The expression of Has genes undergoes rapid and dramatic changes during embryonic development, corresponding to the migration of cells to their final sites in organs [4,14], the formation of specific matrices such as that in cartilages  and general cell proliferation in expanding tissues . In adult tissues, HA synthesis is stimulated by injury, inflammation and neoplastic tumors. A number of cytokines and growth factors, such as platelet-derived growth factor (PDGF) [16,17], fibroblast growth factor-2 , keratinocyte growth factor , epidermal growth factor (EGF) , transforming growth factor-β , interleukin-1β , tumor necrosis factor-α  and interferon-γ , are released from local cells, and also from platelets and leukocytes arriving in the area, and increase Has expression. In addition, Has expression and HA synthesis are sensitive to local mediators, such as prostaglandins , and hormone-type effectors, such as corticosteroids , the latter downregulating Has2, and retinoids, which induce its expression [27,28]. Some of the effectors are shown in Fig. 1. There are large differences between different cell types concerning the stimulants to which they respond. In addition, some of the effectors modulate the expression of all Has genes, whereas others just modulate one or two. For example, Has2 in epidermal keratinocytes is particularly sensitive to EGF receptor ligands, whereas MCF7 breast cancer cells respond weakly, if at all, to EGF. Transforming growth factor-β downregulates Has2 and Has3 in keratinocytes, but enhances the expression of Has1 in fibroblasts  and synoviocytes . These findings suggest that the three Has genes have promoters reacting to common transcriptional signals in addition to their specific responses.
Figure 1. Overview of the first 2500 bp of human Has2 promoter with signals confirmed to influence transcription factor binding The human Has2 promoter contains functional binding sites for transcription factors CREB1, RAR, SP1, STAT and YY1 in human epidermal keratinocytes. The locations of the binding sites and the signal transduction cascades leading to transcription factor activation are shown. AC, adenylate cyclase; atRA, all-trans-retinoic acid; cAMP, cyclic AMP; CREB1, cAMP-response element-binding protein 1; EGF, epidermal growth factor; EGFR, receptor for EGF; G, G-protein; GPCR, G-protein-coupled receptor; IκB, inhibitory κB; IKK, inhibitory κB kinase; JAK, janus kinase; OGT, O-linked N-acetylglucosamine transferase; p, phosphorylation; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A; PLCγ, phospholipase Cγ; p50, subunit of nuclear factor κB; p65, subunit of nuclear factor κB; RAR, retinoic acid receptor; SP1, specificity protein 1; STAT, signal transducer and activator of transcription; TNF-α, tumor necrosis factor-α; TNFR, receptor for tumor necrosis factor; TSS, transcription start site; YY1, yin yang 1.
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