title: Notch1-dependent regulation of p27 determines cell fate in colorectal cancer.
abstract: Enhanced Notch signaling contributes to uncontrolled cell growth and cell death resistance in cancer. Here, we demonstrate that in colorectal carcinoma cells the Notch1-dependent activation of cell cycle and proliferation is mediated by repression of the cyclin-dependent kinase inhibitor (CDKI) p27. The half-life of p27 significantly increased after siRNA‑mediated knockdown of Notch1. Notch1 depletion altered the transcription of SKP2, KPC1 and KPC2, which are E3-ubiquitin ligase subunits targeting p27 for proteasomal degradation in the nucleus and the cytoplasm, respectively. As a consequence, the levels of p27 in both cellular fractions were elevated upon Notch1 knockdown. Importantly, the downregulation of Notch1 significantly sensitized colorectal cancer cells to chemotherapy and ionizing radiation. Our findings support an important role of p27 in Notch1-dependent oncogenic signaling and suggest that Notch1 is a promising target for an experimental therapy of colorectal carcinoma.
authors.affiliation: Molecular Tumor Pathology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Nevyana R
authors.initials: NR
authors.lastname: Hristova
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Tagscherer
authors.forename: Anne
authors.initials: A
authors.lastname: Fassl
authors.forename: Juergen
authors.initials: J
authors.lastname: Kopitz
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D044786:S-Phase Kinase-Associated Proteins; D000077150:Oxaliplatin; D050760:Cyclin-Dependent Kinase Inhibitor p27; C574376:RNF123 protein, human; D044767:Ubiquitin-Protein Ligases; C470798:LMTK2 protein, human; D017346:Protein Serine-Threonine Kinases; D005472:Fluorouracil