University of Rochester Medical Center: Department of Environmental Medicine: EHSC

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Research Programs:

Pulmonary and Cardiovascular Diseases
Neurodevelopment and Neurodegenerative Diesases
Musculoskeletal Diseases

This Web site is supported in part by a grant from the National Institute of Environmental Health Sciences (P30 ES01247).

Thomas A. Gasiewicz
Professor and Chair, Department of Environmental Medicine
B.A. 1972 Canisius College
Ph.D. 1977 University of Rochester
E-Mail: Tom_Gasiewicz@urmc.rochester.edu

Jump to:
Projects in the Lab
Potential for Collaboration
Selected Publications

Receptor-mediated Modulation of Gene Expression and Association with Biological and Toxic Responses

While genetics is known to influence the initiation, progression, and outcome of a variety of human diseases including cancer, it is clear that these are also influenced to a great extent by a number of other factors. These include, for example, exposure to chemicals in the environment, diet and aging.

The overall goal of the research in this laboratory is to determine how certain chemicals and substances in the diet influence, in both a positive and negative manner, the processes that influence the progression and outcomes of disease.
By understanding the molecular mechanisms by which these factors act, we will also be providing information that can be used in the design of tools for more effective diagnosis and treatment of these diseases.

PROJECTS IN THE LAB

The laboratory has two primary areas of ongoing research, both of which focus on the aryl hydrocarbon receptor’s role in human disease. The AhR receptor belongs to a family of transcription factors that are involved in regulating tissue development and cellular differentiation. While the true physiological function of the AhR receptor is not known, activation of AhR by environmental toxins such as dioxins and polycyclic aromatic hydrocarbons (PAH) leads to several adverse effects in humans including cancer.

Role of AhR in hematopoiesis and hematopoietic disease

Our laboratory has demonstrated that persistent activation of AhR by dioxin results in altered numbers and functions of hematopoietic stem cells (HSCs) in mouse bone marrow. Combined with data showing that a lack of AhR function also results in altered HSC characteristics and hematopoietic diseases (such as leukemia), our findings strongly suggest that a normal role for AhR may be to regulate HSC’s. The lab is currently studying this connection as well as how changing AhR regulation and function leads to hematopoietic diseases.

Ongoing Questions for the Lab:

Are HSC's direct targets of AhR activation?

How does loss of AhR affect HSC function?

What is the molecular basis for altered HSC characteristics and function following AhR dysregulation

Is the down regulation of the AhR necessary for the normal proliferation of HSC's?

How does the AhR regulate normal HSC function?

Selected reading (For more publications, see below):
Singh, et al 2009. Treatment of mice with the Ah receptor agonist and human carcinogen dioxin results in altered numbers and function of hematopoietic stem cells. Carcinogenesis. Jan;30(1):11-9. Epub 2008 Sep 26.

Interactions of EGCG and Hsp90 in oncogenesis

Several epidemiological studies and clinical trials have shown the effectiveness of green tea (GT) extract for the prevention of UV-induced skin injuries, oxidative DNA damage, as well as prostate cancer. Epigallocatechin-3-gallate (EGCG), a major antioxidant in GT, has been suggested to target several biomedically relevant molecules and disease-related cellular processes. However, the precise molecular and cellular mechanisms by which EGCG acts to modulate tumor growth have yet to be determined.

Through our work on the AhR, we have made the novel discovery that EGCG inhibits the function of the chaperone 90 kD heat shock protein (hsp90). This chaperone protein is known to regulate the activity of the AhR and a number of other transcription factors and proteins many of which are involved in oncogenic processes. Our laboratory is studying the chemical and structural basis by which EGCG and similar molecules affect hsp90, and have a potential anti-tumorigenic effect.

A) B)

A) When not bound to a ligand, AhR is present in the cytoplasm associated with two molecules of hsp90, as well as other proteins (not shown in the diagrams above). Ligand binding initiates a cascade of events, including AhR translocation to the nucleus, release of hsp90, and dimerization with the AhR nuclear translocator (Arnt). The ligand bound AhR-Arnt complex recognize and bind to the AhR-response elements (ARE) located in the promoter region of responsive genes, and affect the transcription of those genes.

B) Unlike many other AhR antagonists that interact directly with the AhR, EGCG appears to block AhR-mediated transcription by binding to hsp90 and preventing dissociation and subsequent DNA binding in the nucleus.

Ongoing Questions for the Lab:

What is the specific binding site for EGCG on hsp90 and how does EGCG binding result in changes in hsp90 conformation and function?

Does EGCG affect the levels and/or activity of particular hsp90 client proteins?

Do other catechins/flavonoids like EGCG inhibit hsp90 activity in a similar manner as EGCG and what is the structure-activity relationships for these interactions?

How is prostatic carcinogenesis affected by EGCG?

