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. 2000 Jan;14(1):77-83.
doi: 10.1038/sj.leu.2401643.

The Impact of Differential Binding of Wild-Type RARalpha, PML-, PLZF- And NPM-RARalpha Fusion Proteins Towards Transcriptional Co-Activator, RIP-140, on Retinoic Acid Responses in Acute Promyelocytic Leukemia

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The Impact of Differential Binding of Wild-Type RARalpha, PML-, PLZF- And NPM-RARalpha Fusion Proteins Towards Transcriptional Co-Activator, RIP-140, on Retinoic Acid Responses in Acute Promyelocytic Leukemia

C W So et al. Leukemia. .
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Abstract

Retinoic acid receptor (RA) heterodimer (RAR/RXR) activities have been shown to be repressed by transcriptional co-repressor, SMRT/N-CoR, in the absence of the ligand while upon all-trans retionic acid (ATRA) treatment, SMRT/N-CoR is dissociated from RARalpha leading to gene expression by the recruitment of transcriptional co-activators to the transcriptional complex. The difference in response to ATRA therapy between acute promyelocytic leukemia (APL) patients with PML-RARalpha fusion and PLZF-RARalpha fusion has recently been found to be partially due to the strong association of the transcriptional co-repressor, SMRT/N-CoR, with PLZF domain. We demonstrate that SMRT association, as with PML-RARalpha, can be released from NPM-RARalpha at pharmacological concentration of ATRA (10-6 M). Moreover, we show for the first time that the interaction between the transcriptional co-activator, RIP-140, and PML-, PLZF- or NPM-RARalpha fusion proteins can be positively stimulated by ATRA although they are less sensitive as compared with the wild-type RARalpha. Our results suggest that the dissociation of transcriptional co-repressors, SMRT/N-CoR, and recruitment of co-activators, eg RIP-140, to APL-associated fusion proteins constitute a common molecular mechanism in APL and underlie the responsiveness of the disease to RA therapy. Leukemia (2000) 14, 77-83.

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