|
|
 Previous Article | Table of Contents | Next Article 
The PML/RAR alpha oncoprotein is a direct molecular target of retinoic acid
in acute promyelocytic leukemia cells
JV Raelson, C Nervi, A Rosenauer, L Benedetti, Y Monczak, M Pearson, PG Pelicci and WH Miller
Lady Davis Institute for Medical Research, Sir Mortimer Davis Jewish
General Hospital, Montreal, Quebec, Canada.
Acute promyelocytic leukemia (APL) is characterized by the translocation,
t(15;17) and the expression of a PML/RAR alpha fusion protein that is
diagnostic of the disease. There is evidence that PML/RAR alpha protein
acts as a dominant negative inhibitor of normal retinoid receptor function
and myeloid differentiation. We now show that the PML/RAR alpha fusion
product is directly downregulated in response to retinoic acid (tRA)
treatment in the human APL cell line, NB4. tRA treatment induces loss of
PML/RAR alpha at the protein level but not at the level of mRNA, as
determined by Northern blots, by Western blots, and by ligand binding
assays and in binding to RA- responsive DNA elements. We present evidence
that this regulation is posttranslational. This evidence suggests that tRA
induces synthesis of a protein that selectively degrades PML/RAR alpha. We
further show that this loss of PML/ RAR-alpha is not limited to the unique
APL cell line. NB4, because PML/RAR alpha protein is selectively
downregulated by tRA when expressed in the transfected myeloid cell line
U937. The loss of PML/RAR alpha may be directly linked to tRA-induced
differentiation, because in a retinoid-resistant subclone of NB4, tRA does
not decrease PML/RAR alpha protein expression. In NB4 cells, the specific
downregulation of the fusion protein decreases the ratio of PML/RAR alpha
to wild-type RAR alpha. Because the ratio of expression of PML/RAR alpha to
wild-type RAR alpha and PML may be important in maintaining the dominant
negative block of myelocytic differentiation, these data suggest a
molecular mechanism for restoration by tRA normal myeloid differentiation
in APL cells.
Volume 88,
Issue 8,
pp. 2826-2832,
10/15/1996
Copyright © 1996 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J. Hu, Y.-F. Liu, C.-F. Wu, F. Xu, Z.-X. Shen, Y.-M. Zhu, J.-M. Li, W. Tang, W.-L. Zhao, W. Wu, et al.
Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia
PNAS,
March 3, 2009;
106(9):
3342 - 3347.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-Y. Wang and Z. Chen
Acute promyelocytic leukemia: from highly fatal to highly curable
Blood,
March 1, 2008;
111(5):
2505 - 2515.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.-B. Zhou, J. Zhang, Z.-Y. Wang, S.-J. Chen, and Z. Chen
Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy
Phil Trans R Soc B,
June 29, 2007;
362(1482):
959 - 971.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. L. Reineke, H. Liu, M. Lam, Y. Liu, and H.-Y. Kao
Aberrant Association of Promyelocytic Leukemia Protein-Retinoic Acid Receptor-{alpha} with Coactivators Contributes to Its Ability to Regulate Gene Expression
J. Biol. Chem.,
June 22, 2007;
282(25):
18584 - 18596.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Cote, S. McNamara, D. Brambilla, A. Bianchini, G. Rizzo, S. V. del Rincon, F. Grignani, C. Nervi, and W. H. Miller Jr
Expression of SMRT{beta} promotes ligand-induced activation of mutated and wild-type retinoid receptors
Blood,
December 15, 2004;
104(13):
4226 - 4235.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Witcher, H. Y. Shiu, Q. Guo, and W. H. Miller Jr
Combination of retinoic acid and tumor necrosis factor overcomes the maturation block in a variety of retinoic acid-resistant acute promyelocytic leukemia cells
Blood,
November 15, 2004;
104(10):
3335 - 3342.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Parrella, M. Gianni', V. Cecconi, E. Nigro, M. M. Barzago, A. Rambaldi, C. Rochette-Egly, M. Terao, and E. Garattini
Phosphodiesterase IV Inhibition by Piclamilast Potentiates the Cytodifferentiating Action of Retinoids in Myeloid Leukemia Cells: CROSS-TALK BETWEEN THE cAMP AND THE RETINOIC ACID SIGNALING PATHWAYS
J. Biol. Chem.,
October 1, 2004;
279(40):
42026 - 42040.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Davison, K. K. Mann, S. Waxman, and W. H. Miller Jr
JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells
Blood,
May 1, 2004;
103(9):
3496 - 3502.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-X. Shen, Z.-Z. Shi, J. Fang, B.-W. Gu, J.-M. Li, Y.-M. Zhu, J.-Y. Shi, P.-Z. Zheng, H. Yan, Y.-F. Liu, et al.