Does EGCG alter the level and/or function of hsp90 client proteins at a sensitive stage of prostate cancer development?

Selected reading (For more publications, see below):
Yin Z, Henry EC, Gasiewicz TA. (-)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor. Biochemistry. 2009 Jan 20;48(2):336-345.

POTENTIAL FOR COLLABORATION

Regulation of HSC and Hematopoietic Cancers:

Presently, our work is being performed in collaboration with several groups whose work is focused on the regulation of HSC's and their role in several hematopoietic cancers, including leukemia. We hope to be able to link alterations of AhR function with the initiation and progression of human hematopoietic disease. We are also interested in working with groups that focus on other stem cell populations, including skin and nervous system, as we hypothesize that AhR may have an important role in regulating other stem cell populations.

Proteomics:

Our work on hsp90 is being done in collaboration with investigators who have expertise in proteomics to define other hsp90 client proteins whose activity may be altered by EGCG. In addition, we are working with groups focused on developing models of prostate cancer and examining molecular mechanisms by which potential therapeutic agents may have potent anti-cancer activity.

SELECTED PUBLICATIONS

Yin Z, Henry EC, Gasiewicz TA. (-)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor. Biochemistry. 2009 Jan 20;48(2):336-345.

Singh KP, Casado FL, Opanashuk LA, Gasiewicz TA. The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations. Biochem Pharmacol. 2009 Feb 15;77(4):577-587.

Singh KP, Wyman A, Casado FL, Garrett RW, Gasiewicz TA. Treatment of mice with the Ah receptor agonist and human carcinogen dioxin results in altered numbers and function of hematopoietic stem cells. Carcinogenesis. 2009 Jan;30(1):11-19.

Vezina CM, Allgeier SH, Moore RW, Lin TM, Bemis JC, Hardin HA, Gasiewicz TA, Peterson RE. Dioxin causes ventral prostate agenesis by disrupting dorsoventral patterning in developing mouse prostate. Toxicol Sci. 2008 Dec;106(2):488-496.

Baglole CJ, Maggirwar SB, Gasiewicz TA, Thatcher TH, Phipps RP, Sime PJ. The aryl hydrocarbon receptor attenuates tobacco smoke-induced cyclooxygenase-2 and prostaglandin production in lung fibroblasts through regulation of the NF-kappaB family member RelB. J Biol Chem. 2008 Oct 24;283(43):28944-28957.

Henry EC, Gasiewicz TA. Molecular determinants of species-specific agonist and antagonist activity of a substituted flavone towards the aryl hydrocarbon receptor. Arch Biochem Biophys. 2008 Apr 15;472(2):77-88.

Collins LL, Williamson MA, Thompson BD, Dever DP, Gasiewicz TA, Opanashuk LA. 2,3,7,8-Tetracholorodibenzo-p-dioxin exposure disrupts granule neuron precursor maturation in the developing mouse cerebellum. Toxicol Sci. 2008 May;103(1):125-136

Ryan EP, Holz JD, Mulcahey M, Sheu TJ, Gasiewicz TA, Puzas JE. Environmental toxicants may modulate osteoblast differentiation by a mechanism involving the aryl hydrocarbon receptor. J Bone Miner Res. 2007 Oct;22(10):1571-1580.

Thatcher TH, Maggirwar SB, Baglole CJ, Lakatos HF, Gasiewicz TA, Phipps RP, Sime PJ. Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kappaB component RelB. Am J Pathol. 2007 Mar;170(3):855-864.

Bemis JC, Alejandro NF, Nazarenko DA, Brooks AI, Baggs RB, Gasiewicz TA. TCDD-induced alterations in gene expression profiles of the developing mouse paw do not influence morphological differentiation of this potential target tissue. Toxicol Sci. 2007 Jan;95(1):240-248.

Garrett RW, Gasiewicz TA. 2006. The aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin alters the circadian rhythms, quiescence, and expression of clock genes in murine hematopoietic stem and progenitor cells. Mol Pharmacol. Jun;69(6):2076-2083

Henry EC, Bemis JC, Henry O, Kende AS, Gasiewicz TA. 2006. A potential endogenous ligand for the aryl hydrocarbon receptor has potent agonist activity in vitro and in vivo. Arch Biochem Biophys. Jun 1;450(1):67-77.

Kim SH, Henry EC, Kim DK, Kim YH, Shin KJ, Han MS, Lee TG, Kang JK, Gasiewicz TA, Ryu SH, Suh PG. 2006. Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol Pharmacol. Jun;69(6):1871-1878.

