NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis

Kelly L Weaver; Marie-Clotilde Alves-Guerra; Ke Jin; Zhiqiang Wang; Xiaoqing Han; Prathibha Ranganathan; Xiaoxia Zhu; Thiago DaSilva; Wei Liu; Francesca Ratti; Renee M Demarest; Cristos Tzimas; Meghan Rice; Rodrigo Vasquez-Del Carpio; Nadia Dahmane; David J Robbins; Anthony J Capobianco

doi:10.1158/0008-5472.CAN-14-1547

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NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis

Journal article

Open access

Peer reviewed

NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis

Kelly L Weaver, Marie-Clotilde Alves-Guerra, Ke Jin, Zhiqiang Wang, Xiaoqing Han, Prathibha Ranganathan, Xiaoxia Zhu, Thiago DaSilva, Wei Liu, Francesca Ratti, …

Cancer research (Chicago, Ill.), Vol.74(17), pp.4741-4751

2014-09-01

DOI: https://doi.org/10.1158/0008-5472.CAN-14-1547

PMCID: PMC4154994

PMID: 25038227

Abstract

Cell Line

Transcriptional Activation - genetics

Humans

Mice, Inbred C57BL

Carcinogenesis - genetics

Receptors, Notch - genetics

Signal Transduction - genetics

DNA-Binding Proteins - genetics

Mice, Knockout

Animals

Mice, Nude

Cell Line, Tumor

Mice

Transcription, Genetic - genetics

Receptor, Notch1 - genetics

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.108 Molecular & Cell Biology - Cancer & Development; 1.108.579 Drosophila
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine

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Title: NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis
Creators: Kelly L Weaver - 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
Marie-Clotilde Alves-Guerra - Inserm U1016, Institut Cochin, Paris, France. CNRS, UMR 8104, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Ke Jin - 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
Zhiqiang Wang - 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
Xiaoqing Han - 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
Prathibha Ranganathan - 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
Xiaoxia Zhu - 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
Thiago DaSilva - 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
Wei Liu - 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
Francesca Ratti - Ecole Normale Supérieure de Lyon, CNRS UMR 5239, Equipe de Différenciation Neuromusculaire, Lyon, France
Renee M Demarest - Rowan University School of Osteopathic Medicine, Department of Molecular Biology, Stratford, NJ
Cristos Tzimas - Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
Meghan Rice - 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
Rodrigo Vasquez-Del Carpio - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Nadia Dahmane - Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
David J Robbins - 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
Anthony J Capobianco - 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
Publication Details: Cancer research (Chicago, Ill.), Vol.74(17), pp.4741-4751
Publisher: United States
Grant note: R01 CA 83736 / NCI NIH HHS U01 HG004080 / NHGRI NIH HHS U42RR024244 / NCRR NIH HHS U01 HG004085 / NHGRI NIH HHS U42 RR024244 / NCRR NIH HHS U01HG004080 / NHGRI NIH HHS U01HG004085 / NHGRI NIH HHS R01 CA169805 / NCI NIH HHS R01 CA083736 / NCI NIH HHS R01 CA 169805-01 / NCI NIH HHS
Academic Unit: Miller School of Medicine; UMMG Department of Surgery; UMMG Dept of Surgery - Div of Surgical Oncology
Language: English
Resource Type: Journal article
PMID: 25038227
PMCID: PMC4154994
Record Identifier: 991031560537602976