Alternative titles; symbols
HGNC Approved Gene Symbol: MED15
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38) : 22:20,507,610-20,587,619 (from NCBI)
MED15 (PCQAP) is a component of the activator-recruited cofactor (ARC) complex or the metazoan Mediator complex and is essential for TGFB (190180)/Activin (see 147290)/Nodal (601265)/Smad2/3 (601366, 603109) signal transduction.
By a subtractive hybridization protocol to identify novel genes preferentially expressed in myeloid lineage cells, Abraham and Solomon (2000) cloned a cDNA from TPA (phorbol ester)-induced K562 cells, which they named TPA-inducible gene-1 (TIG1). The TIG1 cDNA encoded a glutamine repeat-rich protein with an apparent molecular weight of 97 kD. The predicted open reading frame contains a consensus bipartite nuclear localization signal, though no specific DNA-binding domain was found. TIG1 mRNA is ubiquitously expressed. Abraham and Solomon (2000) observed that placental tissue expressed TIG1 mRNA 200 times more than the lowest expressing tissues, including kidney and lung. Abraham and Solomon (2000) also found preferential TIG1 mRNA expression in cells of the bone marrow lineage.
In their efforts to characterize components of the PC2 (positive cofactor-2) Mediator-like complex, Berti et al. (2001) identified 2 protein bands of apparent molecular weight 105 and 108 kD, which they called PCQAP (PC2 glutamine/Q-rich-associated protein). They noted that the PCQAP doublet showed a similar migration pattern on SDS-PAGE gels to the ARC105/TIG1 component of the human ARC complex (Naar et al., 1999). Immunoblot experiments confirmed the identity of PCQAP with the 105/108-kD doublet isolated from the PC2 Mediator complex. The PCQAP open reading frame encodes a 746-amino acid protein. Berti et al. (2001) found that mouse Pcqap protein is 83% identical to human PCQAP, with 96% similarity at the amino- and carboxy-terminal ends. Although Pcqap appeared to be ubiquitously expressed, the authors observed higher levels of Pcqap expression in embryonic mouse frontonasal region, pharyngeal arches, and limb buds.
Berti et al. (2001) determined that the PCQAP gene consists of 17 exons and spans over 80 kb.
Kato et al. (2002) found that PCQAP, which they called ARC105, is essential for TGFB/Activin/Nodal/Smad2/3 signal transduction. Expression of ARC105 stimulated Activin/Nodal/Smad2 signaling in Xenopus laevis embryos, including axis duplication and mesendoderm differentiation, and enhanced TGFB response in human cells. Depletion of ARC105 inhibited downstream signaling and Xenopus axis formation, but not BMP (see 112264)/Smad1 (601595) signaling. ARC105 protein binds to Smad2/3-Smad4 (600993) in response to TGFB and is recruited to Activin/Nodal-response promoters in chromatin in a Smad2-dependent fashion. Thus, Kato et al. (2002) concluded that ARC105 is a specific and key ARC/Mediator component linking TGFB/Activin/Nodal/Smad2/3 signaling to transcriptional activation.
Yang et al. (2006) showed that SREBPs (see 184756) use the evolutionarily conserved ARC105, also called MED15, subunit to activate target genes. Structural analysis of the SREBP-binding domain in ARC105 by nuclear magnetic resonance (NMR) revealed a 3-helix bundle with marked similarity to the CBP/p300 (see 600140) KIX domain. In contrast to SREBPs, the CREB (123810) and c-MYB (189990) activators do not bind the ARC105 KIX domain, although they interact with the CBP KIX domain, revealing a surprising specificity among structurally related activator-binding domains. The C. elegans SREBP homolog Sbp1 promotes fatty acid homeostasis by regulating the expression of lipogenic enzymes. Yang et al. (2006) found that, like Sbp1, the C. elegans ARC105 homolog Mdt15 is required for fatty acid homeostasis, and showed that both Sbp1 and Mdt15 control transcription of genes governing desaturation of stearic acid to oleic acid. Dietary addition of oleic acid significantly rescued various defects of nematodes targeted with RNA interference against Sbp1 and Mdt15, including impaired intestinal fat storage, infertility, decreased size, and slow locomotion, suggesting that regulation of oleic acid levels represents a physiologically critical function of Sbp1 and Mdt15. Yang et al. (2006) concluded that ARC105 is a key effector of SREBP-dependent gene regulation and control of lipid homeostasis in metazoans.
Berti et al. (2001) found that the PCQAP gene overlapped with the genomic sequence of a PAC (GenBank AC004033) and a BAC (GenBank AC007050), both of which map to 22q11.2 in the DiGeorge syndrome typically deleted region. The PCQAP gene is located 74 kb distal to ZNF74 (194548) and 194 kb proximal to HCF2 (142360). Berti et al. (2001) further examined the position of the PCQAP gene by FISH.
The PCQAP gene maps to the DiGeorge syndrome (188400) typically deleted region. Berti et al. (2001) found that the PCQAP gene was deleted in all individuals examined with the typical 22q11 deletion.
Abraham, S., Solomon, W. B. A novel glutamine-rich putative transcriptional adaptor protein (TIG-1), preferentially expressed in placental and bone-marrow tissues. Gene 255: 389-400, 2000. [PubMed: 11024300] [Full Text: https://doi.org/10.1016/s0378-1119(00)00292-4]
Berti, L., Mittler, G., Przemeck, G. K. H., Stelzer, G., Gunzler, B., Amati, F., Conti, E., Dallapiccola, B., Hrabe de Angelis, M., Novelli, G., Meisterernst, M. Isolation and characterization of a novel gene from the DiGeorge chromosomal region that encodes for a mediator subunit. Genomics 74: 320-332, 2001. [PubMed: 11414760] [Full Text: https://doi.org/10.1006/geno.2001.6566]
Kato, Y., Habas, R., Katsuyama, Y., Naar, A. M., He, X. A component of the ARC/Mediator complex required for TGF-beta/Nodal signalling. Nature 418: 641-646, 2002. [PubMed: 12167862] [Full Text: https://doi.org/10.1038/nature00969]
Naar, A. M., Beaurang, P. A., Zhou, S., Abraham, S., Solomon, W., Tjian, R. Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 398: 828-832, 1999. [PubMed: 10235267] [Full Text: https://doi.org/10.1038/19789]
Yang, F., Vought, B. W., Satterlee, J. S., Walker, A. K., Sun, Z.-Y. J., Watts, J. L., DeBeaumont, R., Saito, R. M., Hyberts, S. G., Yang, S., Macol, C., Iyer, L., Tjian, R., van den Heuvel, S., Hart, A. C., Wagner, G., Naar, A. M. An ARC/mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature 442: 700-704, 2006. [PubMed: 16799563] [Full Text: https://doi.org/10.1038/nature04942]