E2F and Ras synergize in transcriptionally activating p14ARF expression.

Eli Berkovich; Yocheved Lamed; Doron Ginsberg

doi:10.4161/cc.2.2.293

E2F and Ras synergize in transcriptionally activating p14ARF expression.

Eli Berkovich, Yocheved Lamed, Doron Ginsberg

Weizmann Institute of Science

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

33 Scopus citations

Abstract

The INK4a/ARF locus, which is frequently inactivated in human tumors, encodes two distinct tumor suppressive proteins, ARF and p16INK4a. ARF stabilizes and activates p53 by negating the effects of mdm2 on p53. Furthermore, its function is not restricted to the p53 pathway and it also inhibits cell proliferation in cells lacking p53. Expression of ARF is up-regulated in response to a number of oncogenic stimuli including E2F1. We show here that while oncogenic Ras does not significantly affect p1(4AR)F expression in normal human cells it activates p1(4AR)F in cells containing deregulated E2F. Moreover, oncogenic Ras and E2F1 synergize in activating p1(4AR)F expression. Activation of p1(4AR)F promoter by E2F1 persists in the absence of the consensus E2F-binding sites in this promoter, indicating that this activation also occurs through non- canonical binding sites. The activation by oncogenic Ras requires both E2F and Sp-1 activity, demonstrating the complex regulation of p14(ARF) in response to oncogenic stimuli.

Original language	English
Pages (from-to)	127-134
Number of pages	8
Journal	Cell Cycle
Volume	2
Issue number	2
DOIs	https://doi.org/10.4161/cc.2.2.293
State	Published - 2003
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported in part by grants from the Israel Cancer Association (ICA), Minerva Foundation (Germany), the Israel Cancer Research Fund (ICRF) and Yad Abraham Research Center for Diagnostics and Therapy. D.G. is an incumbent of the Recanati Career Development chair of cancer research.

Funding

This work was supported in part by grants from the Israel Cancer Association (ICA), Minerva Foundation (Germany), the Israel Cancer Research Fund (ICRF) and Yad Abraham Research Center for Diagnostics and Therapy. D.G. 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
Minerva Foundation
Israel Cancer Association

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title = "E2F and Ras synergize in transcriptionally activating p14ARF expression.",

abstract = "The INK4a/ARF locus, which is frequently inactivated in human tumors, encodes two distinct tumor suppressive proteins, ARF and p16INK4a. ARF stabilizes and activates p53 by negating the effects of mdm2 on p53. Furthermore, its function is not restricted to the p53 pathway and it also inhibits cell proliferation in cells lacking p53. Expression of ARF is up-regulated in response to a number of oncogenic stimuli including E2F1. We show here that while oncogenic Ras does not significantly affect p1(4AR)F expression in normal human cells it activates p1(4AR)F in cells containing deregulated E2F. Moreover, oncogenic Ras and E2F1 synergize in activating p1(4AR)F expression. Activation of p1(4AR)F promoter by E2F1 persists in the absence of the consensus E2F-binding sites in this promoter, indicating that this activation also occurs through non- canonical binding sites. The activation by oncogenic Ras requires both E2F and Sp-1 activity, demonstrating the complex regulation of p14(ARF) in response to oncogenic stimuli.",

author = "Eli Berkovich and Yocheved Lamed and Doron Ginsberg",

note = "Funding Information: This work was supported in part by grants from the Israel Cancer Association (ICA), Minerva Foundation (Germany), the Israel Cancer Research Fund (ICRF) and Yad Abraham Research Center for Diagnostics and Therapy. D.G. is an incumbent of the Recanati Career Development chair of cancer research.",

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doi = "10.4161/cc.2.2.293",

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AU - Berkovich, Eli

AU - Lamed, Yocheved

AU - Ginsberg, Doron

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PY - 2003

Y1 - 2003

N2 - The INK4a/ARF locus, which is frequently inactivated in human tumors, encodes two distinct tumor suppressive proteins, ARF and p16INK4a. ARF stabilizes and activates p53 by negating the effects of mdm2 on p53. Furthermore, its function is not restricted to the p53 pathway and it also inhibits cell proliferation in cells lacking p53. Expression of ARF is up-regulated in response to a number of oncogenic stimuli including E2F1. We show here that while oncogenic Ras does not significantly affect p1(4AR)F expression in normal human cells it activates p1(4AR)F in cells containing deregulated E2F. Moreover, oncogenic Ras and E2F1 synergize in activating p1(4AR)F expression. Activation of p1(4AR)F promoter by E2F1 persists in the absence of the consensus E2F-binding sites in this promoter, indicating that this activation also occurs through non- canonical binding sites. The activation by oncogenic Ras requires both E2F and Sp-1 activity, demonstrating the complex regulation of p14(ARF) in response to oncogenic stimuli.

AB - The INK4a/ARF locus, which is frequently inactivated in human tumors, encodes two distinct tumor suppressive proteins, ARF and p16INK4a. ARF stabilizes and activates p53 by negating the effects of mdm2 on p53. Furthermore, its function is not restricted to the p53 pathway and it also inhibits cell proliferation in cells lacking p53. Expression of ARF is up-regulated in response to a number of oncogenic stimuli including E2F1. We show here that while oncogenic Ras does not significantly affect p1(4AR)F expression in normal human cells it activates p1(4AR)F in cells containing deregulated E2F. Moreover, oncogenic Ras and E2F1 synergize in activating p1(4AR)F expression. Activation of p1(4AR)F promoter by E2F1 persists in the absence of the consensus E2F-binding sites in this promoter, indicating that this activation also occurs through non- canonical binding sites. The activation by oncogenic Ras requires both E2F and Sp-1 activity, demonstrating the complex regulation of p14(ARF) in response to oncogenic stimuli.

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E2F and Ras synergize in transcriptionally activating p14ARF expression.

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