TY - JOUR
T1 - Integrator orchestrates RAS/ERK1/2 signaling transcriptional programs
AU - Yue, Jingyin
AU - Lai, Fan
AU - Beckedorff, Felipe
AU - Zhang, Anda
AU - Pastori, Chiara
AU - Shiekhattar, Ramin
N1 - Funding Information:
We thank Shiekhattar laboratory members for experimental support and discussions, and Ezra Blumenthal for contributing to the introduction of the manuscript as well as editorial support. We thank the Oncogenomics Core Facility at the Sylvester Comprehensive Cancer Center for performing high-throughput sequencing. This work was supported by funds from the University of Miami Miller School of Medicine, the Sylvester Comprehensive Cancer Center, and grants R01 GM078455 and R01 GM105754 (to R.S.) from the National Institute of Health.
Publisher Copyright:
© 2017 Yue et al.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - Activating mutations in the mitogen-activated protein kinase (MAPK) cascade, also known as the RAS–MEK–ex-tracellular signal-related kinase (ERK1/2) pathway, are an underlying cause of >70% of human cancers. While great strides have been made toward elucidating the cytoplasmic components of MAPK signaling, the key downstream coactivators that coordinate the transcriptional response have not been fully illustrated. Here, we demonstrate that the MAPK transcriptional response in human cells is funneled through Integrator, an RNA polymerase II-associated complex. Integrator depletion diminishes ERK1/2 transcriptional responsiveness and cellular growth in human cancers harboring activating mutations in MAPK signaling. Pharmacological inhibition of the MAPK pathway abrogates the stimulus-dependent recruitment of Integrator at immediate early genes and their enhancers. Following epidermal growth factor (EGF) stimulation, activated ERK1/2 is recruited to immediate early genes and phosphor-ylates INTS11, the catalytic subunit of Integrator. Importantly, in contrast to the broad effects of Integrator knockdown on MAPK responsiveness, depletion of a number of critical subunits of the coactivator complex Mediator alters only a few MAPK-responsive genes. Finally, human cancers with activating mutations in the MAPK cascade, rendered resistant to targeted therapies, display diminished growth following depletion of Integrator. We propose Integrator as a crucial transcriptional coactivator in MAPK signaling, which could serve as a downstream therapeutic target for cancer treatment.
AB - Activating mutations in the mitogen-activated protein kinase (MAPK) cascade, also known as the RAS–MEK–ex-tracellular signal-related kinase (ERK1/2) pathway, are an underlying cause of >70% of human cancers. While great strides have been made toward elucidating the cytoplasmic components of MAPK signaling, the key downstream coactivators that coordinate the transcriptional response have not been fully illustrated. Here, we demonstrate that the MAPK transcriptional response in human cells is funneled through Integrator, an RNA polymerase II-associated complex. Integrator depletion diminishes ERK1/2 transcriptional responsiveness and cellular growth in human cancers harboring activating mutations in MAPK signaling. Pharmacological inhibition of the MAPK pathway abrogates the stimulus-dependent recruitment of Integrator at immediate early genes and their enhancers. Following epidermal growth factor (EGF) stimulation, activated ERK1/2 is recruited to immediate early genes and phosphor-ylates INTS11, the catalytic subunit of Integrator. Importantly, in contrast to the broad effects of Integrator knockdown on MAPK responsiveness, depletion of a number of critical subunits of the coactivator complex Mediator alters only a few MAPK-responsive genes. Finally, human cancers with activating mutations in the MAPK cascade, rendered resistant to targeted therapies, display diminished growth following depletion of Integrator. We propose Integrator as a crucial transcriptional coactivator in MAPK signaling, which could serve as a downstream therapeutic target for cancer treatment.
KW - ERK1/2
KW - Epidermal growth factor
KW - Immediate early genes
KW - Integrator
KW - MAPK signaling pathway
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U2 - 10.1101/gad.301697.117
DO - 10.1101/gad.301697.117
M3 - Article
C2 - 28982763
AN - SCOPUS:85031022412
VL - 31
SP - 1809
EP - 1820
JO - Genes and Development
JF - Genes and Development
SN - 0890-9369
IS - 17
ER -