title: NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis.
abstract: The Notch signaling pathway governs many distinct cellular processes by regulating transcriptional programs. The transcriptional response initiated by Notch is highly cell context dependent, indicating that multiple factors influence Notch target gene selection and activity. However, the mechanism by which Notch drives target gene transcription is not well understood. Herein, we identify and characterize a novel Notch-interacting protein, Notch activation complex kinase (NACK), which acts as a Notch transcriptional coactivator. We show that NACK associates with the Notch transcriptional activation complex on DNA, mediates Notch transcriptional activity, and is required for Notch-mediated tumorigenesis. We demonstrate that Notch1 and NACK are coexpressed during mouse development and that homozygous loss of NACK is embryonic lethal. Finally, we show that NACK is also a Notch target gene, establishing a feed-forward loop. Thus, our data indicate that NACK is a key component of the Notch transcriptional complex and is an essential regulator of Notch-mediated tumorigenesis and development.
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Weaver
authors.affiliation: Inserm U1016, Institut Cochin, Paris, France. CNRS, UMR 8104, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Marie-Clotilde
authors.initials: MC
authors.lastname: Alves-Guerra
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Ke
authors.initials: K
authors.lastname: Jin
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Han
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Prathibha
authors.initials: P
authors.lastname: Ranganathan
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Thiago
authors.initials: T
authors.lastname: DaSilva
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida. Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chonqing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Ecole Normale Supérieure de Lyon, CNRS UMR 5239, Equipe de Différenciation Neuromusculaire, Lyon, France.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ratti
authors.affiliation: Rowan University School of Osteopathic Medicine, Department of Molecular Biology, Stratford, NJ.
authors.forename: Renee M
authors.initials: RM
authors.lastname: Demarest
authors.affiliation: Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Cristos
authors.initials: C
authors.lastname: Tzimas
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Meghan
authors.initials: M
authors.lastname: Rice
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Vasquez-Del Carpio
authors.affiliation: Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Nadia
authors.initials: N
authors.lastname: Dahmane
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida. tcapobianco@med.miami.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Capobianco
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D051881:Receptor, Notch1 / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D051881:Receptor, Notch1; D051880:Receptors, Notch