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PMID: 8890168 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Effects on differentiation by the promyelocytic leukemia PML/RARalpha protein depend on the fusion of the PML protein dimerization and RARalpha DNA binding domains.

The EMBO journal ·Vol. 15 ·No. 18 ·1996-09-16 ·Pages 4949-58

Grignani F, Testa U, Rogaia D, Ferrucci PF, Samoggia P, Pinto A, Aldinucci D, Gelmetti V, Fagioli M, Alcalay M, Seeler J, Grignani F, Nicoletti I, Peschle C, Pelicci PG

Abstract

The block of terminal differentiation is a prominent feature of acute promyelocytic leukemia (APL) and its release by retinoic acid correlates with disease remission. Expression of the APL-specific PML/RARalpha fusion protein in hematopoietic precursor cell lines blocks terminal differentiation, suggesting that PML/ RARalpha may have the same activity in APL blasts. We expressed different PML/RARalpha mutants in U937 and TF-1 cells and demonstrated that the integrity of the PML protein dimerization and RARalpha DNA binding domains is crucial for the differentiation block induced by PML/RARalpha, and that these domains exert their functions only within the context of the fusion protein. Analysis of the in vivo dimerization and cell localization properties of the PML/RARalpha mutants revealed that PML/RARalpha--PML and PML/RARalpha--RXR heterodimers are not necessary for PML/RARalpha activity on differentiation. We propose that a crucial mechanism underlying PML/RARalpha oncogenic activity is the deregulation of a transcription factor, RARalpha, through its fusion with the dimerization interface of another nuclear protein, PML.

