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Gene Review

EREG  -  epiregulin

Homo sapiens

Synonyms: ER, Proepiregulin
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Disease relevance of EREG


High impact information on EREG


Biological context of EREG

  • We also identified a gene expression profile, based on MYCN, EREG, and SHH, which discriminated subgroups of IBC patients with good, intermediate, and poor outcome [7].
  • Like EGF, we found that both the epiregulin-induced growth inhibition of HN5 and MDA-MB468 cells and tyrosine phosphorylation of the 170 kDa EGFR on HN5 cells are reversed in the presence of anti-EGFR MAbs ICR62 and ICR80 [8].
  • Future investigations using DNA microarray technique may reveal the repertoire of genes activated in Ar- and Ep-stimulated cumulus cells and may help elucidate the molecular basis of ovulation [9].
  • It is suggested that upregulation of the epiregulin and amphiregulin expression is part of the signal transduction pathway which leads to ovulation and luteinization in the human ovary [10].
  • Expression of ADAMTS1 and ADAM12 was downregulated by cAMP in normal, but not in SV40-transformed cells, suggesting that in normal cells epiregulin and amphiregulin activity is downregulated by a feedback mechanism that may be lost in SV40-transformed cells and their loss of downregulation may be involved in the development of ovarian tumors [11].

Anatomical context of EREG

  • Epiregulin is the newest member of the epidermal growth factor (EGF) family of ligands that was isolated from conditioned medium of the murine fibroblast-derived tumour cell line NIH3T3/T7 [8].
  • We show here that epiregulin is another autocrine growth factor for human keratinocytes [12].
  • We aimed at evaluating whether PGE(2) induces Ar and Ep syntheses in human granulosa cells and whether the inhibition of PGE(2) production by selective COX-2 inhibitor, nimesulide, affects LH-induced Ar and Ep biosynthesis [13].
  • Recently, EGF-like growth factors amphiregulin (Ar) and epiregulin (Ep) were found to be produced in response to LH stimulation and to induce cumulus expansion and oocyte maturation [13].
  • Epiregulin and amphiregulin are growth factors involved in cancer development, but their potential role in signaling in the gonads is still obscure [10].

Associations of EREG with chemical compounds

  • The negative effect of nimesulide on the ovulatory process may be due to the reduction of Ar and Ep biosynthesis, which implies a possible collaborative role between PGE(2) and LH on their induction [13].
  • Moreover, since amphiregulin and epiregulin act as mediators of luteinizing hormone (LH) action in the mammalian ovulatory follicles, regulation of the expression of these factors may open new possibilities in treatment of ovarian malfunction implicated with ovarian hyper-stimulation [14].
  • By contrast, the PLC inhibitor U-73122, only reduced the EPR induced response by 21% [15].
  • Unsaturated lysophosphatidic acid and platelet-derived growth factor-BB, which are potent VSMC dedifferentiation factors, rapidly upregulated epiregulin mRNA expression in an ERK- and p38MAPK-dependent manner [16].
  • We found that normal human lung fibroblasts express transforming growth factor-alpha, heparin-binding epidermal-like growth factor, epiregulin, heregulin-alpha, and amphiregulin, all of which are erbB ligands [17].

Regulatory relationships of EREG

  • The blockade of protein kinase A (PKA) (by H89) and mitogen-activated protein kinase (MAPK) (by UO126) reduced the expression of PGE(2)-induced Ar and Ep biosynthesis [13].
  • Epiregulin stimulated human keratinocyte proliferation under both subconfluent and confluent culture conditions in the absence of exogenous EGF family growth factors [12].

Other interactions of EREG

  • There have been no reports on the HB-EGF, BTC and EPR expression in mesenchymal malignancies of fibrohistiocytic origin including malignant fibrous histiocytoma (MFH) [1].
  • A significantly higher expression of EPI (P < 0.001), HB-EGF (P < 0.001), and TGF-alpha (P < 0.05) were observed in T2-T4 tumors as compared with Ta tumors [6].
  • Immunostaining for epiregulin protein demonstrated increased expression with compression and attenuation with EGFR inhibition [18].
  • In contrast, ErbB3 showed much more restrictive ligand binding specificity and measurable binding was observed only with heregulin, neuregulin2beta, epiregulin and the synthetic heregulin/egf chimera, biregulin [19].
  • Iressa inhibited not only the activation of HER1 caused by insulin but also the insulin-induced increase in the three ligands (heparin-binding epidermal growth factor-like growth factor, epiregulin and amphiregulin) [20].