Inaugural Article: All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia
PNAS,
April 13, 2004;
101(15):
5328 - 5335.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Khan, T. Nomura, T. Chiba, K. Tanaka, H. Yoshida, K. Mori, and S. Ishii
The Fusion Oncoprotein PML-RAR{alpha} Induces Endoplasmic Reticulum (ER)-associated Degradation of N-CoR and ER Stress
J. Biol. Chem.,
March 19, 2004;
279(12):
11814 - 11824.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Fanelli, A. Fantozzi, P. De Luca, S. Caprodossi, S.-i. Matsuzawa, M. A. Lazar, P. G. Pelicci, and S. Minucci
The Coiled-coil Domain Is the Structural Determinant for Mammalian Homologues of Drosophila Sina-mediated Degradation of Promyelocytic Leukemia Protein and Other Tripartite Motif Proteins by the Proteasome
J. Biol. Chem.,
February 13, 2004;
279(7):
5374 - 5379.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Cote, A. Rosenauer, A. Bianchini, K. Seiter, J. Vandewiele, C. Nervi, and W. H. Miller Jr
Response to histone deacetylase inhibition of novel PML/RARalpha mutants detected in retinoic acid-resistant APL cells
Blood,
September 18, 2002;
100(7):
2586 - 2596.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Jing, L. Xia, and S. Waxman
Targeted removal of PML-RARalpha protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia
Blood,
July 18, 2002;
100(3):
1008 - 1013.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Kelly, J. L. Kutok, I. R. Williams, C. L. Boulton, S. M. Amaral, D. P. Curley, T. J. Ley, and D. G. Gilliland
PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model
PNAS,
June 11, 2002;
99(12):
8283 - 8288.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kitareewan, I. Pitha-Rowe, D. Sekula, C. H. Lowrey, M. J. Nemeth, T. R. Golub, S. J. Freemantle, and E. Dmitrovsky
UBE1L is a retinoid target that triggers PML/RARalpha degradation and apoptosis in acute promyelocytic leukemia
PNAS,
March 19, 2002;
99(6):
3806 - 3811.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Gianni', Y. Kalac, I. Ponzanelli, A. Rambaldi, M. Terao, and E. Garattini
Tyrosine kinase inhibitor STI571 potentiates the pharmacologic activity of retinoic acid in acute promyelocytic leukemia cells: effects on the degradation of RAR{alpha} and PML-RAR{alpha}
Blood,
May 15, 2001;
97(10):
3234 - 3243.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Idres, G. Benoît, M. A. Flexor, M. Lanotte, and G. G. Chabot
Granulocytic Differentiation of Human NB4 Promyelocytic Leukemia Cells Induced by All-trans Retinoic Acid Metabolites
Cancer Res.,
January 1, 2001;
61(2):
700 - 705.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
Y. Jing, L. Wang, L. Xia, G.-q. Chen, Z. Chen, W. H. Miller, and S. Waxman
Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo
Blood,
January 1, 2001;
97(1):
264 - 269.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Cote, D. Zhou, A. Bianchini, C. Nervi, R. E. Gallagher, and W. H. Miller Jr
Altered ligand binding and transcriptional regulation by mutations in the PML/RARalpha ligand-binding domain arising in retinoic acid-resistant patients with acute promyelocytic leukemia
Blood,
November 1, 2000;
