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.
| Original language | English |
|---|---|
| Pages (from-to) | 4741-4751 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 74 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 1 2014 |
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NACK is an integral component of the notch transcriptional activation complex and is critical for development and tumorigenesis. / Weaver, Kelly L.; Alves-Guerra, Marie Clotilde; Jin, Ke; Wang, Zhiqiang; Han, Xiaoqing; Ranganathan, Prathibha; Zhu, Xiaoxia; DaSilva, Thiago; Liu, Wei; Ratti, Francesca; Demarest, Renee M.; Tzimas, Cristos; Rice, Meghan; Vasquez-Del Carpio, Rodrigo; Dahmane, Nadia; Robbins, David J; Capobianco, Anthony J.
In: Cancer Research, Vol. 74, No. 17, 01.09.2014, p. 4741-4751.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - NACK is an integral component of the notch transcriptional activation complex and is critical for development and tumorigenesis
AU - Weaver, Kelly L.
AU - Alves-Guerra, Marie Clotilde
AU - Jin, Ke
AU - Wang, Zhiqiang
AU - Han, Xiaoqing
AU - Ranganathan, Prathibha
AU - Zhu, Xiaoxia
AU - DaSilva, Thiago
AU - Liu, Wei
AU - Ratti, Francesca
AU - Demarest, Renee M.
AU - Tzimas, Cristos
AU - Rice, Meghan
AU - Vasquez-Del Carpio, Rodrigo
AU - Dahmane, Nadia
AU - Robbins, David J
AU - Capobianco, Anthony J
PY - 2014/9/1
Y1 - 2014/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84907042788&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907042788&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-14-1547
DO - 10.1158/0008-5472.CAN-14-1547
M3 - Article
C2 - 25038227
AN - SCOPUS:84907042788
VL - 74
SP - 4741
EP - 4751
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 17
ER -