Thomas Gasiewicz

..Defining the molecular mechanisms by which these events occur may lead to the identification of previously undefined roles of this transcription factor in human diseases, particularly those caused or affected by xenobiotics...

..Furthermore, if the difference in toxicity between TCDD and ITE is mediated by differences in gene expression, then it is likely that secondary changes enabled by the persistent TCDD, but not by the shorter lived ITE, are responsible...

..Together, these data demonstrate that activation of the AhR by TCDD disrupts the circadian rhythms associated with murine hematopoietic precursors...

..These results suggest that the maturing B220+ B cell is not the direct target for TCDD-induced bone marrow B-cell alterations...

..Overall, these data are consistent with the hypothesis that TCDD, through AhR activation, alters the ability of HSCs to respond appropriately to signals within the marrow microenvironment...

..The association between RelB and AhR may represent a new therapeutic and more selective target with which to combat inflammation-associated diseases...

..It is also reasonable to hypothesize that this protein has an important function in the regulation of other tissue stem cell populations. Suggestive evidence is consistent with a role in skin and neural stem cells...

..However, the linkage of these changes to detectable biological outcomes in the paw remains unclear...

..This is the first time EGCG has been demonstrated to directly bind hsp90 and the first indication that GT may exert its chemopreventive effects through an interaction with the common chaperone hsp90...

..These data suggest that (1) granule neuroblasts are direct targets for developmental AhR-mediated TCDD neurotoxicity and (2) TCDD exposure may disrupt granule cell neurogenesis...

..Together these data indicate endothelial cells and astrocytes are responsive to TCDD through the AhR-mediated pathway and therefore could be targets of toxicity...

..Studies highlighting AhR regulation of HSCs/HPCs provide a rational framework to understand their biology, a role of the AhR in hematopoietic diseases, and a means to develop interventions for these diseases...

..Here we describe the current understanding of how the AhR may function to regulate both normal and cancerous tissue growth and development...

..EGCG also modified the association of hsp90 with several cochaperones. Overall, these data indicate that EGCG is a novel hsp90 inhibitor. Further studies are needed to determine if this has a role in the antitumor actions of EGCG...

..These seven genes are novel targets for modulation by the TCDD-activated AHR and may be involved in the observed cell-cycle arrest and suppression of early thymocyte development...

..Together, our data suggest that TCDD disrupts a normal physiological role of AhR, resulting in compromised GNP maturation and neuroblast survival, which impacts final cell number in the cerebellum...

..The AHR may not only mediate the effects of toxicants, but with an as yet unidentified ligand, be involved in the differentiation pathways of osteoblasts...

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..Overall, AhR tyrosine 9, which is not a phosphorylated residue itself but is required for DNA binding, appears to play a crucial role in AhR activity by permitting proper phosphorylation of the AhR...

..However, depending on its concentration as well as the promoter context of a particular gene, the ability of 3'M4'NF to act as an AhR antagonist or agonist may appear different for various genes...

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..These data support a molecular mechanism for an AhR ligand to disrupt the homeostatic cell signaling of HSCs that may promote altered HSC function...

..Overall, these data strongly suggest that the putative posttranslational modification at, or mediated by, tyrosine 9, and not any other individual mouse AhR tyrosine residue, is necessary for AhR DRE binding and transcriptional activity...

..Furthermore, these events are intimately tied with the process of aging and a variety of diseases, including cancer, whose incidence increases with age. ..

..Finally, recent data has suggested a role of the AhR in the normal development of the immune system. Immune progenitor cells in animals lacking the AhR will be further characterized to determine this. ..

..Additional studies will determine the modulated expression of the transgene following exposure of developing animals to TCDD. ..

..These data will provide for the first time information on the cell and gene targets associated with in vivo responses to TCDD. ..

..Furthermore, these events are intimately tied with the process of aging and a variety of diseases, including cancer, whose incidence increases with age. ..

..Further studies examining phenotypic alterations and patterns of stem cell commitment in AhR null allele cells will further define a putative role of the AhR. ..

..Understanding the role of ITE and the AhR in modulating inflammatory processes may lead to possible therapeutic interventions. ..

..Additional studies will determine if EGCG alters the levels and/or activity of several hsp90 client proteins that may play a role in the malignant transformation or growth of tumor cells. ..

..Overall, data from these investigations will indicate the precise amino acid residues that are phosphorylated and their functional significance. ..

..Finally, additional studies will define nuclear factors that influence AhR-Arnt transcriptional activity and determine how altered phosphorylation of these affect this activity. ..

..The expression of genes which determine T-cell functionally will also be examined. The studies will focus on the T-cell Receptor (TcR) and the functionally linked molecule CD3...

..Finally, the possibility that the ART protein may represent only one of a family of proteins having the ability to interact with the AhR in a TCDD-dependent manner to form a gene regulatory complex will be examined...

..These studies may suggest what controls this receptor in vivo, as well as the possible physiological role of this molecule...