Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
8
|
| pubmed:dateCreated |
1998-5-12
|
| pubmed:abstractText |
Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARalpha fusion protein and responsiveness to treatment with all-trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARalpha fusion protein. Both PML- and PLZF-RARalpha possess identical RAR sequences and inhibit ATRA-induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARalpha protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARalpha, it had a very little effect on its association with the PLZF-RARalpha fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARalpha was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARalpha fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARalpha on ATRA response. Taken together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARalpha-associated leukemias to ATRA.
|
| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
AIM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Kruppel-Like Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/NCOR1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Receptor Co-Repressor 1,
http://linkedlifedata.com/resource/pubmed/chemical/Oncogene Proteins, Fusion,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Tretinoin,
http://linkedlifedata.com/resource/pubmed/chemical/ZBTB16 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/promyelocytic leukemia-retinoic...
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Apr
|
| pubmed:issn |
0006-4971
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
15
|
| pubmed:volume |
91
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
2634-42
|
| pubmed:dateRevised |
2009-11-19
|
| pubmed:meshHeading |
pubmed-meshheading:9531570-Chromosomes, Human, Pair 15,
pubmed-meshheading:9531570-Chromosomes, Human, Pair 17,
pubmed-meshheading:9531570-DNA-Binding Proteins,
pubmed-meshheading:9531570-Drug Resistance, Neoplasm,
pubmed-meshheading:9531570-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:9531570-Humans,
pubmed-meshheading:9531570-Kruppel-Like Transcription Factors,
pubmed-meshheading:9531570-Leukemia, Promyelocytic, Acute,
pubmed-meshheading:9531570-Neoplasm Proteins,
pubmed-meshheading:9531570-Nuclear Proteins,
pubmed-meshheading:9531570-Nuclear Receptor Co-Repressor 1,
pubmed-meshheading:9531570-Oncogene Proteins, Fusion,
pubmed-meshheading:9531570-Protein Binding,
pubmed-meshheading:9531570-Repressor Proteins,
pubmed-meshheading:9531570-Transcription Factors,
pubmed-meshheading:9531570-Translocation, Genetic,
pubmed-meshheading:9531570-Tretinoin,
pubmed-meshheading:9531570-Tumor Cells, Cultured,
pubmed-meshheading:9531570-Zinc Fingers
|
| pubmed:year |
1998
|
| pubmed:articleTitle |
Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia.
|
| pubmed:affiliation |
Leukaemia Research Fund Centre at the Institute of Cancer Research, Chester Beatty Laboratories, London, UK.
|
| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
|