NACK Is an Integral Component of the Notch Transcriptional Activation Complex and Is Critical for Development and Tumorigenesis

Authors

Kelly L Weaver, University of Miami
Marie-Clotilde Alves-Guerra, Paris Descartes University
Ke Jin, University of Miami
Zhiqiang Wang, University of Miami
Xiaoqing Han, University of Miami
Prathibha Ranganathan, University of Miami
Xiaoxia Zhu, University of Miami
Thiago DaSilva, University of Miami
Wei Liu, University of Miami
Francesca Ratti, Ecole Normale Superieure de Lyon
Renee M Demarest, Rowan University
Cristos Tzimas, Academy of Athens
Meghan Rice, University of Miami
Rodrigo Vasquez-Del Carpio, Icahn School of Medicine at Mount Sinai
Nadia Dahmane, University of Pennsylvania
David J Robbins, University of Miami
Anthony J Capobianco, University of Miami

Document Type

Article

Version Deposited

Accepted for publication (PostPrint)

Publication Date

9-1-2014

Publication Title

Cancer Research

DOI

10.1158/0008-5472.CAN-14-1547

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.

Comments

This manuscript has been accepted for publication in Cancer Research, which is published by the American Association for Cancer Research. The publisher's final edited version of this article is available free at Cancer Research.

Recommended Citation

Weaver KL, Alves-Guerra MC, Jin K, Wang Z, Han X, Ranganathan P, Zhu X, DaSilva T, Liu W, Ratti F, Demarest RM, Tzimas C, Rice M, Vasquez-Del Carpio R, Dahmane N, Robbins DJ, Capobianco AJ. NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis. Cancer Research. 2014 Sep 1;74(17):4741-51. Epub 2014 Jul 18. doi: 10.1158/0008-5472.CAN-14-1547. PMID: 25038227; PMCID: PMC4154994.