NDLI: NACK and INTEGRATOR act coordinately to activate Notch-mediated transcription in tumorigenesis

Content Provider	Springer Nature : BioMed Central
Author	Shersher, Elena Lahiry, Mohini Alvarez-Trotta, Annamil Diluvio, Giulia Robbins, David J. Shiekhattar, Ramin Capobianco, Anthony J.
Abstract	Background Notch signaling drives many aspects of neoplastic phenotype. Here, we report that the Integrator complex (INT) is a new component of the Notch transcriptional supercomplex. Together with Notch Activation Complex Kinase (NACK), INT activates Notch1 target genes by driving RNA polymerase II (RNAPII)-dependent transcription, leading to tumorigenesis. Methods Size exclusion chromatography and CBF-1/RBPJ/Suppressor of Hairless/Lag-1 (CSL)-DNA affinity fast protein liquid chromatography (FPLC) was used to purify Notch/CSL-dependent complexes for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Chromatin immunoprecipitation (ChIP) and quantitative polymerase chain reaction (qPCR) were performed to investigate transcriptional regulation of Notch target genes. Transfection of Notch Ternary Complex components into HEK293T cells was used as a recapitulation assay to study Notch-mediated transcriptional mechanisms. Gene knockdown was achieved via RNA interference and the effects of protein depletion on esophageal adenocarcinoma (EAC) proliferation were determined via a colony formation assay and murine xenografts. Western blotting was used to examine expression of INT subunits in EAC cells and evaluate apoptotic proteins upon INT subunit 11 knockdown (INTS11 KD). Gene KD effects were further explored via flow cytometry. Results We identified the INT complex as part of the Notch transcriptional supercomplex. INT, together with NACK, activates Notch-mediated transcription. While NACK is required for the recruitment of RNAPII to a Notch-dependent promoter, the INT complex is essential for RNAPII phosphorylated at serine 5 (RNAPII-S5P), leading to transcriptional activation. Furthermore, INT subunits are overexpressed in EAC cells and INTS11 KD results in G2/M cell cycle arrest, apoptosis, and cell growth arrest in EAC. Conclusions This study identifies the INT complex as a novel co-factor in Notch-mediated transcription that together with NACK activates Notch target genes and leads to cancer cell proliferation. Video abstract
Related Links	https://biosignaling.biomedcentral.com/counter/pdf/10.1186/s12964-021-00776-1.pdf
Ending Page	12
Page Count	12
Starting Page	1
File Format	HTM / HTML
DOI	10.1186/s12964-021-00776-1
Journal	Cell Communication and Signaling
Issue Number	1
Volume Number	19
Language	English
Publisher	BioMed Central
Publisher Date	2021-09-22
Access Restriction	Open
Subject Keyword	Cell Biology Protein-Ligand Interactions Receptors Cytokines and Growth Factors Notch signaling NACK Integrator Esophageal adenocarcinoma Tumorigenesis Transcriptional activation SGK223
Content Type	Text
Resource Type	Article
Subject	Biochemistry Cell Biology Molecular Biology
Journal Impact Factor	8.2/2023
5-Year Journal Impact Factor	8/2023

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

ATF5 and HIF1α cooperatively activate HIF1 signaling pathway in esophageal cancer

Optogenetic control of NOTCH1 signaling

Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling

Signal integrator function of CXXC5 in Cancer

NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma

Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation

Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway

A role for Fra1 in the control of transcriptional network reorganization following ras transformation

CD6-mediated inhibition of T cell activation via modulation of Ras

NACK and INTEGRATOR act coordinately to activate Notch-mediated transcription in tumorigenesis

Similar Documents

ATF5 and HIF1α cooperatively activate HIF1 signaling pathway in esophageal cancer

Optogenetic control of NOTCH1 signaling

Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling

Signal integrator function of CXXC5 in Cancer

NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma

Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation

Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway

A role for Fra1 in the control of transcriptional network reorganization following ras transformation

CD6-mediated inhibition of T cell activation via modulation of Ras

NACK and INTEGRATOR act coordinately to activate Notch-mediated transcription in tumorigenesis