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Chemical Compound Review

SureCN106826     2-(2-furyl)-3-(5-nitro-2- furyl)prop-2-enamide

Synonyms: AG-F-28968, CTK0H5914, CTK4H7325, AC1L2E0P, 18819-45-9
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Disease relevance of FURYLFURAMIDE

  • Evidence for impaired retinoic acid receptor-thyroid hormone receptor AF-2 cofactor activity in human lung cancer [1].
  • The rescue function mapped to the cysteine-histidine rich domain CH3, a region of p300/CBP that we found to interact directly with the conserved COOH-terminal activation domain (AF-2) of ER-alpha. p300 and ER-alpha were also found to interact in vivo and to colocalize within the nucleus in breast cancer cells [2].
  • Mutation of the AF-2 helix 12 domain partially inhibits the induction of nuclease hypersensitivity, but the inhibition was relieved in the absence of tau1, suggesting the occurrence of an important interaction between the two domains [3].
  • Thus, we believe that resistance in certain prostate cancers occurs as a consequence of receptor mutations that enable antagonist-and/or nonclassical ligand-bound AR to present a wild-type-like AF-2 conformation [4].
  • Additionally, to determine the impact of RXR for erythroid cell development, dominant interfering mutant RXRs, lacking the transcriptional activator functions AF-1 and AF-2, or AF-2 only, or the entire DNA-binding domain, were introduced into erythroid progenitor cells via recombinant retrovirus vectors and analyzed for RXR-specific effects [5].

Psychiatry related information on FURYLFURAMIDE

  • This system has several advantages compared with the conventional umu test: drastic reduction of the sample volume, less time-consuming for beta-galactosidase detection (free from substrate reaction time) and lower detection limit for the three mutagens (AF-2, MMC, 2-AA) [6].

High impact information on FURYLFURAMIDE

  • The modulating functions display a marked specificity in their cooperation with the AF-2 transactivation functions, cooperation that depends on the receptor origin of the modulating and transactivation functions and the promoter context of the RA-responsive gene, thus accounting for the specific transactivation properties of RAR and RXR types [7].
  • In each monomer, the AF-2 helix protrudes away from the core domain and spans into the coactivator binding site in the adjacent monomer of the symmetric dimer [8].
  • The DRIPs are distinct from known nuclear receptor coactivators, although like these coactivators, their interaction also requires the AF-2 transactivation motif of VDR [9].
  • Estrogen- and antiestrogen-regulated, AF-2-dependent transcriptional activation by purified full-length human estrogen receptor (ER) was carried out with chromatin templates in vitro [10].
  • Trans-activation depends critically on the ligand-dependent transcriptional activation function AF-2 of RAR alpha [11].

Chemical compound and disease context of FURYLFURAMIDE


Biological context of FURYLFURAMIDE

  • Thus, AF-1 and AF-2 of distinct RARs exert specific cellular and molecular functions in a cell-autonomous system mimicking physiological situations, and their phosphorylation by kinases belonging to two main signalling pathways is required to enable RARs to transduce the RA signal during F9 cell differentiation [17].
  • Inhibition of SMRT binding by the AF-2 helix requires specific amino acid sequences and the helical structure [18].
  • Retinoid receptor activity resides in several regions, including the DNA and ligand binding domains, a dimerization interface, and both a ligand-independent (AF-1) and a ligand-dependent (AF-2) transactivation function [19].
  • The effects of AF-1 or AF-2 were not secondary to enhanced viability, since neither overall cell survival nor the number of retinal ganglion cells remaining in culture after 6 d was affected by the presence of the factors [20].
  • Expression of RARs with deletions of amino acids 413 and 414 in the transactivation-2 (AF-2) domain also reduced RA inhibition, while deletions and point mutations beyond amino acid 414 behaved like the wild-type RARalpha [21].

Anatomical context of FURYLFURAMIDE

  • We show that activation function 2 of the retinoid X receptors (RXR AF-2) does not activate transcription from a minimal promoter in Cos cells [22].
  • Mutant analysis showed that DNA binding and a functional AF-2 transactivation domain are required for proliferation stimulation and differentiation arrest. c-myb was identified as a potential target gene of the GR in erythroblasts [23].
  • GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors [24].
  • The concentration of AF-1 is considerably higher in CM than in optic nerve homogenates, suggesting that it is actively secreted; AF-2 has a similar concentration intra- and extracellularly [20].
  • However, AF-2 of RXR alpha, but not AF-1, is required for differentiation of labyrinthine trophoblast cells, a late step in the formation of the placental barrier [25].

