Down-stream regions of the POZ-domain influence the interaction of the t(11;17)-associated PLZF/RARalpha fusion protein with the histone-deacetylase recruiting co-repressor complex.

Abstract

INTRODUCTION:

Acute promyelocytic leukemia (APL) patients with t(15;17)(PML/RARalpha positive) achieve remission upon t-RA treatment, whereas patients with t(11;17)(PLZF/RARalpha positive) do not. Both APL translocation products bind to the histone deacetylase (HD)-recruiting nuclear co-repressor complex (HD-NCR) in a ligand-dependent manner through their RARalpha portion. Differently to PML/RARalpha, PLZF/RARalpha also binds the HD-NCR in a ligand-independent manner through the PLZF portion of the fusion protein (PLZF#), which seems to be crucial for the t-RA resistance of t(11;17) APL patients.

MATERIALS AND METHODS:

The t-RA sensitivity of U937 cells was tested by the nitro-blue tetrazolium reduction (NBT) assay and by analysis of t-RA-induced type II transglutaminase activity. The interaction between HD-NCR and PLZF/RARalpha was investigated by in vitro binding assays.

RESULTS:

(i) Deletions in PLZF# convert PLZF/RARalpha from a repressor to an activator of t-RA response in U937 cells; (ii) the effect of PLZF/RARalpha on t-RA-signaling is regulated by the POZ-domain and its down-stream regions of PLZF#; (iii) there are additional binding sites for HD-NCR in PLZF# and (iv) PLZF# not only directly binds but also regulates the binding of PLZF/RARalpha to the HD-NCR.

CONCLUSIONS:

At least two different mechanisms responsible for the aberrant recruitment of HD-NCR complexes by PLZF# are regulating the different t-RA-sensitivity of the PLZF/RARalpha and PML/RARalpha positive APL blasts: one is related to the direct binding of the different members of the HD-NCR complex to PLZF#; the other is an enforcing effect of PLZF# on the affinity of the PLZF/RARalpha fusion protein to the HD-NCR complex.

• Authors: E Puccetti, B Sennewald, F Fosca-Ferrara, S Boehrer, A Bianchini, D Hoelzer, O G Ottmann, C Nervi, M Ruthardt
• Journal: The hematology journal : the official journal of the European Haematology Association (Hematol J) Vol. 2 Issue 6 Pg. 385-92 ( 2001) ISSN: 1466-4860 [Print] England
• PMID: 11920278 (Publication Type: Journal Article)

Chemical References

• DNA-Binding Proteins
• Kruppel-Like Transcription Factors
• Neoplasm Proteins
• Oncogene Proteins, Fusion
• PLZF-RARalpha fusion protein, human
• Promyelocytic Leukemia Zinc Finger Protein
• Repressor Proteins
• Transcription Factors
• ZBTB16 protein, human
• Tretinoin
• Histone Deacetylases

Topics

• Chromosomes, Human, Pair 11
• Chromosomes, Human, Pair 17
• DNA-Binding Proteins (genetics, physiology)
• Drug Resistance, Neoplasm
• Histone Deacetylases (metabolism)
• Humans
• Kruppel-Like Transcription Factors
• Leukemia, Promyelocytic, Acute (etiology, genetics)
• Mutation
• Neoplasm Proteins (genetics, metabolism, pharmacology)
• Oncogene Proteins, Fusion (genetics, metabolism, pharmacology)
• Promyelocytic Leukemia Zinc Finger Protein
• Protein Binding
• Repressor Proteins (metabolism, physiology)
• Signal Transduction (drug effects)
• Transcription Factors (genetics, physiology)
• Translocation, Genetic
• Tretinoin (pharmacology)
• U937 Cells
• Zinc Fingers (genetics)