96(9):
3200 - 3208.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Xiao, J. G. McCarthy, J. C. Aster, and J. A. Fletcher
ZNF198-FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain
Blood,
July 15, 2000;
96(2):
699 - 704.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Zhu, M. Gianni, E. Kopf, N. Honore, M. Chelbi-Alix, M. Koken, F. Quignon, C. Rochette-Egly, and H. de The
Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor alpha (RARalpha ) and oncogenic RARalpha fusion proteins
PNAS,
December 21, 1999;
96(26):
14807 - 14812.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Jing, J. Dai, R. M.E. Chalmers-Redman, W. G. Tatton, and S. Waxman
Arsenic Trioxide Selectively Induces Acute Promyelocytic Leukemia Cell Apoptosis Via a Hydrogen Peroxide-Dependent Pathway
Blood,
September 15, 1999;
94(6):
2102 - 2111.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Du, R. L. Redner, M. P. Cooke, and C. Lavau
Overexpression of Wild-Type Retinoic Acid Receptor alpha (RARalpha ) Recapitulates Retinoic Acid-Sensitive Transformation of Primary Myeloid Progenitors by Acute Promyelocytic Leukemia RARalpha -Fusion Genes
Blood,
July 15, 1999;
94(2):
793 - 802.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. L. Coco, D. Diverio, B. Falini, A. Biondi, C. Nervi, and P. G. Pelicci
Genetic Diagnosis and Molecular Monitoring in the Management of Acute Promyelocytic Leukemia
Blood,
July 1, 1999;
94(1):
12 - 22.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Melnick and J. D. Licht
Deconstructing a Disease: RAR{alpha}, Its Fusion Partners, and Their Roles in the Pathogenesis of Acute Promyelocytic Leukemia
Blood,
May 15, 1999;
93(10):
3167 - 3215.
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Lallemand-Breitenbach, M.-C. Guillemin, A. Janin, M.-T. Daniel, L. Degos, S. C. Kogan, J. Michael Bishop, and H. de The
Retinoic Acid and Arsenic Synergize to Eradicate Leukemic Cells in a Mouse Model of Acute Promyelocytic Leukemia
J. Exp. Med.,
April 5, 1999;
189(7):
1043 - 1052.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Fanelli, S. Minucci, V. Gelmetti, C. Nervi, C. Gambacorti-Passerini, and P. G. Pelicci
Constitutive Degradation of PML/RARalpha Through the Proteasome Pathway Mediates Retinoic Acid Resistance
Blood,
March 1, 1999;
93(5):
1477 - 1481.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Muller, W. H. Miller Jr, and A. Dejean
Trivalent Antimonials Induce Degradation of the PML-RARalpha Oncoprotein and Reorganization of the Promyelocytic Leukemia Nuclear Bodies in Acute Promyelocytic Leukemia NB4 Cells
Blood,
December 1, 1998;
92(11):
4308 - 4316.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Nervi, F. F. Ferrara, M. Fanelli, M. R. Rippo, B. Tomassini, P. F. Ferrucci, M. Ruthardt, V. Gelmetti, C. Gambacorti-Passerini, D. Diverio, et al.
Caspases Mediate Retinoic Acid-Induced Degradation of the Acute Promyelocytic Leukemia PML/RARalpha Fusion Protein
Blood,
October 1, 1998;
92(7):
2244 - 2251.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Imaizumi, H. Suzuki, M. Yoshinari, A. Sato, T. Saito, A. Sugawara, S. Tsuchiya, Y. Hatae, T. Fujimoto, A. Kakizuka, et al.
