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Reduced retinoic ac...
Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia
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- Guidez, F (författare)
- Chester Beatty Laboratories, London, UK
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- Ivins, S (författare)
- Chester Beatty Laboratories, London, UK
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- Zhu, J (författare)
- Chester Beatty Laboratories, London, UK
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- Söderström, Mats (författare)
- Linköpings universitet,Cellbiologi,Hälsouniversitetet
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- Waxman, S (författare)
- Mount Sinai School of Medicine, New York, USA
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- Zelent, A (författare)
- Chester Beatty Laboratories, London, UK
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(creator_code:org_t)
- American Society of Hematology, 1998
- 1998
- Engelska.
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 91:8, s. 2634-2642
- Relaterad länk:
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http://bloodjournal....
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- 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.
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- art (ämneskategori)
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