Analytical, diagnostic and therapeutic context of EREG


  1. Expression of betacellulin, heparin-binding epidermal growth factor and epiregulin in human malignant fibrous histiocytoma. Yamamoto, T., Akisue, T., Marui, T., Nakatani, T., Kawamoto, T., Hitora, T., Nagira, K., Fujita, I., Matsumoto, K., Kurosaka, M. Anticancer Res. (2004) [Pubmed]
  2. Neuregulin growth factors and their ErbB receptors form a potential signaling network for schwannoma tumorigenesis. Stonecypher, M.S., Chaudhury, A.R., Byer, S.J., Carroll, S.L. J. Neuropathol. Exp. Neurol. (2006) [Pubmed]
  3. Distribution of mRNA for human epiregulin, a differentially expressed member of the epidermal growth factor family. Toyoda, H., Komurasaki, T., Uchida, D., Morimoto, S. Biochem. J. (1997) [Pubmed]
  4. Epiregulin is Up-regulated in pancreatic cancer and stimulates pancreatic cancer cell growth. Zhu, Z., Kleeff, J., Friess, H., Wang, L., Zimmermann, A., Yarden, Y., Büchler, M.W., Korc, M. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  5. Molecular characterization of human telomerase reverse transcriptase-immortalized human fibroblasts by gene expression profiling: activation of the epiregulin gene. Lindvall, C., Hou, M., Komurasaki, T., Zheng, C., Henriksson, M., Sedivy, J.M., Björkholm, M., Teh, B.T., Nordenskjöld, M., Xu, D. Cancer Res. (2003) [Pubmed]
  6. A subclass of HER1 ligands are prognostic markers for survival in bladder cancer patients. Thøgersen, V.B., Sørensen, B.S., Poulsen, S.S., Orntoft, T.F., Wolf, H., Nexo, E. Cancer Res. (2001) [Pubmed]
  7. Molecular profiling of inflammatory breast cancer: identification of a poor-prognosis gene expression signature. Bièche, I., Lerebours, F., Tozlu, S., Espie, M., Marty, M., Lidereau, R. Clin. Cancer Res. (2004) [Pubmed]
  8. Anti-EGFR monoclonal antibodies which act as EGF, TGF alpha, HB-EGF and BTC antagonists block the binding of epiregulin to EGFR-expressing tumours. Modjtahedi, H., Komurasaki, T., Toyoda, H., Dean, C. Int. J. Cancer (1998) [Pubmed]
  9. Novel function of ovarian growth factors: combined studies by DNA microarray, biochemical and physiological approaches. Ben-Ami, I., Freimann, S., Armon, L., Dantes, A., Ron-El, R., Amsterdam, A. Mol. Hum. Reprod. (2006) [Pubmed]
  10. EGF-like factor epiregulin and amphiregulin expression is regulated by gonadotropins/cAMP in human ovarian follicular cells. Freimann, S., Ben-Ami, I., Dantes, A., Ron-El, R., Amsterdam, A. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  11. Differential expression of genes coding for EGF-like factors and ADAMTS1 following gonadotropin stimulation in normal and transformed human granulosa cells. Freimann, S., Ben-Ami, I., Dantes, A., Armon, L., Ben Ya'cov-Klein, A., Ron-El, R., Amsterdam, A. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  12. Epiregulin, a novel member of the epidermal growth factor family, is an autocrine growth factor in normal human keratinocytes. Shirakata, Y., Komurasaki, T., Toyoda, H., Hanakawa, Y., Yamasaki, K., Tokumaru, S., Sayama, K., Hashimoto, K. J. Biol. Chem. (2000) [Pubmed]
  13. PGE2 up-regulates EGF-like growth factor biosynthesis in human granulosa cells: new insights into the coordination between PGE2 and LH in ovulation. Ben-Ami, I., Freimann, S., Armon, L., Dantes, A., Strassburger, D., Friedler, S., Raziel, A., Seger, R., Ron-El, R., Amsterdam, A. Mol. Hum. Reprod. (2006) [Pubmed]
  14. Drug development for ovarian hyper-stimulation and anti-cancer treatment: blocking of gonadotropin signaling for epiregulin and amphiregulin biosynthesis. Freimann, S., Ben-Ami, I., Hirsh, L., Dantes, A., Halperin, R., Amsterdam, A. Biochem. Pharmacol. (2004) [Pubmed]
  15. Epiregulin is more potent than EGF or TGFalpha in promoting in vitro wound closure due to enhanced ERK/MAPK activation. Draper, B.K., Komurasaki, T., Davidson, M.K., Nanney, L.B. J. Cell. Biochem. (2003) [Pubmed]
  16. Epiregulin as a major autocrine/paracrine factor released from ERK- and p38MAPK-activated vascular smooth muscle cells. Takahashi, M., Hayashi, K., Yoshida, K., Ohkawa, Y., Komurasaki, T., Kitabatake, A., Ogawa, A., Nishida, W., Yano, M., Monden, M., Sobue, K. Circulation (2003) [Pubmed]
  17. Differentiation of human airway epithelia is dependent on erbB2. Vermeer, P.D., Panko, L., Karp, P., Lee, J.H., Zabner, J. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  18. Bronchial epithelial compression regulates epidermal growth factor receptor family ligand expression in an autocrine manner. Chu, E.K., Foley, J.S., Cheng, J., Patel, A.S., Drazen, J.M., Tschumperlin, D.J. Am. J. Respir. Cell Mol. Biol. (2005) [Pubmed]
  19. Binding specificities and affinities of egf domains for ErbB receptors. Jones, J.T., Akita, R.W., Sliwkowski, M.X. FEBS Lett. (1999) [Pubmed]
  20. Insulin-induced proliferation of bladder cancer cells is mediated through activation of the epidermal growth factor system. Ornskov, D., Nexo, E., Sorensen, B.S. FEBS J. (2006) [Pubmed]
  21. Regulation of amphiregulin and epiregulin expression in human colonic subepithelial myofibroblasts. Inatomi, O., Andoh, A., Yagi, Y., Bamba, S., Tsujikawa, T., Fujiyama, Y. Int. J. Mol. Med. (2006) [Pubmed]
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