Associations of FURYLFURAMIDE with other chemical compounds

  • We show that the AF-2 region mediates transactivation as well as transcriptional interference (squelching), not only between the thyroid hormone and vitamin (type II) receptors, but also between type II and steroid hormone (type I) receptors [26].
  • Our results suggest a definitive mechanistic role for E2 in the activity of ER--namely, to alter receptor conformation to promote an association of the amino- and carboxyl-terminal regions, leading to transcriptional synergism between AF-1 and AF-2 [27].
  • Coactivator recruitment by 9-cis-RA requires the ligand-dependent transactivation domains (AF-2) of both heterodimeric partners [28].
  • The human estrogen receptor (ER) is a ligand-inducible transcription factor that contains two transcriptional activation functions, one located in the NH2-terminal region of the protein (AF-1) and the second in the COOH-terminal region (AF-2) [29].
  • A ligand-inducible transactivation function (AF-2) exists in the extreme carboxyl terminus of the vitamin D receptor (VDR) that is essential for 1alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3)-activated transcription and p160 coactivator interaction [30].

Gene context of FURYLFURAMIDE

  • One class of the nuclear receptor AF-2 coactivator complexes contains the SRC-1/TIF2 family, CBP/p300 and an RNA coactivator, SRA [31].
  • In an agonist- and AF-2-dependent manner FHL2 selectively increases the transcriptional activity of the AR, but not that of any other nuclear receptor [32].
  • The hormone-activated glucocorticoid receptor (GR), through its N- and C-terminal transcriptional activation functions AF-1 and AF-2, controls the transcription of target genes presumably through interaction(s) with transcriptional regulatory factors [33].
  • In agreement with these data, showing that TAF(II)28 is limiting in the AF-2 activation pathway in Cos cells, TAF(II)28 is selectively depleted in Cos cell TFIID [22].
  • However, coexpression of human (h) TAF(II)28 promotes a strong ligand-dependent activity of the RXR AF-2 on a minimal promoter and potentiates the ability of the RXRalpha AF-2 to activate transcription from a complex promoter [22].

Analytical, diagnostic and therapeutic context of FURYLFURAMIDE

  • To investigate a potential ligand-dependent transcriptional activation domain (AF-2) in the C-terminal region of the human vitamin D receptor (hVDR), two conserved residues, Leu-417 and Glu-420, were replaced with alanines by site-directed mutagenesis (L417A and E420A) [34].
  • We demonstrate further, in a mammalian two-hybrid assay, that this physical interaction also requires the presence of the AF-2 region of RXR to interact with the LXXLL motif of PGC-1, which is consistent with our protein-protein interaction results [35].
  • Transformation was seen in only one of four cultures 145 days after treatment for 6 h with AF-2 [36].
  • Sequence analysis of the PML-RARalpha transcript in NB4/RA cells indicated a Pro (CCG) to Leu (CTG) mutation at codon 900 (type L) in AF-2 domain, while the RARalpha transcript had a normal sequence [37].
  • The metabolic studies involving HPLC analysis of products followed by spectrophotometric examination have also suggested that furylfuramide can be degraded very rapidly through the aerobic metabolism by liver microsomes [38].


