To identify Egr-1 target genes important in pulmonary disease

Institution:	The Burnham Institute for Medical Research
Investigator(s):	Ian de Belle, Ph.D.
Award Cycle:	2000 (Cycle 9)	Grant #: 9KT-0078	Award: $430,539
Subject Area:	Pulmonary Disease
Award Type:	New Investigator Awards

Abstracts

Initial Award Abstract

Inhalation of smoke into the lung causes a multiplicity of effects on the cells of the lung, all of which can be considered toxic or stressful in nature. These initial toxic stresses to the cells of the lung are the first stages in the development of a variety of tobacco related diseases including fibrosis, atherosclerosis and lung cancer. Of critical importance is understanding exactly how these stresses are translated into tobacco related diseases, in order to develop effective diagnostic and therapeutic strategies. Although the complete understanding of this question remains elusive, what is known is that some of the first responses of lung cells to the stresses, imparted as a result of smoke inhalation, occur in the nucleus of the cell where changes in gene activity are seen. In many cases these changes consist of either overactivity or underactivity of certain genes. While the exact number and complete nature of these changes is not known, we do know that a specialized class of important proteins, called transcription factors, are the controllers of these changes. We are studying one of these transcription factors, called Egr-1, which is remarkably sensitive to many stresses imposed on cells including those generated by smoking. Furthermore, studies have shown a striking correlation between the role of Egr-1 in controlling gene activity, and the development of numerous lung diseases. Since Egr-1 is a transcription factor, it works by changing the activity of those genes it associates with. It is clear that in order to understand how Egr-1 contributes to diseases of the lung, we must identify the genes whose activity it influences, and this proposal is directly aimed at obtaining this exact type of knowledge.

We have recently developed a technique which allows, for the first time, a detailed analysis of the position of transcription factor binding on DNA by chemically “locking” the protein in position in living cells. Using antibodies we can then purify Egr-1 together with chemically attached DNA. We propose to exploit this methodology to describe the exact complement of genes to which Egr-1 is bound in the nucleus of a living cell. The new method will generate “libraries” of previously unknown as well as known genes that are controlled by Egr-1 in the lung. This selection of genes will represent those in the human genome that are important in stress responses occurring in lung cells as they develop disease states. To begin developing newer and more effective treatments for tobacco related diseases, it is critical to have a more complete knowledge of the key genetic events that take place when lung cells are placed under stressful conditions.

Publications

The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling.
Periodical: Nature Cell Biology			Index Medicus:
Authors: Virolle T, Adamson ED, Baron V, Birle D, Mercola D, Mustelin T, and de Belle I				ART
Yr: 2001	Vol:	Nbr:	Abs:	Pg:

In vivo cloning and characterization of a new growth suppressor protein TOE1 as a direct target gene of Egr-1
Periodical: Journal of Biological Chemistry			Index Medicus:
Authors: de Belle I, Wu J-X, Sperandio S, Mercola D, Adamson ED				ART
Yr: 2003	Vol: 278	Nbr:	Abs:	Pg: 14306-14312

PTEN is directly transactivated in vivo by Egr-1 during irradiation-induced signalling.
Periodical: Nature Cell Biology			Index Medicus:
Authors: Virolle T, Adamson ED, de Belle I, Baron D, Birle D, Mercola T,				ART
Yr: 2001	Vol: 3	Nbr:	Abs:	Pg: 1124 - 1128

Egrl signaling in prostate cancer.
Periodical: Cancer Biology and Therapy			Index Medicus:
Authors: Adamson ED, de Belle I, Mittal S, Wang Y, Hayakawa K et al				ART
Yr: 2003	Vol: 2	Nbr:	Abs:	Pg: 610 - 616

Co-activating factors p300 and CBP and transcriptionally cross-regulated by Egrl in prostate cells, leading to divergent responses.
Periodical: Molecular Cell			Index Medicus:
Authors: Yu J, de Belle I, Liang H, Adamson ED				ART
Yr: 2004	Vol: 15	Nbr:	Abs:	Pg: 83 - 94

The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling.
Periodical: Nature Cell Biology			Index Medicus:
Authors: Virolle T, Adamson ED, Baron V, Birle D, Mercola D, Mustelin T, and de Belle I				ART
Yr: 2001	Vol:	Nbr:	Abs:	Pg:

In vivo cloning and characterization of a new growth suppressor protein TOE1 as a direct target gene of Egr-1
Periodical: Journal of Biological Chemistry			Index Medicus:
Authors: de Belle I, Wu J-X, Sperandio S, Mercola D, Adamson ED				ART
Yr: 2003	Vol: 278	Nbr:	Abs:	Pg: 14306-14312

PTEN is directly transactivated in vivo by Egr-1 during irradiation-induced signalling.
Periodical: Nature Cell Biology			Index Medicus:
Authors: Virolle T, Adamson ED, de Belle I, Baron D, Birle D, Mercola T,				ART
Yr: 2001	Vol: 3	Nbr:	Abs:	Pg: 1124 - 1128

Egrl signaling in prostate cancer.
Periodical: Cancer Biology and Therapy			Index Medicus:
Authors: Adamson ED, de Belle I, Mittal S, Wang Y, Hayakawa K et al				ART
Yr: 2003	Vol: 2	Nbr:	Abs:	Pg: 610 - 616

Co-activating factors p300 and CBP and transcriptionally cross-regulated by Egrl in prostate cells, leading to divergent responses.
Periodical: Molecular Cell			Index Medicus:
Authors: Yu J, de Belle I, Liang H, Adamson ED				ART
Yr: 2004	Vol: 15	Nbr:	Abs:	Pg: 83 - 94