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p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells

p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells
p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells
The negative-regulatory feedback loop between p53 and hdm2 forms part of a finely balanced regulatory network of proteins that controls cell cycle progression and commitment to apoptosis. Expression of hdm2, and its mouse orthologue mdm2, is known to be induced by p53, but recent evidence has demonstrated mdm2 expression can also be regulated via p53-independent pathways. However the p53 independent mechanisms that control transcription of the human hdm2 gene have not been studied.

Differential levels of hdm2 mRNA and protein expression have been reported in several types of human malignancy, including breast cancers in which hdm2 expression correlates with positive estrogen receptor {alpha} (ER{alpha}) status. Experimental models have demonstrated that hdm2 overexpression can promote breast cancer development. Here, we show that the elevated level of hdm2 protein in ER{alpha}+ve breast cancer cell lines such as MCF-7 and T47D is because of transcription from the p53-inducible P2 promoter of hdm2.

The P2 promoter is inactive in ER{alpha}-ve cell lines such as SKBr3. Hdm2-P2 promoter activity in T47D cells is independent of p53, as well as of known regulators of the mouse mdm2-P2 promoter, including ER{alpha} and ras-raf-mitogen-activated protein/extracellular signal-regulated kinase (MEK) mitogen-activated protein kinase (MAPK) signaling. We show that hdm2-P2 activity in T47D cells is dependent on the integrity of both an evolutionarily conserved composite binding site for AP1 and ETS family transcription factors (AP1-ETS) and a nonconserved upstream (nnGGGGC)5 repeat sequence.

Lack of hdm2-P2 activity in ER{alpha}-ve cells is shown to be a consequence of reduced transcriptional activation through the AP1-ETS element. Overexpression of ETS2 in SKBr3 cells reconstitutes AP1-ETS element-dependent hdm2-P2 promoter activity, resulting in increased levels of hdm2 protein in the cells. Our findings support the hypothesis that the elevated levels of hdm2 expression reported in cancers such as ER{alpha}+ve breast tumors play an important role in the development of these tumors.
0008-5472
2616-2623
Phelps, Monika
d10e3367-3e1d-46f4-8fb9-577d7c6de35b
Darley, Matthew
7be23780-a781-4dd4-a74c-f5affbb79521
Primrose, John N.
d85f3b28-24c6-475f-955b-ec457a3f9185
Blaydes, Jeremy P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Phelps, Monika
d10e3367-3e1d-46f4-8fb9-577d7c6de35b
Darley, Matthew
7be23780-a781-4dd4-a74c-f5affbb79521
Primrose, John N.
d85f3b28-24c6-475f-955b-ec457a3f9185
Blaydes, Jeremy P.
e957f999-fd91-4f77-ad62-5b4ef069b15b

Phelps, Monika, Darley, Matthew, Primrose, John N. and Blaydes, Jeremy P. (2003) p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells. Cancer Research, 63 (10), 2616-2623.

Record type: Article

Abstract

The negative-regulatory feedback loop between p53 and hdm2 forms part of a finely balanced regulatory network of proteins that controls cell cycle progression and commitment to apoptosis. Expression of hdm2, and its mouse orthologue mdm2, is known to be induced by p53, but recent evidence has demonstrated mdm2 expression can also be regulated via p53-independent pathways. However the p53 independent mechanisms that control transcription of the human hdm2 gene have not been studied.

Differential levels of hdm2 mRNA and protein expression have been reported in several types of human malignancy, including breast cancers in which hdm2 expression correlates with positive estrogen receptor {alpha} (ER{alpha}) status. Experimental models have demonstrated that hdm2 overexpression can promote breast cancer development. Here, we show that the elevated level of hdm2 protein in ER{alpha}+ve breast cancer cell lines such as MCF-7 and T47D is because of transcription from the p53-inducible P2 promoter of hdm2.

The P2 promoter is inactive in ER{alpha}-ve cell lines such as SKBr3. Hdm2-P2 promoter activity in T47D cells is independent of p53, as well as of known regulators of the mouse mdm2-P2 promoter, including ER{alpha} and ras-raf-mitogen-activated protein/extracellular signal-regulated kinase (MEK) mitogen-activated protein kinase (MAPK) signaling. We show that hdm2-P2 activity in T47D cells is dependent on the integrity of both an evolutionarily conserved composite binding site for AP1 and ETS family transcription factors (AP1-ETS) and a nonconserved upstream (nnGGGGC)5 repeat sequence.

Lack of hdm2-P2 activity in ER{alpha}-ve cells is shown to be a consequence of reduced transcriptional activation through the AP1-ETS element. Overexpression of ETS2 in SKBr3 cells reconstitutes AP1-ETS element-dependent hdm2-P2 promoter activity, resulting in increased levels of hdm2 protein in the cells. Our findings support the hypothesis that the elevated levels of hdm2 expression reported in cancers such as ER{alpha}+ve breast tumors play an important role in the development of these tumors.

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Published date: 2003

Identifiers

Local EPrints ID: 26522
URI: http://eprints.soton.ac.uk/id/eprint/26522
ISSN: 0008-5472
PURE UUID: fb3d61f0-1a44-426a-9c21-641b604bc686
ORCID for John N. Primrose: ORCID iD orcid.org/0000-0002-2069-7605
ORCID for Jeremy P. Blaydes: ORCID iD orcid.org/0000-0001-8525-0209

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Date deposited: 19 Apr 2006
Last modified: 16 Mar 2024 03:18

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Contributors

Author: Monika Phelps
Author: Matthew Darley

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