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  2. p300 Modulates the BRCA1 inhibition of estrogen receptor activity. Fan, S., Ma, Y.X., Wang, C., Yuan, R.Q., Meng, Q., Wang, J.A., Erdos, M., Goldberg, I.D., Webb, P., Kushner, P.J., Pestell, R.G., Rosen, E.M. Cancer Res. (2002) [Pubmed]
  3. Glucocorticoid receptor domain requirements for chromatin remodeling and transcriptional activation of the mouse mammary tumor virus promoter in different nucleoprotein contexts. Keeton, E.K., Fletcher, T.M., Baumann, C.T., Hager, G.L., Smith, C.L. J. Biol. Chem. (2002) [Pubmed]
  4. Evaluation of ligand-dependent changes in AR structure using peptide probes. Chang, C.Y., McDonnell, D.P. Mol. Endocrinol. (2002) [Pubmed]
  5. Retinoid X receptor and c-cerbA/thyroid hormone receptor regulate erythroid cell growth and differentiation. Bartůnĕk, P., Zenke, M. Mol. Endocrinol. (1998) [Pubmed]
  6. Electrochemical mutagen screening using microbial chip. Matsui, N., Kaya, T., Nagamine, K., Yasukawa, T., Shiku, H., Matsue, T. Biosensors & bioelectronics. (2006) [Pubmed]
  7. Promoter context- and response element-dependent specificity of the transcriptional activation and modulating functions of retinoic acid receptors. Nagpal, S., Saunders, M., Kastner, P., Durand, B., Nakshatri, H., Chambon, P. Cell (1992) [Pubmed]
  8. Structural basis for autorepression of retinoid X receptor by tetramer formation and the AF-2 helix. Gampe, R.T., Montana, V.G., Lambert, M.H., Wisely, G.B., Milburn, M.V., Xu, H.E. Genes Dev. (2000) [Pubmed]
  9. A novel protein complex that interacts with the vitamin D3 receptor in a ligand-dependent manner and enhances VDR transactivation in a cell-free system. Rachez, C., Suldan, Z., Ward, J., Chang, C.P., Burakov, D., Erdjument-Bromage, H., Tempst, P., Freedman, L.P. Genes Dev. (1998) [Pubmed]
  10. p300 and estrogen receptor cooperatively activate transcription via differential enhancement of initiation and reinitiation. Kraus, W.L., Kadonaga, J.T. Genes Dev. (1998) [Pubmed]
  11. Retinoid-dependent in vitro transcription mediated by the RXR/RAR heterodimer. Valcárcel, R., Holz, H., Jiménez, C.G., Barettino, D., Stunnenberg, H.G. Genes Dev. (1994) [Pubmed]
  12. The retinoid X receptor ligand restores defective signalling by the vitamin D receptor. S??nchez-Mart??nez, R., Castillo, A.I., Steinmeyer, A., Aranda, A. EMBO Rep. (2006) [Pubmed]
  13. The mutational specificity of 2-(2-furyl)-3-(5-nitro-2-furyl)-acrylamide (AF2) in the lacI gene of Escherichia coli. Lambert, I.B., Chin, T.A., Bryant, D.W., Gordon, A.J., Glickman, B.W., McCalla, D.R. Carcinogenesis (1991) [Pubmed]
  14. Potentiation of CCNU toxicity by AF-2 in V79 spheroids: implications for mechanisms of chemosensitization. Durand, R.E., Olive, P.L. Int. J. Radiat. Oncol. Biol. Phys. (1986) [Pubmed]
  15. The enhancement effect of phenobarbital on toxicity of furylfuramide in mouse embryo. Nomura, T., Kondo, S. Mutat. Res. (1976) [Pubmed]
  16. Effects of nine active ingredients in Chinese herbal medicine sho-saiko-to on 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide mutagenicity. Ohtsuka, M., Fukuda, K., Yano, H., Kojiro, M. Jpn. J. Cancer Res. (1995) [Pubmed]
  17. Phosphorylation of activation functions AF-1 and AF-2 of RAR alpha and RAR gamma is indispensable for differentiation of F9 cells upon retinoic acid and cAMP treatment. Taneja, R., Rochette-Egly, C., Plassat, J.L., Penna, L., Gaub, M.P., Chambon, P. EMBO J. (1997) [Pubmed]
  18. Interactions that determine the assembly of a retinoid X receptor/corepressor complex. Ghosh, J.C., Yang, X., Zhang, A., Lambert, M.H., Li, H., Xu, H.E., Chen, J.D. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  19. Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of retinoic acid receptor alpha. Tate, B.F., Allenby, G., Janocha, R., Kazmer, S., Speck, J., Sturzenbecker, L.J., Abarzúa, P., Levin, A.A., Grippo, J.F. Mol. Cell. Biol. (1994) [Pubmed]
  20. Two factors secreted by the goldfish optic nerve induce retinal ganglion cells to regenerate axons in culture. Schwalb, J.M., Boulis, N.M., Gu, M.F., Winickoff, J., Jackson, P.S., Irwin, N., Benowitz, L.I. J. Neurosci. (1995) [Pubmed]