Contact Us EHSC Calendar of Events Alphabetical list of Faculty

Copyright 2009 University of Rochester Medical Center, Dept of Environmental Medicine.
Revised August 20 2009 (vgl/gbi)

PROJECTS IN THE LAB

The laboratory has two primary areas of ongoing research, both of which focus on the aryl hydrocarbon receptor’s role in human disease. The AhR receptor belongs to a family of transcription factors that are involved in regulating tissue development and cellular differentiation. While the true physiological function of the AhR receptor is not known, activation of AhR by environmental toxins such as dioxins and polycyclic aromatic hydrocarbons (PAH) leads to several adverse effects in humans including cancer.
Role of AhR in hematopoiesis and hematopoietic disease Our laboratory has demonstrated that persistent activation of AhR by dioxin results in altered numbers and functions of hematopoietic stem cells (HSCs) in mouse bone marrow. Combined with data showing that a lack of AhR function also results in altered HSC characteristics and hematopoietic diseases (such as leukemia), our findings strongly suggest that a normal role for AhR may be to regulate HSC’s. The lab is currently studying this connection as well as how changing AhR regulation and function leads to hematopoietic diseases.
	Ongoing Questions for the Lab: Are HSC's direct targets of AhR activation? How does loss of AhR affect HSC function? What is the molecular basis for altered HSC characteristics and function following AhR dysregulation Is the down regulation of the AhR necessary for the normal proliferation of HSC's? How does the AhR regulate normal HSC function?
Selected reading (For more publications, see below): Singh, et al 2009. Treatment of mice with the Ah receptor agonist and human carcinogen dioxin results in altered numbers and function of hematopoietic stem cells. Carcinogenesis. Jan;30(1):11-9. Epub 2008 Sep 26.
Interactions of EGCG and Hsp90 in oncogenesis Several epidemiological studies and clinical trials have shown the effectiveness of green tea (GT) extract for the prevention of UV-induced skin injuries, oxidative DNA damage, as well as prostate cancer. Epigallocatechin-3-gallate (EGCG), a major antioxidant in GT, has been suggested to target several biomedically relevant molecules and disease-related cellular processes. However, the precise molecular and cellular mechanisms by which EGCG acts to modulate tumor growth have yet to be determined. Through our work on the AhR, we have made the novel discovery that EGCG inhibits the function of the chaperone 90 kD heat shock protein (hsp90). This chaperone protein is known to regulate the activity of the AhR and a number of other transcription factors and proteins many of which are involved in oncogenic processes. Our laboratory is studying the chemical and structural basis by which EGCG and similar molecules affect hsp90, and have a potential anti-tumorigenic effect.
A)	B)
A) When not bound to a ligand, AhR is present in the cytoplasm associated with two molecules of hsp90, as well as other proteins (not shown in the diagrams above). Ligand binding initiates a cascade of events, including AhR translocation to the nucleus, release of hsp90, and dimerization with the AhR nuclear translocator (Arnt). The ligand bound AhR-Arnt complex recognize and bind to the AhR-response elements (ARE) located in the promoter region of responsive genes, and affect the transcription of those genes. B) Unlike many other AhR antagonists that interact directly with the AhR, EGCG appears to block AhR-mediated transcription by binding to hsp90 and preventing dissociation and subsequent DNA binding in the nucleus.
Ongoing Questions for the Lab: What is the specific binding site for EGCG on hsp90 and how does EGCG binding result in changes in hsp90 conformation and function? Does EGCG affect the levels and/or activity of particular hsp90 client proteins? Do other catechins/flavonoids like EGCG inhibit hsp90 activity in a similar manner as EGCG and what is the structure-activity relationships for these interactions? How is prostatic carcinogenesis affected by EGCG? Does EGCG alter the level and/or function of hsp90 client proteins at a sensitive stage of prostate cancer development?
Selected reading (For more publications, see below): Yin Z, Henry EC, Gasiewicz TA. (-)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor. Biochemistry. 2009 Jan 20;48(2):336-345.

POTENTIAL FOR COLLABORATION

	Regulation of HSC and Hematopoietic Cancers: Presently, our work is being performed in collaboration with several groups whose work is focused on the regulation of HSC's and their role in several hematopoietic cancers, including leukemia. We hope to be able to link alterations of AhR function with the initiation and progression of human hematopoietic disease. We are also interested in working with groups that focus on other stem cell populations, including skin and nervous system, as we hypothesize that AhR may have an important role in regulating other stem cell populations.
Proteomics: Our work on hsp90 is being done in collaboration with investigators who have expertise in proteomics to define other hsp90 client proteins whose activity may be altered by EGCG. In addition, we are working with groups focused on developing models of prostate cancer and examining molecular mechanisms by which potential therapeutic agents may have potent anti-cancer activity.

Contact Us	EHSC Calendar of Events	Alphabetical list of Faculty
Copyright 2009 University of Rochester Medical Center, Dept of Environmental Medicine. Revised August 20 2009 (vgl/gbi)