Identification and characterization of an aryl hydrocarbon receptor nuclear translocator protein variant /
The Aryl hydrocarbon receptor nuclear translocator (Arnt)
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1997.
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| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=736824641&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | The Aryl hydrocarbon receptor nuclear translocator (Arnt) protein is a basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) transcription factor which plays an essential role in ligand- and physiologically-induced cellular signaling mechanisms. Arnt serves as a cofactor for the aryl hydrocarbon receptor (AhR) in the transcriptional response to aryl hydrocarbon exposure. Upon binding 2, 3, 7, 8-tetrachlorodibenzo-p- dioxin (TCDD, dioxin) or dioxin-like compounds, the AhR interacts with Arnt to form a ligand-induced transcription factor in Ah-responsive cell lines and animal models. MDA-MB- 231 human breast cancer cells are Ah-nonresponsive and it was determined that high level expression of a variant Arnt protein contributes to the Ah-nonresponsive phenotype in these cells. Sequence analysis confirmed that this variant lacks the C-terminal transactivation domain (TAD) which is required for Ah-responsiveness in a cell type-specific fashion. Arnt also interacts with hypoxia-inducible factor-1 [] (HIF-1[]) to form the HIF-1 transcription factor under conditions of low cellular oxygen tension. It is generally accepted that aggressive tumor growth is perpetuated by tumor cell secretion of angiogenic factors, many of which are transcriptionally inducible under hypoxic conditions via a HIF-1-mediated mechanism. The MDA-MB-231 cell line has been used as a model for aggressive tumor growth and expresses TAD-Arnt (HIF-1 []) . While nonfunctional in the context of ligand-induced signaling mechanisms, TAD-Arnt/HIF-[] is not required for the transcriptional response to hypoxia in MDA- MB-231 cells. Expression of TAD-Arnt correlates with Ah- nonresponsiveness in several transformed human cell lines and correlates with estrogen receptor (ER)-negativity in some breast cancer cell lines. Thus, the relationship between several prognostic indicators and TAD-Arnt expression was assessed in a panel of human breast tumors. Moderate correlations were observed between tumor size, node status, and TAD-Arnt expression. The results of this project suggest that TAD-Arnt contributes to Ah-nonresponsiveness in some cell lines, functions in a cell-type and promoter-specific manner, and may play a role in human neoplastic breast disease. |
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| Item Description: | Vita. "Major Subject: Toxicology". |
| Physical Description: | xiv, 213 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilms Inc. |
| Bibliography: | Includes bibliographical references: pages 148-210. |