Mutations in the E-Domain of RARalpha Portion of the PML/RARalpha Chimeric Gene May Confer Clinical Resistance to All-trans Retinoic Acid in Acute Promyelocytic Leukemia
Blood,
July 15, 1998;
92(2):
374 - 382.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Makishima, K. Umesono, K. Shudo, T. Naoe, K. Kishi, and Y. Honma
Induction of Differentiation in Acute Promyelocytic Leukemia Cells by 9-cis Retinoic Acid alpha -Tocopherol Ester (9-cis Tretinoin Tocoferil)
Blood,
June 15, 1998;
91(12):
4715 - 4726.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Gianni, M. H.M. Koken, M. K. Chelbi-Alix, G. Benoit, M. Lanotte, Z. Chen, and H. de The
Combined Arsenic and Retinoic Acid Treatment Enhances Differentiation and Apoptosis in Arsenic-Resistant NB4 Cells
Blood,
June 1, 1998;
91(11):
4300 - 4310.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Slack and M. Yu
Constitutive Expression of the Promyelocytic Leukemia-Associated Oncogene PML-RARalpha in TF1 Cells: Isoform-Specific and Retinoic Acid-Dependent Effects on Growth, bcl-2 Expression, and Apoptosis
Blood,
May 1, 1998;
91(9):
3347 - 3356.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Guidez, S. Ivins, J. Zhu, M. Soderstrom, S. Waxman, and A. Zelent
Reduced Retinoic Acid-Sensitivities of Nuclear Receptor Corepressor Binding to PML- and PLZF-RARalpha Underlie Molecular Pathogenesis and Treatment of Acute Promyelocytic Leukemia
Blood,
April 15, 1998;
91(8):
2634 - 2642.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T Cao, E Duprez, K. Borden, P. Freemont, and L. Etkin
Ret finger protein is a normal component of PML nuclear bodies and interacts directly with PML
J. Cell Sci.,
January 5, 1998;
111(10):
1319 - 1329.
[Abstract]
[PDF]
|
|
|
|
|
|
|
D. Grimwade, P. Gorman, E. Duprez, K. Howe, S. Langabeer, F. Oliver, H. Walker, D. Culligan, J. Waters, M. Pomfret, et al.
Characterization of Cryptic Rearrangements and Variant Translocations in Acute Promyelocytic Leukemia
Blood,
December 15, 1997;
90(12):
4876 - 4885.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Monczak, M. Trudel, W. W. Lamph, and W. H. Miller Jr
Induction of Apoptosis Without Differentiation by Retinoic Acid in PLB-985 Cells Requires the Activation of Both RAR and RXR
Blood,
November 1, 1997;
90(9):
3345 - 3355.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. H. M. Koken, A. Reid, F. Quignon, M. K. Chelbi-Alix, J. M. Davies, J. H. S. Kabarowski, J. Zhu, S. Dong, S.-J. Chen, Z. Chen, et al.
Leukemia-associated retinoic acid receptor alpha fusion partners, PML and PLZF, heterodimerize and colocalize to nuclear bodies
PNAS,
September 16, 1997;
94(19):
10255 - 10260.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Yu, J.-H. Tong, M. Mao, L.-X. Kan, M.-M. Liu, Y.-W. Sun, G. Fu, Y.-K. Jing, L. Yu, D. Lepaslier, et al.
Cloning of a gene (RIG-G) associated with retinoic acid-induced differentiation of acute promyelocytic leukemia cells and representing a new member of a family of interferon-stimulated genes
PNAS,
July 8, 1997;
94(14):
7406 - 7411.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Shao, L. Benedetti, W. W. Lamph, C. Nervi, and W. H. Miller Jr
A Retinoid-Resistant Acute Promyelocytic Leukemia Subclone Expresses a Dominant Negative PML-RARalpha Mutation
Blood,
June 15, 1997;
89(12):
4282 - 4289.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Rego, L.-Z. He, R. P. Warrell Jr., Z.-G. Wang, and P. P. Pandolfi
Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARalpha and PLZF-RARalpha oncoproteins
PNAS,
August 29, 2000;
97(18):
10173 - 10178.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
