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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 

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RARA  -  retinoic acid receptor, alpha

Homo sapiens

 
 
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Disease relevance of RARA

 

Psychiatry related information on RARA

 

High impact information on RARA

 

Chemical compound and disease context of RARA

 

Biological context of RARA

  • In more than 99% of cases, this disruption results in the formation of a PML-RARA gene fusion [9].
  • Finally, cAMP restored both RA-triggered differentiation and PML-RARA transcriptional activation in mutant RA-resistant APL cells [15].
  • PML-RARA-specific response elements were identified, which all conveyed a major transcriptional response to RA only in APL cells [15].
  • Thus, enforced RARA dimerization is critical not only for triggering transcriptional repression but also for extending the repertoire of target genes [16].
  • Of particular interest, in view of the known teratogenic role of retinoic acid, was a significant association with the RARA PstI RFLP (P = .016; not corrected for multiple testing) [17].
 

Anatomical context of RARA

 

Associations of RARA with chemical compounds

 

Physical interactions of RARA

  • In the majority (42 of 60), molecular analyses revealed underlying PML/RAR alpha rearrangements due to insertions (28 of 42) or more complex mechanisms, including 3-way and simple variant translocations (14 of 42) [26].
  • This RAR-binding activity represented in part the expression of RAR alpha and RAR gamma genes, whose transcripts were expressed in similar abundance in undifferentiated NHEK [27].
  • Heterodimers of retinoid X receptor (RXR) and retinoic acid receptor (RAR) bind preferentially to directly repeated elements with spacing of two (DR2) or five (DR5) base pairs, due to the specific heterocooperative interaction of their DNA binding domains (DBDs) on these elements [28].
  • Nuclear extracts prepared from COS-1 cells transfected with an expression vector for the nuclear RA receptors RAR alpha or RAR beta were enriched (20- to 100-fold) with a RA-binding activity that coeluted by size-exclusion HPLC with the putative RAR from HL-60 cells [29].
  • Remarkably, a region homologous to the CoR box which is necessary for TR and RAR to interact with N-CoR is not required for RevErb [30].
 

Co-localisations of RARA

  • We report that PML colocalizes with the nonphosphorylated fraction of the retinoblastoma protein (pRB) within nuclear bodies and that pRB is delocalized by PML-RAR alpha expression [31].
 

Regulatory relationships of RARA

 

Other interactions of RARA

  • Identical PML-RAR alpha fusion points are found in several patients [37].
  • The discovery of two human nuclear receptors for RA (hRAR alpha and hRAR beta) acting as transcriptional RA-inducible enhancer factors has provided a basis for understanding how RA controls gene expression [38].
  • The ER-ligand-binding domain, unlike RAR, also exhibited some basal interaction with coactivators in unstimulated cells that was abolished by the receptor antagonists tamoxifen or ICI182,780 [39].
  • The present analyses were undertaken to determine whether D4S175 or D4S192 is significantly associated with CL +/- P in a sample of unrelated patients that have previously provided evidence of associations between CL +/- P and both TGFA and RARA [40].
  • To test this hypothesis in hematopoietic cells, we used retrovirus-mediated gene transduction to introduce the RA receptors RAR-alpha, RAR-beta, and RAR-gamma as well as RXR-alpha into a mutant subclone of the HL-60 promyelocytic leukemia cell line (designated HL-60R) that is relatively resistant to RA-induced granulocytic differentiation [41].
 

