In SW480, Hela, and 293 cells, oncogenic KRAS(V12) downregulated BMP4 RNA levels, a BMP4 promoter luciferase construct, and Bmp4 protein levels. The MEK inhibitor PD98059 but not the phosphatidylinositol 3-kinase inhibitor LY294002 blocked this downregulation of BMP4. To identify the region of the BMP4 promoter that mediated this regulation by KRAS, serial 5'-deletions of the promoter were generated. An inhibitory region was identified between -3,285 and -3,258 bp in the Bmp4 promoter. In summary, oncogenic KRAS can downregulate Bmp4 through a transcriptional pathway that depends on ERK. These findings point to a unique link between two pathways that are frequently altered in colon cancer.
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