The wnt target jagged-1 mediates the activation of notch signaling by progastrin in human colorectal cancer cells.
The Wnt and Notch signaling pathways are both abnormally activated in colorectal cancer (CRC). We recently showed that progastrin depletion inhibited Wnt signaling and increased goblet cell differentiation of CRC cells. Here, we show that progastrin down-regulation restores the expression by CRC cells of the early secretory lineage marker Math-1/Hath-1 due to an inhibition of Notch signaling. This effect is mediated by a decreased transcription of the Notch ligand Jagged-1, downstream of beta-catenin/Tcf-4. Accordingly, recombinant progastrin sequentially activated the transcription of Wnt and Notch target genes in progastrin-depleted cells. In addition, restoration of Jagged-1 levels in these cells is sufficient to activate Tcf-4 activity, demonstrating the occurrence of a feedback regulation from Notch toward Wnt signaling. These results suggest that progastrin could be instrumental in maintaining the concomitant activation of Wnt and Notch pathways in CRC cells, further highlighting the interest of progastrin targeting for the clinical management of CRC.
Pannequin
Julie
J
Centre National de la Recherche Scientifique UMR5203, Institut National de la Sante et de la Recherche Medicale U661, University of Montpellier I, Montpellier, France.
Bonnans
Caroline
C
Delaunay
Nathalie
N
Ryan
Joanne
J
Bourgaux
Jean-François
JF
Joubert
Dominique
D
Hollande
Frédéric
F
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D005755:Gastrins / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D055262:Mucin-2 / Q000096:biosynthesis; D011498:Protein Precursors / Q000172:deficiency / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051880:Receptors, Notch / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005755:Gastrins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D055262:Mucin-2; D011498:Protein Precursors; D012333:RNA, Messenger; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C500942:ATOH1 protein, human; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C524625:MUC2 protein, human; C532096:TCF4 protein, human; C013706:big gastrin