Analytical, diagnostic and therapeutic context of RARA

References

  1. PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia. Padua, R.A., Larghero, J., Robin, M., le Pogam, C., Schlageter, M.H., Muszlak, S., Fric, J., West, R., Rousselot, P., Phan, T.H., Mudde, L., Teisserenc, H., Carpentier, A.F., Kogan, S., Degos, L., Pla, M., Bishop, J.M., Stevenson, F., Charron, D., Chomienne, C. Nat. Med. (2003) [Pubmed]
  2. PLZF-RAR alpha fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors. Chen, Z., Guidez, F., Rousselot, P., Agadir, A., Chen, S.J., Wang, Z.Y., Degos, L., Zelent, A., Waxman, S., Chomienne, C. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  3. Genetic mapping of the breast-ovarian cancer syndrome to a small interval on chromosome 17q12-21: exclusion of candidate genes EDH17B2 and RARA. Simard, J., Feunteun, J., Lenoir, G., Tonin, P., Normand, T., Luu The, V., Vivier, A., Lasko, D., Morgan, K., Rouleau, G.A. Hum. Mol. Genet. (1993) [Pubmed]
  4. A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657. Sohal, J., Phan, V.T., Chan, P.V., Davis, E.M., Patel, B., Kelly, L.M., Abrams, T.J., O'Farrell, A.M., Gilliland, D.G., Le Beau, M.M., Kogan, S.C. Blood (2003) [Pubmed]
  5. Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice identify cooperating events and genetic pathways to acute promyelocytic leukemia. Le Beau, M.M., Davis, E.M., Patel, B., Phan, V.T., Sohal, J., Kogan, S.C. Blood (2003) [Pubmed]
  6. Variability in the levels of PML-RAR alpha fusion transcripts detected by the laboratories participating in an external quality control program using several reverse transcription polymerase chain reaction protocols. Bolufer, P., Lo Coco, F., Grimwade, D., Barragán, E., Diverio, D., Cassinat, B., Chomienne, C., Gonzalez, M., Colomer, D., Gomez, M.T., Marugan, I., Román, J., Delgado, M.D., García-Marco, J.A., Bornstein, R., Vizmanos, J.L., Martinez, B., Jansen, J., Villegas, A., de Blas, J.M., Cabello, P., Sanz, M.A. Haematologica (2001) [Pubmed]
  7. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Epping, M.T., Wang, L., Edel, M.J., Carlée, L., Hernandez, M., Bernards, R. Cell (2005) [Pubmed]
  8. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. Soignet, S.L., Maslak, P., Wang, Z.G., Jhanwar, S., Calleja, E., Dardashti, L.J., Corso, D., DeBlasio, A., Gabrilove, J., Scheinberg, D.A., Pandolfi, P.P., Warrell, R.P. N. Engl. J. Med. (1998) [Pubmed]
  9. Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Wells, R.A., Catzavelos, C., Kamel-Reid, S. Nat. Genet. (1997) [Pubmed]
  10. Synergic effects of arsenic trioxide and cAMP during acute promyelocytic leukemia cell maturation subtends a novel signaling cross-talk. Zhu, Q., Zhang, J.W., Zhu, H.Q., Shen, Y.L., Flexor, M., Jia, P.M., Yu, Y., Cai, X., Waxman, S., Lanotte, M., Chen, S.J., Chen, Z., Tong, J.H. Blood (2002) [Pubmed]
  11. Activation of retinoic acid receptor alpha is sufficient for full induction of retinoid responses in SK-BR-3 and T47D human breast cancer cells. Schneider, S.M., Offterdinger, M., Huber, H., Grunt, T.W. Cancer Res. (2000) [Pubmed]
  12. Regulation of retinoic acid receptor beta expression by peroxisome proliferator-activated receptor gamma ligands in cancer cells. James, S.Y., Lin, F., Kolluri, S.K., Dawson, M.I., Zhang, X.K. Cancer Res. (2003) [Pubmed]
  13. Expression of retinoic acid receptor beta in human renal cell carcinomas correlates with sensitivity to the antiproliferative effects of 13-cis-retinoic acid. Hoffman, A.D., Engelstein, D., Bogenrieder, T., Papandreou, C.N., Steckelman, E., Dave, A., Motzer, R.J., Dmitrovsky, E., Albino, A.P., Nanus, D.M. Clin. Cancer Res. (1996) [Pubmed]
  14. Rapid diagnosis of acute promyelocytic leukemia by immunohistochemical localization of PML/RAR-alpha protein. Dyck, J.A., Warrell, R.P., Evans, R.M., Miller, W.H. Blood (1995) [Pubmed]
