ATM is a target for positive regulation by E2F-1

Eli Berkovich; Doron Ginsberg

doi:10.1038/sj.onc.1206144

ATM is a target for positive regulation by E2F-1

Eli Berkovich, Doron Ginsberg

Weizmann Institute of Science

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

103 Scopus citations

Abstract

The E2F-1 transcription factor is a critical downstream target of the tumor suppressor, RB. When activated, E2F-1 induces cell proliferation. In addition, deregulation of E2F-1 constitutes an oncogenic stress that can induce apoptosis. The protein kinase ATM is a pivotal mediator of the response to another type of stress, genotoxic stress. In response to ionizing radiation, ATM activates the tumor suppressor p53, a key player in the control of cell growth and viability. We show here that E2F-1 elevates ATM promoter activity and induces an increase in ATM mRNA and protein levels. This is accompanied by an E2F-induced increase in p53 phosphorylation. Expression of the E7 protein of HPV16, which dissociates RB/E2F complexes, also induces the elevation of ATM levels and p53 phosphorylation, implicating endogenous E2F in these phenomena. These data demonstrate that ATM is transcriptionally regulated by E2F-1 and suggest that ATM serves as a novel, ARF-independent functional link between the RB/E2F pathway and p53.

Original language	English
Pages (from-to)	161-167
Number of pages	7
Journal	Oncogene
Volume	22
Issue number	2
DOIs	https://doi.org/10.1038/sj.onc.1206144
State	Published - 16 Jan 2003
Externally published	Yes

Bibliographical note

Funding Information:
We thank Dr Moshe Oren for pBABE-E7 and pBABE-E7D (21–35) and anti-p53 antibodies, Dr Yossi Shiloh for anti-ATM antibodies, Dr Kristian Helin for pBABE-HA-ER-E2F-1 and Dr Reuven Agami for pRetroSuper-p53siRNA. We are indebted to Drs Shiloh and Oren for discussions and a critical reading of this manuscript. This study was supported by the Israel Cancer Research Fund (ICRF) and Yad Abraham Research Center for Diagnostics and Therapy. DG is an incumbent of the Recanati Career Development chair of cancer research.

Funding

We thank Dr Moshe Oren for pBABE-E7 and pBABE-E7D (21–35) and anti-p53 antibodies, Dr Yossi Shiloh for anti-ATM antibodies, Dr Kristian Helin for pBABE-HA-ER-E2F-1 and Dr Reuven Agami for pRetroSuper-p53siRNA. We are indebted to Drs Shiloh and Oren for discussions and a critical reading of this manuscript. This study was supported by the Israel Cancer Research Fund (ICRF) and Yad Abraham Research Center for Diagnostics and Therapy. DG is an incumbent of the Recanati Career Development chair of cancer research.

Funders	Funder number
Yad Abraham Research Center for Diagnostics and Therapy
Israel Cancer Research Fund

Keywords

ATM
E2F
Oncogenic stress

UN SDGs

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

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10.1038/sj.onc.1206144

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abstract = "The E2F-1 transcription factor is a critical downstream target of the tumor suppressor, RB. When activated, E2F-1 induces cell proliferation. In addition, deregulation of E2F-1 constitutes an oncogenic stress that can induce apoptosis. The protein kinase ATM is a pivotal mediator of the response to another type of stress, genotoxic stress. In response to ionizing radiation, ATM activates the tumor suppressor p53, a key player in the control of cell growth and viability. We show here that E2F-1 elevates ATM promoter activity and induces an increase in ATM mRNA and protein levels. This is accompanied by an E2F-induced increase in p53 phosphorylation. Expression of the E7 protein of HPV16, which dissociates RB/E2F complexes, also induces the elevation of ATM levels and p53 phosphorylation, implicating endogenous E2F in these phenomena. These data demonstrate that ATM is transcriptionally regulated by E2F-1 and suggest that ATM serves as a novel, ARF-independent functional link between the RB/E2F pathway and p53.",

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N2 - The E2F-1 transcription factor is a critical downstream target of the tumor suppressor, RB. When activated, E2F-1 induces cell proliferation. In addition, deregulation of E2F-1 constitutes an oncogenic stress that can induce apoptosis. The protein kinase ATM is a pivotal mediator of the response to another type of stress, genotoxic stress. In response to ionizing radiation, ATM activates the tumor suppressor p53, a key player in the control of cell growth and viability. We show here that E2F-1 elevates ATM promoter activity and induces an increase in ATM mRNA and protein levels. This is accompanied by an E2F-induced increase in p53 phosphorylation. Expression of the E7 protein of HPV16, which dissociates RB/E2F complexes, also induces the elevation of ATM levels and p53 phosphorylation, implicating endogenous E2F in these phenomena. These data demonstrate that ATM is transcriptionally regulated by E2F-1 and suggest that ATM serves as a novel, ARF-independent functional link between the RB/E2F pathway and p53.

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ATM is a target for positive regulation by E2F-1

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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