Regulation of human Cripto-1 gene expression by TGF-β1 and BMP-4 in embryonal and colon cancer cells

Mario Mancino, Luigi Strizzi, Christian Wechselberger, Kazuhide Watanabe, Monica Gonzales, Shin Hamada, Nicola Normanno, David S. Salomon, Caterina Bianco

Research output: Contribution to journalArticle

Abstract

Human Cripto-1 (CR-1) is a cell membrane protein that is overexpressed in several different types of human carcinomas. In the present study we investigated the mechanisms that regulate the expression of CR-1 gene in cancer cells. We cloned a 2,481 bp 5′-flanking region of the human CR-1 gene into a luciferase reporter vector and transfected NTERA-2 human embryonal carcinoma cells and LS174-T colon cancer cells to test for promoter activity. Activity of CR-1 promoter in both cell lines was modulated by two TGF-β family members, TGF-β1 and BMP-4. In particular, TGF-β1 significantly up-regulated CR-1 promoter activity, whereas a dramatic reduction in CR-1 promoter activity was observed with BMP-4 in NTERA-2 and LS174-T cells. Changes in the CR-1 promoter activity following TGF-β1 and BMP-4 treatments correlated with changes in CR-1 mRNA and protein expression in NTERA-2 and LS174-T cells. We also identified three Smad binding elements (SBEs) within the CR-1 promoter and point mutation of SBE1 (-2,197/-2,189) significantly reduced response of the CR-1 promoter to both TGF-β1 and BMP-4 in NTERA-2 and LS174-T cells. Chromatin immunoprecipitation assay also demonstrated binding of Smad-4 to a CR-1 promoter DNA sequence containing SBE1 in LS174-T cells. Finally, BMP-4 inhibited migration of LS174-T cells and F9 mouse embryonal carcinoma cells by downregulation of CR-1 protein. In conclusion, these results suggest a differential modulation of CR-1 gene expression in embryonal and colon cancer cells by two different members of the TGF-β family.

Original languageEnglish
Pages (from-to)192-203
Number of pages12
JournalJournal of Cellular Physiology
Volume215
Issue number1
DOIs
Publication statusPublished - Apr 2008

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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    Mancino, M., Strizzi, L., Wechselberger, C., Watanabe, K., Gonzales, M., Hamada, S., Normanno, N., Salomon, D. S., & Bianco, C. (2008). Regulation of human Cripto-1 gene expression by TGF-β1 and BMP-4 in embryonal and colon cancer cells. Journal of Cellular Physiology, 215(1), 192-203. https://doi.org/10.1002/jcp.21301