  15. PML-RARA-RXR oligomers mediate retinoid and rexinoid/cAMP cross-talk in acute promyelocytic leukemia cell differentiation. Kamashev, D., Vitoux, D., De Thé, H. J. Exp. Med. (2004) [Pubmed]
  16. Dimerization-induced corepressor binding and relaxed DNA-binding specificity are critical for PML/RARA-induced immortalization. Zhou, J., Pérès, L., Honoré, N., Nasr, R., Zhu, J., de Thé, H. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  17. Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci. Chenevix-Trench, G., Jones, K., Green, A.C., Duffy, D.L., Martin, N.G. Am. J. Hum. Genet. (1992) [Pubmed]
  18. CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Truong, B.T., Lee, Y.J., Lodie, T.A., Park, D.J., Perrotti, D., Watanabe, N., Koeffler, H.P., Nakajima, H., Tenen, D.G., Kogan, S.C. Blood (2003) [Pubmed]
  19. Highly purified primitive hematopoietic stem cells are PML-RARA negative and generate nonclonal progenitors in acute promyelocytic leukemia. Turhan, A.G., Lemoine, F.M., Debert, C., Bonnet, M.L., Baillou, C., Picard, F., Macintyre, E.A., Varet, B. Blood (1995) [Pubmed]
  20. Rearrangements in the second intron of the RARA gene are present in a large majority of patients with acute promyelocytic leukemia and are used as molecular marker for retinoic acid-induced leukemic cell differentiation. Chen, S.J., Zhu, Y.J., Tong, J.H., Dong, S., Huang, W., Chen, Y., Xiang, W.M., Zhang, L., Li, X.S., Qian, G.Q. Blood (1991) [Pubmed]
  21. Molecular cytogenetics of the acute promyelocytic leukemia-derived cell line NB4 and of four all-trans retinoic acid-resistant subclones. Mozziconacci, M.J., Rosenauer, A., Restouin, A., Fanelli, M., Shao, W., Fernandez, F., Toiron, Y., Viscardi, J., Gambacorti-Passerini, C., Miller, W.H., Lafage-Pochitaloff, M. Genes Chromosomes Cancer (2002) [Pubmed]
  22. Prognostic significance of the RT-PCR assay of PML-RARA transcripts in acute promyelocytic leukemia. The Leukemia Study Group of the Ministry of Health and Welfare (Kouseisho). Fukutani, H., Naoe, T., Ohno, R., Yoshida, H., Kiyoi, H., Miyawaki, S., Morishita, H., Sano, F., Kamibayashi, H., Matsue, K. Leukemia (1995) [Pubmed]
  23. Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway. Yoshida, H., Kitamura, K., Tanaka, K., Omura, S., Miyazaki, T., Hachiya, T., Ohno, R., Naoe, T. Cancer Res. (1996) [Pubmed]
  24. A mutated PML/RARA found in the retinoid maturation resistant NB4 subclone, NB4-R2, blocks RARA and wild-type PML/RARA transcriptional activities. Duprez, E., Benoit, G., Flexor, M., Lillehaug, J.R., Lanotte, M. Leukemia (2000) [Pubmed]
  25. Fluorescence in situ hybridization investigation of cutaneous lesions in acute promyelocytic leukemia. Wrede, J.E., Sundram, U., Kohler, S., Cherry, A.M., Arber, D.A., George, T.I. Mod. Pathol. (2005) [Pubmed]
  26. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies". Grimwade, D., Biondi, A., Mozziconacci, M.J., Hagemeijer, A., Berger, R., Neat, M., Howe, K., Dastugue, N., Jansen, J., Radford-Weiss, I., Lo Coco, F., Lessard, M., Hernandez, J.M., Delabesse, E., Head, D., Liso, V., Sainty, D., Flandrin, G., Solomon, E., Birg, F., Lafage-Pochitaloff, M. Blood (2000) [Pubmed]
  27. Retinoic acid receptors as regulators of human epidermal keratinocyte differentiation. Vollberg, T.M., Nervi, C., George, M.D., Fujimoto, W., Krust, A., Jetten, A.M. Mol. Endocrinol. (1992) [Pubmed]
  28. The dimerization interfaces formed between the DNA binding domains of RXR, RAR and TR determine the binding specificity and polarity of the full-length receptors to direct repeats. Zechel, C., Shen, X.Q., Chen, J.Y., Chen, Z.P., Chambon, P., Gronemeyer, H. EMBO J. (1994) [Pubmed]
