scholarly journals Opposite effects of the acute promyelocytic leukemia PML-retinoic acid receptor alpha (RAR alpha) and PLZF-RAR alpha fusion proteins on retinoic acid signalling.

1997 ◽  
Vol 17 (8) ◽  
pp. 4859-4869 ◽  
Author(s):  
M Ruthardt ◽  
U Testa ◽  
C Nervi ◽  
P F Ferrucci ◽  
F Grignani ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Protein Interactions ◽  
Fusion Proteins ◽  
Retinoic Acid Receptor ◽  
Type Ii ◽  
Inhibitory Effects ◽  
Retinoic Acid Receptor Alpha ◽  
Hematopoietic Precursor

Fusion proteins involving the retinoic acid receptor alpha (RAR alpha) and the PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemias (APLs). APLs with the PML-RAR alpha or the PLZF-RAR alpha fusion protein are phenotypically indistinguishable except that they differ in their sensitivity to retinoic acid (RA)-induced differentiation: PML-RAR alpha blasts are sensitive to RA and patients enter disease remission after RA treatment, while patients with PLZF-RAR alpha do not. We here report that (i) like PML-RAR alpha expression, PLZF-RAR alpha expression blocks terminal differentiation of hematopoietic precursor cell lines (U937 and HL-60) in response to different stimuli (vitamin D3, transforming growth factor beta1, and dimethyl sulfoxide); (ii) PML-RAR alpha, but not PLZF-RAR alpha, increases RA sensitivity of hematopoietic precursor cells and restores RA sensitivity of RA-resistant hematopoietic cells; (iii) PML-RAR alpha and PLZF-RAR alpha have similar RA binding affinities; and (iv) PML-RAR alpha enhances the RA response of RA target genes (those for RAR beta, RAR gamma, and transglutaminase type II [TGase]) in vivo, while PLZF-RAR alpha expression has either no effect (RAR beta) or an inhibitory activity (RAR gamma and type II TGase). These data demonstrate that PML-RAR alpha and PLZF-RAR alpha have similar (inhibitory) effects on RA-independent differentiation and opposite (stimulatory or inhibitory) effects on RA-dependent differentiation and that they behave in vivo as RA-dependent enhancers or inhibitors of RA-responsive genes, respectively. Their different activities on the RA signalling pathway might underlie the different responses of PML-RAR alpha and PLZF-RAR alpha APLs to RA treatment. The PLZF-RAR alpha fusion protein contains an approximately 120-amino-acid N-terminal motif (called the POZ domain), which is also found in a variety of zinc finger proteins and a group of poxvirus proteins and which mediates protein-protein interactions. Deletion of the PLZF POZ domain partially abrogated the inhibitory effect of PLZF-RAR alpha on RA-induced differentiation and on RA-mediated type II TGase up-regulation, suggesting that POZ-mediated protein interactions might be responsible for the inhibitory transcriptional activities of PLZF-RAR alpha.

scholarly journals In vivo analysis of the role of aberrant histone deacetylase recruitment and RARα blockade in the pathogenesis of acute promyelocytic leukemia

2006 ◽  
Vol 203 (4) ◽  
pp. 821-828 ◽  
Author(s):  
Hiromichi Matsushita ◽  
Pier Paolo Scaglioni ◽  
Mantu Bhaumik ◽  
Eduardo M. Rego ◽  
Lu Fan Cai ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Acute Promyelocytic Leukemia ◽  
Histone Deacetylases ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Dominant Negative

The promyelocytic leukemia–retinoic acid receptor α (PML-RARα) protein of acute promyelocytic leukemia (APL) is oncogenic in vivo. It has been hypothesized that the ability of PML-RARα to inhibit RARα function through PML-dependent aberrant recruitment of histone deacetylases (HDACs) and chromatin remodeling is the key initiating event for leukemogenesis. To elucidate the role of HDAC in this process, we have generated HDAC1–RARα fusion proteins and tested their activity and oncogenicity in vitro and in vivo in transgenic mice (TM). In parallel, we studied the in vivo leukemogenic potential of dominant negative (DN) and truncated RARα mutants, as well as that of PML-RARα mutants that are insensitive to retinoic acid. Surprisingly, although HDAC1-RARα did act as a bona fide DN RARα mutant in cellular in vitro and in cell culture, this fusion protein, as well as other DN RARα mutants, did not cause a block in myeloid differentiation in vivo in TM and were not leukemogenic. Comparative analysis of these TM and of TM/PML−/− and p53−/− compound mutants lends support to a model by which the RARα and PML blockade is necessary, but not sufficient, for leukemogenesis and the PML domain of the fusion protein provides unique functions that are required for leukemia initiation.