MeSH Terms
Binding Sites Blotting, Western Cell Differentiation/drug effects DNA/metabolism Fluorescent Antibody Technique Humans Leukemia, Promyelocytic, Acute/metabolism Mutagenesis, Site-Directed Neoplasm Proteins/genetics,metabolism Nuclear Proteins Oncogene Proteins, Fusion/genetics,metabolism Phenotype Promyelocytic Leukemia Protein Protein Conformation Receptors, Retinoic Acid/metabolism Retinoid X Receptors Structure-Activity Relationship Transcription Factors/metabolism Tretinoin/metabolism Tumor Suppressor Proteins
Chemicals
Neoplasm Proteins Nuclear Proteins Oncogene Proteins, Fusion Promyelocytic Leukemia Protein Receptors, Retinoic Acid Retinoid X Receptors Transcription Factors Tumor Suppressor Proteins promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein PML protein, human Tretinoin DNA
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Grignani F
Istituto di Clinica Medica I, Policlinico Monteluce, Perugia University, Italy.
Testa U
Rogaia D
Ferrucci P F
Samoggia P
Pinto A
Aldinucci D
Gelmetti V
Fagioli M
Alcalay M
Seeler J
Grignani F
Nicoletti I
Peschle C
Pelicci P G
References (40)
40 references, click to expand
  1. Molecular evaluation of response to all-trans-retinoic acid therapy in patients with acute promyelocytic leukemia.
    Blood. 1991 Apr 15;77(8):1657-9 PMID: 1849758
  2. Negative autoregulation of c-myc gene expression is inactivated in transformed cells.
    EMBO J. 1990 Dec;9(12):3913-22 PMID: 2249657
  3. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML.
    Cell. 1991 Aug 23;66(4):663-74 PMID: 1652368
  4. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR.
    Cell. 1991 Aug 23;66(4):675-84 PMID: 1652369
  5. RXR beta: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements.
    Cell. 1991 Dec 20;67(6):1251-66 PMID: 1662118
  6. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently.
    Cell. 1992 Jan 24;68(2):377-95 PMID: 1310259
  7. Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors.
    Nature. 1992 Jan 30;355(6359):441-6 PMID: 1310350
  8. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling.
    Nature. 1992 Jan 30;355(6359):446-9 PMID: 1310351
  9. Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins.
    EMBO J. 1992 Feb;11(2):629-42 PMID: 1311253
  10. Alternative splicing of PML transcripts predicts coexpression of several carboxy-terminally different protein isoforms.
    Oncogene. 1992 Jun;7(6):1083-91 PMID: 1594241
  11. Characterization of the PML-RAR alpha chimeric product of the acute promyelocytic leukemia-specific t(15;17) translocation.
    Cancer Res. 1992 Jul 1;52(13):3687-92 PMID: 1319828
  12. A novel zinc finger coiled-coil domain in a family of nuclear proteins.
    Trends Biochem Sci. 1992 Sep;17(9):344-5 PMID: 1412709
  13. Identification and preliminary characterization of a protein motif related to the zinc finger.
    Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2112-6 PMID: 7681583
  14. Acute promyelocytic leukemia.
    N Engl J Med. 1993 Jul 15;329(3):177-89 PMID: 8515790
  15. PMLRAR homodimers: distinct DNA binding properties and heteromeric interactions with RXR.
    EMBO J. 1993 Aug;12(8):3171-82 PMID: 8393784
  16. The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells.
    Cell. 1993 Aug 13;74(3):423-31 PMID: 8394219
  17. Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia.
    Science. 1993 Aug 20;261(5124):1041-4 PMID: 8351518
  18. PML protein expression in hematopoietic and acute promyelocytic leukemia cells.
    Blood. 1993 Sep 15;82(6):1858-67 PMID: 8400236
  19. Cloning of the ALL-1 fusion partner, the AF-6 gene, involved in acute myeloid leukemias with the t(6;11) chromosome translocation.
    Cancer Res. 1993 Dec 1;53(23):5624-8 PMID: 8242616
  20. Isolation and characterization of cDNA encoding a human nuclear antigen predominantly recognized by autoantibodies from patients with primary biliary cirrhosis.
    J Immunol. 1990 Dec 15;145(12):4338-47 PMID: 2258622
  21. Promyelocytic leukemia-specific PML-retinoic acid alpha receptor fusion protein interferes with erythroid differentiation of human erythroleukemia K562 cells.
    Cancer Res. 1995 Jan 15;55(2):440-3 PMID: 7529139
  22. Characterization of a new monoclonal antibody (PG-M3) directed against the aminoterminal portion of the PML gene product: immunocytochemical evidence for high expression of PML proteins on activated macrophages, endothelial cells, and epithelia.
    Blood. 1995 Apr 1;85(7):1871-80 PMID: 7535592
  23. The solution structure of the RING finger domain from the acute promyelocytic leukaemia proto-oncoprotein PML.
    EMBO J. 1995 Apr 3;14(7):1532-41 PMID: 7729428
  24. The PML growth-suppressor has an altered expression in human oncogenesis.
    Oncogene. 1995 Apr 6;10(7):1315-24 PMID: 7731682
  25. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia.
    Proc Natl Acad Sci U S A. 1995 May 23;92(11):4917-21 PMID: 7761424
  26. Acute promyelocytic leukemia: from genetics to treatment.
    Blood. 1994 Jan 1;83(1):10-25 PMID: 8274729
  27. A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein.
    Cell. 1994 Jan 28;76(2):333-43 PMID: 8293467
  28. Retinoic acid regulates aberrant nuclear localization of PML-RAR alpha in acute promyelocytic leukemia cells.
    Cell. 1994 Jan 28;76(2):345-56 PMID: 8293468
  29. The t(15;17) translocation alters a nuclear body in a retinoic acid-reversible fashion.
    EMBO J. 1994 Mar 1;13(5):1073-83 PMID: 8131741
  30. A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-4, AF-9 nor ENL.
    Oncogene. 1994 Apr;9(4):1039-45 PMID: 8134107
  31. PML/RAR alpha+ U937 mutant and NB4 cell lines: retinoic acid restores the monocytic differentiation response to vitamin D3.
    Cancer Res. 1994 Aug 15;54(16):4508-15 PMID: 7519122
  32. Leucine-zipper dimerization motif encoded by the AF17 gene fused to ALL-1 (MLL) in acute leukemia.
    Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8107-11 PMID: 8058765
  33. PML, a growth suppressor disrupted in acute promyelocytic leukemia.
    Mol Cell Biol. 1994 Oct;14(10):6858-67 PMID: 7935403
  34. Chromosomal translocations in human cancer.
    Nature. 1994 Nov 10;372(6502):143-9 PMID: 7969446
  35. Lymphohematopoietic progenitors immortalized by a retroviral vector harboring a dominant-negative retinoic acid receptor can recapitulate lymphoid, myeloid, and erythroid development.
    Genes Dev. 1994 Dec 1;8(23):2831-41 PMID: 7995521
  36. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs.
    Nucleic Acids Res. 1987 Oct 26;15(20):8125-48 PMID: 3313277
  37. A segment of the 5' nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation.
    J Virol. 1988 Aug;62(8):2636-43 PMID: 2839690
  38. Identification and analysis of human erythropoietin receptors on a factor-dependent cell line, TF-1.
    Blood. 1989 Feb;73(2):375-80 PMID: 2537111
  39. Antibodies specific to the retinoic acid human nuclear receptors alpha and beta.
    Proc Natl Acad Sci U S A. 1989 May;86(9):3089-93 PMID: 2541430
  40. Structure and origin of the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoid-binding and transactivation properties.
    Oncogene. 1991 Jul;6(7):1285-92 PMID: 1650447
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1996-09-16
Pages
4949-58
Language
English
Region
England
NLM ID
8208664
PMCID
PMC452232
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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