Transcriptional regulation of tenascin genes

Abstract

Extracellular matrix proteins of the tenascin family resemble each other in their domain structure, and also share functions in modulating cell adhesion and cellular responses to growth factors. Despite these common features, the 4 vertebrate tenascins exhibit vastly different expression patterns. Tenascin-R is specific to the central nervous system. Tenascin-C is an "oncofetal" protein controlled by many stimuli (growth factors, cytokines, mechanical stress), but with restricted occurrence in space and time. In contrast, tenascin-X is a constituitive component of connective tissues, and its level is barely affected by external factors. Finally, the expression of tenascin-W is similar to that of tenascin-C but even more limited. In accordance with their highly regulated expression, the promoters of the tenascin-C and -W genes contain TATA boxes, whereas those of the other 2 tenascins do not. This article summarizes what is currently known about the complex transcriptional regulation of the 4 tenascin genes in development and disease.

Keywords: AKT, v-akt murine thymoma viral oncogene homolog; ALK, anaplastic lymphoma kinase; AP-1, activator protein-1; ATF, activating transcription factor; BMP, bone morphogenetic protein; CBP, CREB binding protein; CREB, cAMP response element-binding protein; CREB-RP, CREB-related protein; CYP21A2, cytochrome P450 family 21 subfamily A polypeptide 2; ChIP, chromatin immunoprecipitation; EBS, Ets binding site; ECM, extracellular matrix; EGF, epidermal growth factor; ERK1/2, extracellular signal-regulated kinase 1/2; ETS, E26 transformation-specific; EWS-ETS, Ewing sarcoma-Ets fusion protein; Evx1, even skipped homeobox 1; FGF, fibroblast growth factor; HBS, homeodomain binding sequence; IL, interleukin; ILK, integrin-linked kinase; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; MHCIII, major histocompatibility complex class III; MKL1, megakaryoblastic leukemia-1; NFκB, nuclear factor kappa B; NGF, nerve growth factor; NFAT, nuclear factor of activated T-cells; OTX2, orthodenticle homolog 2; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; POU3F2, POU domain class 3 transcription factor 2; PRRX1, paired-related homeobox 1; RBPJk, recombining binding protein suppressor of hairless; ROCK, Rho-associated, coiled-coil-containing protein kinase; RhoA, ras homolog gene family member A; SAP, SAF-A/B, Acinus, and PIAS; SCX, scleraxix; SEAP, secreted alkaline phosphatase; SMAD, small body size - mothers against decapentaplegic; SOX4, sex determining region Y-box 4; SRE, serum response element; SRF, serum response factor; STAT, signal transducer and activator of transcription; TGF-β, transforming growth factor-β; TNC, tenascin-C; TNF-α, tumor necrosis factor-α; TNR, tenascin-R; TNW, tenascin-W; TNX, tenascin-X; TSS, transcription start site; UTR, untranslated region; WNT, wingless-related integration site; cancer; cytokine; development; extracellular matrix; gene promoter; gene regulation; glucocorticoid; growth factor; homeobox gene; matricellular; mechanical stress; miR, micro RNA; p38 MAPK, p38 mitogen activated protein kinase; tenascin; transcription factor.

Figure 1.

Schematic representation of all tenascin genes. Gene models of TNC, tenascin-C; TNN, tenascin-W; TNR, tenascin-R; TNXB, tenascin-X were captured from the NCBI database (http://www.ncbi.nlm.nih.gov/gene/). TNC, TNN and TNR have a single transcription start site (TSS1) whereas the TNXB gene has 4 closely clustered TSSs(TSS1–4) in its principle promoter shown here. Non-coding exons up to the first coding exons (indicated by the translation start codon ATG) as well as the last exons are numbered with e1, 2, … below the models. Note that the TNC and TNN genes possess TATA boxes (red triangles) whereas the TNR and the TNXB genes do not.

Figure 2.

Scheme of the gene promoters of the 4 tenascins. The transcription start sites (TSS) are indicated with blue arrows in front of the first exons (e1; blue boxes). The start codons (ATG) of the translation start sites are marked with red arrows in the second (e2) or third exon (e3; for TNR), respectively. The upstream promoter sequences are represented by horizontal light blue lines, on which the experimentally confirmed transcription factor binding sites are marked by vertical bars. Dark blue color refers to those sites reported for the human promoters; sites described so far in the mouse promoters only are labeled in green. For nomenclature of binding sites and transcription factors, see the list of abbreviations. For additional information and publications on individual binding sites, refer to Table 1. Note that the promoter sequences are not drawn to scale. However, the exact location of each binding site is indicated below the bars; numbers refer to the distance in base pairs from the transcription start site.