  29. Identification and characterization of nuclear retinoic acid-binding activity in human myeloblastic leukemia HL-60 cells. Nervi, C., Grippo, J.F., Sherman, M.I., George, M.D., Jetten, A.M. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  30. A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with distinct repression domains. Zamir, I., Harding, H.P., Atkins, G.B., Hörlein, A., Glass, C.K., Rosenfeld, M.G., Lazar, M.A. Mol. Cell. Biol. (1996) [Pubmed]
  31. The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein. Alcalay, M., Tomassoni, L., Colombo, E., Stoldt, S., Grignani, F., Fagioli, M., Szekely, L., Helin, K., Pelicci, P.G. Mol. Cell. Biol. (1998) [Pubmed]
  32. A retinoid-resistant acute promyelocytic leukemia subclone expresses a dominant negative PML-RAR alpha mutation. Shao, W., Benedetti, L., Lamph, W.W., Nervi, C., Miller, W.H. Blood (1997) [Pubmed]
  33. Retinoic acid, GABA-ergic, and TGF-beta signaling systems are involved in human cleft palate fibroblast phenotype. Baroni, T., Bellucci, C., Lilli, C., Pezzetti, F., Carinci, F., Becchetti, E., Carinci, P., Stabellini, G., Calvitti, M., Lumare, E., Bodo, M. Mol. Med. (2006) [Pubmed]
  34. Establishment and characterization of cell lines from three human thyroid carcinomas: Responses to all-trans-retinoic acid and mutations in the BRAF gene. Koh, C.S., Ku, J.L., Park, S.Y., Kim, K.H., Choi, J.S., Kim, I.J., Park, J.H., Oh, S.K., Chung, J.K., Lee, J.H., Kim, W.H., Kim, C.W., Cho, B.Y., Park, J.G. Mol. Cell. Endocrinol. (2007) [Pubmed]
  35. Retinoid induced apoptosis in leukemia cells through a retinoic acid nuclear receptor-independent pathway. Hsu, C.A., Rishi, A.K., Su-Li, X., Gerald, T.M., Dawson, M.I., Schiffer, C., Reichert, U., Shroot, B., Poirer, G.C., Fontana, J.A. Blood (1997) [Pubmed]
  36. Retinoic acid-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid receptor-alpha. Drach, J., McQueen, T., Engel, H., Andreeff, M., Robertson, K.A., Collins, S.J., Malavasi, F., Mehta, K. Cancer Res. (1994) [Pubmed]
  37. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. de Thé, H., Lavau, C., Marchio, A., Chomienne, C., Degos, L., Dejean, A. Cell (1991) [Pubmed]
  38. Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin. Zelent, A., Krust, A., Petkovich, M., Kastner, P., Chambon, P. Nature (1989) [Pubmed]
  39. Ligand-dependent interactions of coactivators steroid receptor coactivator-1 and peroxisome proliferator-activated receptor binding protein with nuclear hormone receptors can be imaged in live cells and are required for transcription. Llopis, J., Westin, S., Ricote, M., Wang, Z., Cho, C.Y., Kurokawa, R., Mullen, T.M., Rose, D.W., Rosenfeld, M.G., Tsien, R.Y., Glass, C.K., Wang, J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  40. Evidence for an association between nonsyndromic cleft lip with or without cleft palate and a gene located on the long arm of chromosome 4. Mitchell, L.E., Healey, S.C., Chenevix-Trench, G. Am. J. Hum. Genet. (1995) [Pubmed]
  41. Multiple members of the retinoic acid receptor family are capable of mediating the granulocytic differentiation of HL-60 cells. Robertson, K.A., Emami, B., Mueller, L., Collins, S.J. Mol. Cell. Biol. (1992) [Pubmed]
  42. The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia. Arnould, C., Philippe, C., Bourdon, V., Gr goire, M.J., Berger, R., Jonveaux, P. Hum. Mol. Genet. (1999) [Pubmed]
  43. Identification of illegitimate recombination hot spot of the retinoic acid receptor alpha gene involved in 15;17 chromosomal translocation of acute promyelocytic leukemia. Tashiro, S., Kotomura, N., Tanaka, K., Suzuki, K., Kyo, T., Dohy, H., Niwa, O., Kamada, N. Oncogene (1994) [Pubmed]
  44. Molecular analysis of simple variant translocations in acute promyelocytic leukemia. Borrow, J., Shipley, J., Howe, K., Kiely, F., Goddard, A., Sheer, D., Srivastava, A., Antony, A.C., Fioretos, T., Mitelman, F. Genes Chromosomes Cancer (1994) [Pubmed]
 
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