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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2244-2251
Caspases Mediate Retinoic Acid-Induced Degradation of the Acute
Promyelocytic Leukemia PML/RAR Fusion Protein
Clara Nervi,
Fabiana F. Ferrara,
Mirco Fanelli,
Maria Rita Rippo,
Barbara Tomassini,
Pier Francesco Ferrucci,
Martin Ruthardt,
Vania Gelmetti,
Carlo Gambacorti-Passerini,
Daniela Diverio,
Francesco Grignani,
Pier Giuseppe Pelicci, and
Roberto Testi
From the Dipartimento di Istologia ed Embriologia Medica and
Dipartimento di Biotecnologie Cellulari e Ematologia, University of
Rome "La Sapienza," Rome; the European Institute of Oncology,
Department of Experimental Oncology, Milan; the Dipartimento di
Medicina Sperimentale e Scienze Biochimiche, University of Rome "Tor
Vergata," Rome; Istituto di Medicina Interna e Scienze Oncologiche,
Perugia University, Perugia; the Division of Experimental Oncology D,
Istituto Nazionale Tumori, Milan, Italy; and the Department of
Hematology, J.-W. Goethe University, Frankfurt, Germany.
All-trans-retinoic acid (RA) treatment induces morphological
remission in acute promyelocytic leukemia (APL) patients carrying the
t(15;17) and expressing the PML/RAR product by inducing terminal differentiation of the leukemic clone. RA treatment induces
downregulation of PML/RAR and reorganization of the PML-nuclear
bodies. These events have been proposed to be essential for the
induction of APL cell differentiation by RA. Here, we show that in the
APL-derived NB4 cell line as well as in myeloid precursor U937 cells
expressing the PML/RAR (U937/PR9) and in blasts from APL patients,
the PML/RAR fusion protein is cleaved by a caspase 3-like activity
induced by RA treatment. In fact, a caspase 3-like activity is
detectable in PML/RAR expressing cells after RA treatment, and
selective caspase inhibitor peptides are able to prevent the RA-induced degradation of the fusion protein in vivo and in vitro. Using recombinant caspases and PML/RAR deletion mutants we mapped a caspase 3 cleavage site (Asp 522) within the -helix
region of the PML component of the fusion protein. The extent of
PML/RAR cleavage directly correlates with the ability of RA to
restore the normal PML nuclear bodies (NBs) pattern. However,
RA-induced differentiation is not prevented by the persistence of the
fusion product and occurs in the absence of normally structured PML
NBs. These results indicate that PML/RAR is directly involved in
conferring RA sensitivity of APL cells and that the RA-induced
reassembly of PML NBs is the consequence of the disappearance of
PML/RAR.
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|
|
|
|
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|
|
|
|
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|
|
|
|
|
|
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W. H. Miller Jr., H. M. Schipper, J. S. Lee, J. Singer, and S. Waxman
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62(14):
3893 - 3903.
[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
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99(6):
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Lallemand-Breitenbach, J. Zhu, F. Puvion, M. Koken, N. Honore, A. Doubeikovsky, E. Duprez, P. P. Pandolfi, E. Puvion, P. Freemont, et al.
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J. Exp. Med.,
June 18, 2001;
193(12):
1361 - 1372.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Gianni', Y. Kalac, I. Ponzanelli, A. Rambaldi, M. Terao, and E. Garattini
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May 15, 2001;
97(10):
3234 - 3243.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. C. Kogan, D. E. Brown, D. B. Shultz, B.-T. H. Truong, V. Lallemand-Breitenbach, M.-C. Guillemin, E. Lagasse, I. L. Weissman, and J. M. Bishop
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J. Exp. Med.,
February 19, 2001;
193(4):
531 - 544.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. McCabe Jr., K. P. Singh, S. A. Reddy, B. Chelladurai, J. G. Pounds, J. J. Reiners Jr., and J. C. States
Sensitivity of Myelomonocytic Leukemia Cells to Arsenite-Induced Cell Cycle Disruption, Apoptosis, and Enhanced Differentiation Is Dependent on the Inter-Relationship between Arsenic Concentration, Duration of Treatment, and Cell Cycle Phase
J. Pharmacol. Exp. Ther.,
November 1, 2000;
295(2):
724 - 733.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
E. M. Rego, L.-Z. He, R. P. Warrell Jr., Z.-G. Wang, and P. P. Pandolfi
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PNAS,
August 17, 2000;
(2000)
180290497.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
E. Puccetti, S. Güller, A. Orleth, N. Brüggenolte, D. Hoelzer, O. G. Ottmann, and M. Ruthardt
BCR-ABL Mediates Arsenic Trioxide-induced Apoptosis Independently of Its Aberrant Kinase Activity
Cancer Res.,
July 1, 2000;
60(13):
3409 - 3413.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
H. Li, C. Leo, J. Zhu, X. Wu, J. O'Neil, E.-J. Park, and J. D. Chen
Sequestration and Inhibition of Daxx-Mediated Transcriptional Repression by PML
Mol. Cell. Biol.,
March 1, 2000;
20(5):
1784 - 1796.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
J. L. Slack, C. L. Willman, J. W. Andersen, Y.-P. Li, D. S. Viswanatha, C. D. Bloomfield, M. S. Tallman, and R. E. Gallagher
Molecular analysis and clinical outcome of adult APL patients with the type V PML-RARalpha isoform: results from Intergroup protocol 0129
Blood,
January 15, 2000;
95(2):
398 - 403.
[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]
|
|
|
|
|
|
|
T. Naoe, K. Kitamura;, M. Fanelli, and P. G. Pelicci
Relationship Between Degradation of PML-RARalpha and Differentiation
Blood,
August 15, 1999;
94(4):
1478 - 1479.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Sternsdorf, E. Puccetti, K. Jensen, D. Hoelzer, H. Will, O. G. Ottmann, and M. Ruthardt
PIC-1/SUMO-1-Modified PML-Retinoic Acid Receptor alpha Mediates Arsenic Trioxide-Induced Apoptosis in Acute Promyelocytic Leukemia
Mol. Cell. Biol.,
July 1, 1999;
19(7):
5170 - 5178.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
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