4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in Tumors

Qing Bai She; Ensar Halilovic; Qing Ye; Wei Zhen; Senji Shirasawa; Takehiko Sasazuki; David B. Solit; Neal Rosen

doi:10.1016/j.ccr.2010.05.023

4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in Tumors

Qing Bai She, Ensar Halilovic, Qing Ye, Wei Zhen, Senji Shirasawa, Takehiko Sasazuki, David B. Solit, Neal Rosen

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

355 Scopus citations

Abstract

PIK3CA and PTEN alterations are common in human cancer, but only a fraction of such tumors are dependent upon AKT signaling. AKT independence is associated with redundant activation of cap-dependent translation mediated by convergent regulation of the translational repressor 4E-BP1 by the AKT and ERK pathways. This provides mechanistic bases for the limited activity of AKT and MEK inhibitors in tumors with comutation of both pathways and the profound synergy observed with combined inhibition. Whereas such tumors are sensitive to a dominant active 4E-BP1 mutant, knockdown of 4E-BP1 expression reduces their dependence on AKT/ERK signaling for translation or survival. Thus, 4E-BP1 plays a prominent role in mediating the effects of these pathways in tumors in which they are activated by mutation.

Original language	English
Pages (from-to)	39-51
Number of pages	13
Journal	Cancer Cell
Volume	18
Issue number	1
DOIs	https://doi.org/10.1016/j.ccr.2010.05.023
State	Published - Jul 2010

Bibliographical note

Funding Information:
We thank N. Sonenberg for providing 4E-BP1 constructs, H.G. Wendel for the eIF4E construct, B. Vogelstein and V.E. Velculescu for providing the HCT116 and DLD-1 isogenic cell lines, and E. DeStanchina, H. Zhao, and D. Domingo for technical assistance. This work was supported by NIH Grants P01-CA094060 and P01-CA129243, the Breast Cancer Research Foundation, the Taub Foundation, and the William H. and Alice Goodwin Foundation.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccr.2010.05.023

Cite this

@article{384c555c113a4bc7ba321b3297fdfb5c,

title = "4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in Tumors",

abstract = "PIK3CA and PTEN alterations are common in human cancer, but only a fraction of such tumors are dependent upon AKT signaling. AKT independence is associated with redundant activation of cap-dependent translation mediated by convergent regulation of the translational repressor 4E-BP1 by the AKT and ERK pathways. This provides mechanistic bases for the limited activity of AKT and MEK inhibitors in tumors with comutation of both pathways and the profound synergy observed with combined inhibition. Whereas such tumors are sensitive to a dominant active 4E-BP1 mutant, knockdown of 4E-BP1 expression reduces their dependence on AKT/ERK signaling for translation or survival. Thus, 4E-BP1 plays a prominent role in mediating the effects of these pathways in tumors in which they are activated by mutation.",

author = "She, {Qing Bai} and Ensar Halilovic and Qing Ye and Wei Zhen and Senji Shirasawa and Takehiko Sasazuki and Solit, {David B.} and Neal Rosen",

note = "Funding Information: We thank N. Sonenberg for providing 4E-BP1 constructs, H.G. Wendel for the eIF4E construct, B. Vogelstein and V.E. Velculescu for providing the HCT116 and DLD-1 isogenic cell lines, and E. DeStanchina, H. Zhao, and D. Domingo for technical assistance. This work was supported by NIH Grants P01-CA094060 and P01-CA129243, the Breast Cancer Research Foundation, the Taub Foundation, and the William H. and Alice Goodwin Foundation. ",

year = "2010",

month = jul,

doi = "10.1016/j.ccr.2010.05.023",

language = "English",

volume = "18",

pages = "39--51",

number = "1",

}

TY - JOUR

T1 - 4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in Tumors

AU - She, Qing Bai

AU - Halilovic, Ensar

AU - Ye, Qing

AU - Zhen, Wei

AU - Shirasawa, Senji

AU - Sasazuki, Takehiko

AU - Solit, David B.

AU - Rosen, Neal

N1 - Funding Information: We thank N. Sonenberg for providing 4E-BP1 constructs, H.G. Wendel for the eIF4E construct, B. Vogelstein and V.E. Velculescu for providing the HCT116 and DLD-1 isogenic cell lines, and E. DeStanchina, H. Zhao, and D. Domingo for technical assistance. This work was supported by NIH Grants P01-CA094060 and P01-CA129243, the Breast Cancer Research Foundation, the Taub Foundation, and the William H. and Alice Goodwin Foundation.

PY - 2010/7

Y1 - 2010/7

N2 - PIK3CA and PTEN alterations are common in human cancer, but only a fraction of such tumors are dependent upon AKT signaling. AKT independence is associated with redundant activation of cap-dependent translation mediated by convergent regulation of the translational repressor 4E-BP1 by the AKT and ERK pathways. This provides mechanistic bases for the limited activity of AKT and MEK inhibitors in tumors with comutation of both pathways and the profound synergy observed with combined inhibition. Whereas such tumors are sensitive to a dominant active 4E-BP1 mutant, knockdown of 4E-BP1 expression reduces their dependence on AKT/ERK signaling for translation or survival. Thus, 4E-BP1 plays a prominent role in mediating the effects of these pathways in tumors in which they are activated by mutation.

AB - PIK3CA and PTEN alterations are common in human cancer, but only a fraction of such tumors are dependent upon AKT signaling. AKT independence is associated with redundant activation of cap-dependent translation mediated by convergent regulation of the translational repressor 4E-BP1 by the AKT and ERK pathways. This provides mechanistic bases for the limited activity of AKT and MEK inhibitors in tumors with comutation of both pathways and the profound synergy observed with combined inhibition. Whereas such tumors are sensitive to a dominant active 4E-BP1 mutant, knockdown of 4E-BP1 expression reduces their dependence on AKT/ERK signaling for translation or survival. Thus, 4E-BP1 plays a prominent role in mediating the effects of these pathways in tumors in which they are activated by mutation.

UR - http://www.scopus.com/inward/record.url?scp=77954296394&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954296394&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2010.05.023

DO - 10.1016/j.ccr.2010.05.023

M3 - Article

C2 - 20609351

AN - SCOPUS:77954296394

SN - 1535-6108

VL - 18

SP - 39

EP - 51

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in Tumors

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this