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REGULATION OF GENE EXPRESSION BY TCDD 157 using imnnuinoaffinity techniques. Anti-receptor anti- bodies sheuld permit more detailed analyses of receptor heterogeneity, receptor modification, receptor synthesis and degradFition, and the temperature-dependent acti- vation event that occurs during transduction of the TCDD signal. In addition, sequence analysis of the de- natured prol;ein should permit the synthesis of an oligon- ucleotide(s) that might be used to isolate the correspond- ing gene. Other approaches to receptor purification may also be useful. Foi. - example, the functional similarities between TCDD receptors and steroid receptors suggest that struc- tural simiLarities may also exist. Therefore, it may be possible to find antibodies, raised against purified steroid receptors, that cross-react with TCDD receptors. Such antibodies could be used in receptor purification. In addition, we, may find that the TCDD-receptor complex recognizes a specific DNA sequence. If so, oligonucleo- tides that contain this sequence may be useful affinity reagents for the purification of the TCDD-receptor com- plex (see, for example, refs. 84 and 149). Anti-receptor antibodies presumably could be used to clone the gene(s) for the TCDD receptor. An alternative approach ndght be to insert either genomic DNA or cDNA into an appropriate expression vector and to use the recombinant to complement the lesion in receptor- defective variant cells, with the selection procedure de- veloped by van Gurp and Hankinson (167). Cloning and characterizEition of,the TCDD receptor gene(s) will per- mit studies of its expression and lead to a better under- standing of the factors which regulate the intracellular concentra tion of the receptor. The TCDD receptor presumably consists of multiple functional domains, including a ligand-binding domain, a DNA (chromatin)-binding domain, and possibly, a domain(s) tlhat interacts with other transcription factors. Cloning and expression of cDNA for the TCDD receptor, when coml ined with mutagenesis and gene transfer methodologies, should permit a detailed analysis of its functional domains (see, for example, refs. 46, 48, and 105). Furthermore, given the similarities between the TCDD receptor and steroid receptors described above, it will be intriguing to learn whether the TCDD receptor is a member of the hormone receptor family that is related to the viral erb A oncogene (51). Variant cells have been very useful in characterizing the TCDD-responsive system to date; the study of addi- tional variants would seem to be worthwhile in the future. For example, Hankinson and coworkers (62) have al- ready identified by complementation analysis cells which presumab'';ly contain defects at other steps in the signal transducti.on pathway. In the future, the isolation of temperature-sensitive variants would allow us to analyze the reversibility of particular steps in signal transduction and to study the requirements for the maintenance of TCDD-induced changes in gene expression. Selection of cells that overproduce TCDD receptors might be useful for purifying the receptor and for cloning its gene, as well as for studying quantitative aspects of signal trans- duction. A great deal remains to be learned about the mecha- nism by which the dioxin-responsive element, together with the TCDD-receptor complex, functions as a tran- scriptional enhancer. Mutagenesis and gene transfer techniques can be used to define the functional bounda- ries of various DREs. DNA sequence analyses should reveal whether each DRE contains a specific sequence that forms part of the recognition site for the TCDD- receptor complex. The development of an enhancer- dependent in vitro transcription system (see, for exam- ple, ref. 151) would facilitate the functional analysis of the dioxin-responsive pathway. In view of what is known about other enhancer systems (126, 155), it seems likely that the DRE will be found to interact with several other proteins, in addition to the TCDD-receptor complex. If so, the task of understanding the mechanism by which the inducer-receptor complex activates transcription will become substantially more complicated. The chromatin structure (124, 169, 170) of TCDD- responsive genes is an interesting area for future study. For example, we know very little about the nucleoprotein organization of the DRE and other linked regulatory components (38). Are these elements associated with histones or other chromosomal [e.g., high-mobility group (HMG)] proteins? Are they organized into nucleosomes in vivo? If so, how do these structural features influence the function of the regulatory elements? If (as seems more likely) the DRE does not assume a nucleosomal structure in,vivo, why not? What determines the chro- matin structure of the DRE? Does the nucleoprotein structure of the element change upon its interaction with the TCDD-receptor complex? If so, is the structural alteration local or does it propagate along the chromatin fiber? What is the mechanism by which a change in structure leads to activation of gene transcription? Fu- ture studies that address these issues may generate in- teresting information that is relevant to transcriptional enhancement in general. In addition, studies in other systems suggest that transcriptionally active regions of chromatin may be preferentially associated with the nu- clear matrix (80, 114). The role that the nuclear matrix plays in the cellular response to TCDD may also be a productive area for future,research. We know that TCDD induces the activity of UDP- glucuronyltransferase and NADPH:quinone reductase, apparently by activating the transcription of the corre- sponding gene (79, 147, 176). However, we do not yet know whether the activation of these other genes occurs in the absence of ongoing protein synthesis (i.e., if in- duction reflects a primary response to the TCDD-recep- tor complex). For example, others have proposed that TCDD induces a protein that secondarily activates a

158 W HI'1'LOCK battery o f other genes (54, 140). In fact, some glucocor- ticoid-responsive genes appear to display this type of regulation (2, 7). The study of additional (i.e., non- cytochronse P-450) TCDD-responsive genes might pro- vide evidence for a protein(s) that mediates a TCDD- induced cascade of biological responses. The isolation and chamcterization of such a factor would be funda- mental to our understanding of the mechanism by which TCDD elicits its diverse effects. The TCDD-responsive signalling system could also diminish the rate of tran- scriptiornn of some genes, either directly via the TCDD- receptor complea, or indirectly, via the synthesis of an inhibitory factor. This idea is testable, in principle. Also, the study,of additional TCDD-responsive genes can in- crease our knowledge of how the dioxin-responsive en- hancer system functions in other regulatory contexts, in combination with different promoters, silencers, and en- hancers. Such information could make a valuable contri- bution to our understanding of the principles that govern the combinatorial control of gene transcription. Appro- priate T(' MD-responsive cell systems are available to begin the study of these problems (1, 25, 93, 122, 145). The results of on-going epidemiological inyestigations suggest that exposure to TCDD poses less of a human health risk than was once feared, although the issue remains somewhat controversial (21, 70, 72, 109, 161). Most of us probably have accumulated some TCDD in our cells (123); however, it is not clear that this consti- tutes any m easurable risk to the well-being of the general population. However, we cannot rule out the possibility that certain individuals are relatively susceptible to the effects of T'CDD, either because of a genetic predisposi- tion (34, 94, 141) and/or because of exposure to an additionat: environmental chemical(s). 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