scholarly journals Pharmacological Activity of Retinoic Acid Receptor Alpha-Selective Antagonists in Vitro and in Vivo

2013 ◽  
Vol 4 (5) ◽  
pp. 446-450 ◽  
Author(s):  
Sanny S. W. Chung ◽  
Rebecca A. D. Cuellar ◽  
Xiangyuan Wang ◽  
Peter R. Reczek ◽  
Gunda I. Georg ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Pharmacological Activity ◽  
Retinoic Acid Receptor ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Selective Antagonists

scholarly journals Recruitment of the Histone Methyltransferase SUV39H1 and Its Role in the Oncogenic Properties of the Leukemia-Associated PML-Retinoic Acid Receptor Fusion Protein

2006 ◽  
Vol 26 (4) ◽  
pp. 1288-1296 ◽  
Author(s):  
Roberta Carbone ◽  
Oronza A. Botrugno ◽  
Simona Ronzoni ◽  
Alessandra Insinga ◽  
Luciano Di Croce ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Fusion Proteins ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Histone Methyltransferase ◽  
Dna Methyltransferases ◽  
Histone Deacetylation ◽  
Leukemic Cells ◽  
Acid Receptor

ABSTRACT Leukemia-associated fusion proteins establish aberrant transcriptional programs, which result in the block of hematopoietic differentiation, a prominent feature of the leukemic phenotype. The dissection of the mechanisms of deregulated transcription by leukemia fusion proteins is therefore critical for the design of tailored antileukemic strategies, aimed at reestablishing the differentiation program of leukemic cells. The acute promyelocytic leukemia (APL)-associated fusion protein PML-retinoic acid receptor (RAR) behaves as an aberrant transcriptional repressor, due to its ability to induce chromatin modifications (histone deacetylation and DNA methylation) and silencing of PML-RAR target genes. Here, we indicate that the ultimate result of PML-RAR action is to impose a heterochromatin-like structure on its target genes, thereby establishing a permanent transcriptional silencing. This effect is mediated by the previously described association of PML-RAR with chromatin-modifying enzymes (histone deacetylases and DNA methyltransferases) and by recruitment of the histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3.

Interactions of STAT5b-RARα, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2637-2646 ◽  
Author(s):  
Shuo Dong ◽  
David J. Tweardy
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Acute Promyelocytic Leukemia ◽  
Nuclear Receptor ◽  
Fusion Proteins ◽  
Transcriptional Activity ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Maturation Arrest ◽  
Acid Receptor

Abstract Signal transducer and activator of transcription (STAT) 5b-retinoic acid receptor (RAR) α is the fifth fusion protein identified in acute promyelocytic leukemia (APL). Initially described in a patient with all-trans retinoic acid (ATRA)–unresponsive disease, STAT5b-RARα resulted from an interstitial deletion on chromosome 17. To determine the molecular mechanisms of myeloid leukemogenesis and maturation arrest in STAT5b-RARα+ APL and its unresponsiveness to ATRA, we examined the effect of STAT5b-RARα on the activity of myeloid transcription factors including RARα/retinoid X receptor (RXR) α, STAT3, and STAT5 as well as its molecular interactions with the nuclear receptor corepressor, SMRT, and nuclear receptor coactivator, TRAM-1. STAT5b-RARα bound to retinoic acid response elements (RAREs) both as a homodimer and as a heterodimer with RXRα and inhibited wild-type RARα/RXRα transactivation. Although STAT5b-RARα had no effect on ligand-induced STAT5b activation, it enhanced interleukin 6–induced STAT3-dependent reporter activity, an effect shared by other APL fusion proteins including promyelocytic leukemia-RARα and promyelocytic leukemia zinc finger (PLZF)–RARα. SMRT was released from STAT5b-RARα/SMRT complexes by ATRA at 10−6 M, whereas TRAM-1 became associated with STAT5b-RARα at 10−7 M. The coiled-coil domain of STAT5b was required for formation of STAT5b-RARα homodimers, for the inhibition of RARα/RXRα transcriptional activity, and for stability of the STAT5b-RARα/SMRT complex. Thus, STAT5b-RARα contributes to myeloid maturation arrest by binding to RARE as either a homodimer or as a heterodimer with RXRα resulting in the recruitment of SMRT and inhibition of RARα/RXRα transcriptional activity. In addition, STAT5b-RARα and other APL fusion proteins may contribute to leukemogenesis by interaction with the STAT3 oncogene pathway.

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