Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma

Verline Justilien; Syed A. Ali; Lee Jamieson; Ning Yin; Adrienne D. Cox; Channing J. Der; Nicole R. Murray; Alan P. Fields

doi:10.1016/j.ccell.2016.12.010

Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma

Verline Justilien, Syed A. Ali, Lee Jamieson, Ning Yin, Adrienne D. Cox, Channing J. Der, Nicole R. Murray, Alan P. Fields

Cancer Biology

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

Abstract

The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor upstream binding factor 1 (UBF1) on rDNA promoters and recruiting Rac1 and its downstream effector nucleophosmin (NPM) to rDNA. Protein kinase Cι (PKCι)-mediated Ect2 phosphorylation stimulates Ect2-dependent rDNA transcription. Thus, Ect2 regulates rRNA synthesis through a PKCι-Ect2-Rac1-NPM signaling axis that is required for lung tumorigenesis.

Original language	English (US)
Pages (from-to)	256-269
Number of pages	14
Journal	Cancer cell
Volume	31
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2016.12.010
State	Published - Feb 13 2017

Keywords

Ect2
nucleophosmin, NPM
protein kinase Cι, PKCι
rRNA synthesis
tumor initiation
upstream binding factor 1, UBF1

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccell.2016.12.010

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title = "Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma",

abstract = "The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor upstream binding factor 1 (UBF1) on rDNA promoters and recruiting Rac1 and its downstream effector nucleophosmin (NPM) to rDNA. Protein kinase Cι (PKCι)-mediated Ect2 phosphorylation stimulates Ect2-dependent rDNA transcription. Thus, Ect2 regulates rRNA synthesis through a PKCι-Ect2-Rac1-NPM signaling axis that is required for lung tumorigenesis.",

keywords = "Ect2, nucleophosmin, NPM, protein kinase Cι, PKCι, rRNA synthesis, tumor initiation, upstream binding factor 1, UBF1",

author = "Verline Justilien and Ali, {Syed A.} and Lee Jamieson and Ning Yin and Cox, {Adrienne D.} and Der, {Channing J.} and Murray, {Nicole R.} and Fields, {Alan P.}",

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year = "2017",

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AU - Justilien, Verline

AU - Ali, Syed A.

AU - Jamieson, Lee

AU - Yin, Ning

AU - Cox, Adrienne D.

AU - Der, Channing J.

AU - Murray, Nicole R.

AU - Fields, Alan P.

PY - 2017/2/13

Y1 - 2017/2/13

N2 - The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor upstream binding factor 1 (UBF1) on rDNA promoters and recruiting Rac1 and its downstream effector nucleophosmin (NPM) to rDNA. Protein kinase Cι (PKCι)-mediated Ect2 phosphorylation stimulates Ect2-dependent rDNA transcription. Thus, Ect2 regulates rRNA synthesis through a PKCι-Ect2-Rac1-NPM signaling axis that is required for lung tumorigenesis.

AB - The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor upstream binding factor 1 (UBF1) on rDNA promoters and recruiting Rac1 and its downstream effector nucleophosmin (NPM) to rDNA. Protein kinase Cι (PKCι)-mediated Ect2 phosphorylation stimulates Ect2-dependent rDNA transcription. Thus, Ect2 regulates rRNA synthesis through a PKCι-Ect2-Rac1-NPM signaling axis that is required for lung tumorigenesis.

KW - Ect2

KW - nucleophosmin, NPM

KW - protein kinase Cι, PKCι

KW - rRNA synthesis

KW - tumor initiation

KW - upstream binding factor 1, UBF1

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Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma

Abstract

Keywords

ASJC Scopus subject areas

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