Expression in Adipose Tissue

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Aromatase is expressed in the undifferentiated stromal mesenchymal cells of adipose tissue (preadipocytes) and not in the mature lipid-laden adipocytes.41 Under normal circumstances, adipose stromal cells contain CYP19 transcripts derived primarily from promoter I.4. This TATA-less promoter is stimulated by class 1 cytokines [e.g., oncostatin M and interleukin-6 (IL-6)] and tumor necrosis factor-a (TNF-a). In addition, activity of promoter I.4 has an obligate requirement for glucocorticoids.42 The action of class 1 cytokines is transduced by the JAK-STAT pathway (Fig. 8.4). Specifically, activation of gp130-coupled receptors in adipose stromal cells leads to tyrosine phosphorylation and activation of JAK-1 and subsequent activation of signal transducer and activator of transcription 3 (STAT3) homodimers, which bind to an interferon-y-activating sequence (GAS element) within promoter I.4.43 The action of TNF-a is less well understood. Treatment of adipose stromal cells with TNF-a leads to rapid elevation in intracellular levels of c-fos and c-jun, which appear to bind as a heterodimer to an imperfect activating protein-1 (AP-1) site upstream of the GAS element.44 More recent studies have shown that TNF-a induces other early-response genes of the egr-1 family that can bind and activate promoter I.4 through a GC-rich sequence located within exon I.4.45 This GC-rich sequence also constitutes a consensus Sp1 binding site. Since mutation of the site markedly diminishes basal transcription42 as well as TNF-a-in-duced transcription,45 it seems likely that Sp1 is involved in the regulation of promoter I.4 along with egr-1 and AP-1.

As mentioned above, the action of class 1 cy-tokines and TNF-a requires the presence of glu-cocorticoids, although glucocorticoids by themselves are ineffective. This permissive effect of glucocorticoids is mediated by a glucocorticoid response element (GRE) that binds the activated glucocorticoid receptor (GR).42 Functional interactions between GR and STAT proteins have been reported for a number of genes,46 and preliminary studies suggest that STAT3 and GR may interact physically, at least in yeast, to regulate promoter I.4. Since STAT proteins are known to also interact directly with Sp1,47 one can envisage the existence of a large transcriptional complex consisting of promoter-bound STAT3, GR, Sp1, and associated coregulator proteins, such as p300, coordinating the transcriptional response to cytokines and glucocorticoids.

Although the majority of CYP19 transcripts in adipose stromal cells contain exon I.4-specific sequences, transcripts derived from promoters II and I.3 are also expressed.48,49 As in the ovary, promoters II and I.3 are stimulated by cAMP. Interestingly, phorbol esters markedly potentiate the effect of cAMP in adipose stromal cells, whereas in the ovary they inhibit promoter II.50 Thus, activation of protein kinase A (PKA) and PKC signaling pathways maximally stimulates aromatase expression via promoters II and I.3. To identify endogenous factors that activate these pathways in adipose stromal cells and, thus, regulate aromatase expression, we examined a variety of hormones and neurotransmit-ters for effects on aromatase activity.51,52 The most potent agent was prostaglandin E2 (PGE2),

Figure 8.4 Regulation of aromatase gene expression from promoter 1.4 in human adipose stromal cells. Jak1 kinase is bound to the common receptor subunit gp130 and activated following ligand binding and receptor dimerization as a consequence of phosphory-lation on tyrosine residues. Signal transducer and activator of transcription 3 (STAT3) is recruited to binding sites on gp130 and phosphorylated on tyrosine residues by Jak1. These phosphotyrosine residues are recognized by SH2-homology domains on STAT3, resulting in dimerization followed by translocation to the nucleus and binding to the GAS element of pro moter I.4. Following binding of glucocorticoid (GC) receptors to the glucocorticoid response element (GRE) and Sp1 to its site on untranslated exon I.4, activation of transcription of the aromatase gene from promoter I.4 is initiated. Tumor necrosis factor a (TNFa) action is presumed to be through sequential activation of mitogen-activated protein kinases (MAPKs) and early response genes, including the egr-1 family members c-fos and c-jun. GAS, interferon-y-activating sequence; OSM, oncostatin M; IL, inter-leukin; LIFR, leukemia-inhibiting factor receptor.

Figure 8.4 Regulation of aromatase gene expression from promoter 1.4 in human adipose stromal cells. Jak1 kinase is bound to the common receptor subunit gp130 and activated following ligand binding and receptor dimerization as a consequence of phosphory-lation on tyrosine residues. Signal transducer and activator of transcription 3 (STAT3) is recruited to binding sites on gp130 and phosphorylated on tyrosine residues by Jak1. These phosphotyrosine residues are recognized by SH2-homology domains on STAT3, resulting in dimerization followed by translocation to the nucleus and binding to the GAS element of pro moter I.4. Following binding of glucocorticoid (GC) receptors to the glucocorticoid response element (GRE) and Sp1 to its site on untranslated exon I.4, activation of transcription of the aromatase gene from promoter I.4 is initiated. Tumor necrosis factor a (TNFa) action is presumed to be through sequential activation of mitogen-activated protein kinases (MAPKs) and early response genes, including the egr-1 family members c-fos and c-jun. GAS, interferon-y-activating sequence; OSM, oncostatin M; IL, inter-leukin; LIFR, leukemia-inhibiting factor receptor.

which binds to E-prostanoid (EP)x and EP2 receptors in adipose stromal cells that couple to PKA and PKC, respectively. Since PGE2 is a major secretory product of breast tumor epithelial cells, this hormone has great potential to influence aromatase expression in breast adipose tissue containing a tumor.

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Confident Kids

Confident Kids

Although nobody gets a parenting manual or bible in the delivery room, it is our duty as parents to try to make our kids as well rounded, happy and confident as possible. It is a lot easier to bring up great kids than it is to try and fix problems caused by bad parenting, when our kids have become adults. Our children are all individuals - they are not our property but people in their own right.

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