  21. The AF-2 region of the retinoic acid receptor alpha mediates retinoic acid inhibition of estrogen receptor function in breast cancer cells. Pratt, M.A., Deonarine, D., Teixeira, C., Novosad, D., Tate, B.F., Grippo, J.F. J. Biol. Chem. (1996) [Pubmed]
  22. Human TAF(II28) promotes transcriptional stimulation by activation function 2 of the retinoid X receptors. May, M., Mengus, G., Lavigne, A.C., Chambon, P., Davidson, I. EMBO J. (1996) [Pubmed]
  23. The glucocorticoid receptor is a key regulator of the decision between self-renewal and differentiation in erythroid progenitors. Wessely, O., Deiner, E.M., Beug, H., von Lindern, M. EMBO J. (1997) [Pubmed]
  24. GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Hong, H., Kohli, K., Garabedian, M.J., Stallcup, M.R. Mol. Cell. Biol. (1997) [Pubmed]
  25. Differential contributions of AF-1 and AF-2 activities to the developmental functions of RXR alpha. Mascrez, B., Mark, M., Krezel, W., Dupé, V., LeMeur, M., Ghyselinck, N.B., Chambon, P. Development (2001) [Pubmed]
  26. Characterization of the ligand-dependent transactivation domain of thyroid hormone receptor. Barettino, D., Vivanco Ruiz, M.M., Stunnenberg, H.G. EMBO J. (1994) [Pubmed]
  27. Ligand-dependent, transcriptionally productive association of the amino- and carboxyl-terminal regions of a steroid hormone nuclear receptor. Kraus, W.L., McInerney, E.M., Katzenellenbogen, B.S. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  28. A permissive retinoid X receptor/thyroid hormone receptor heterodimer allows stimulation of prolactin gene transcription by thyroid hormone and 9-cis-retinoic acid. Castillo, A.I., Sánchez-Martínez, R., Moreno, J.L., Martínez-Iglesias, O.A., Palacios, D., Aranda, A. Mol. Cell. Biol. (2004) [Pubmed]
  29. Different regions in activation function-1 of the human estrogen receptor required for antiestrogen- and estradiol-dependent transcription activation. McInerney, E.M., Katzenellenbogen, B.S. J. Biol. Chem. (1996) [Pubmed]
  30. The autonomous transactivation domain in helix H3 of the vitamin D receptor is required for transactivation and coactivator interaction. Kraichely, D.M., Collins, J.J., DeLisle, R.K., MacDonald, P.N. J. Biol. Chem. (1999) [Pubmed]
  31. A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor alpha coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA. Watanabe, M., Yanagisawa, J., Kitagawa, H., Takeyama , K., Ogawa, S., Arao, Y., Suzawa, M., Kobayashi, Y., Yano, T., Yoshikawa, H., Masuhiro, Y., Kato, S. EMBO J. (2001) [Pubmed]
  32. FHL2, a novel tissue-specific coactivator of the androgen receptor. Müller, J.M., Isele, U., Metzger, E., Rempel, A., Moser, M., Pscherer, A., Breyer, T., Holubarsch, C., Buettner, R., Schüle, R. EMBO J. (2000) [Pubmed]
  33. Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins. Hittelman, A.B., Burakov, D., Iñiguez-Lluhí, J.A., Freedman, L.P., Garabedian, M.J. EMBO J. (1999) [Pubmed]
  34. Mutations in the 1,25-dihydroxyvitamin D3 receptor identifying C-terminal amino acids required for transcriptional activation that are functionally dissociated from hormone binding, heterodimeric DNA binding, and interaction with basal transcription factor IIB, in vitro. Jurutka, P.W., Hsieh, J.C., Remus, L.S., Whitfield, G.K., Thompson, P.D., Haussler, C.A., Blanco, J.C., Ozato, K., Haussler, M.R. J. Biol. Chem. (1997) [Pubmed]
  35. PGC-1 functions as a transcriptional coactivator for the retinoid X receptors. Delerive, P., Wu, Y., Burris, T.P., Chin, W.W., Suen, C.S. J. Biol. Chem. (2002) [Pubmed]
  36. Neoplastic transformation induced by furylfuramide and nitromethylfuran of embryonic hamster cells in tissue culture. Nishi, Y., Taketomi, M., Inui, N. Int. J. Cancer (1977) [Pubmed]
  37. Mutant AF-2 domain of PML-RARalpha in retinoic acid-resistant NB4 cells: differentiation induced by RA is triggered directly through PML-RARalpha and its down-regulation in acute promyelocytic leukemia. Kitamura, K., Kiyoi, H., Yoshida, H., Saito, H., Ohno, R., Naoe, T. Leukemia (1997) [Pubmed]
  38. Metabolic deactivation of furylfuramide by cytochrome P450 in human and rat liver microsomes. Shimada, T., Yamazaki, H., Shimura, H., Tanaka, R., Guengerich, F.P. Carcinogenesis (1990) [Pubmed]
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