Journal
MOLECULAR CELL
Volume 5, Issue 5, Pages 821-830Publisher
CELL PRESS
DOI: 10.1016/S1097-2765(00)80322-6
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Funding
- NCI NIH HHS [CA54418] Funding Source: Medline
- NICHD NIH HHS [HD27183] Funding Source: Medline
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The t(15;17) chromosomal translocation in acute promyelocytic leukemia (APL) generates the PML-RAR alpha fusion protein. The recruitment of nuclear receptor corepressor SMRT/N-CoR and subsequent repression of retinoid target genes is critical for the oncogenic function of PML-RAR alpha. Here we show that the ability of PML-RAR alpha to form homodimers is both necessary and sufficient for its increased binding efficiency to corepressor and inhibitory effects on hormonal responses in myeloid differentiation. We further provide evidence that altered stoichiometric interaction of SMRT with PML-RAR alpha homodimers may underlie these processes. Finally, we demonstrate that a RXR AF2 mutant recapitulates many biochemical and functional properties of PML-RAR alpha. Taken together, our results provide an example that altered dimerization of a transcription factor can be directly linked to cellular transformation and implicate dimerization interfaces of oncogenes as potential drug targets.
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