A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RAR alpha and T18 oncoproteins

Citation
S. Zhong et al., A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RAR alpha and T18 oncoproteins, NAT GENET, 23(3), 1999, pp. 287-295
Citations number
48
Categorie Soggetti
Molecular Biology & Genetics
Journal title
NATURE GENETICS
ISSN journal
10614036 → ACNP
Volume
23
Issue
3
Year of publication
1999
Pages
287 - 295
Database
ISI
SICI code
1061-4036(199911)23:3<287:ARTSTC>2.0.ZU;2-G
Abstract
PML and Tif1a are fused to RARA and Braf, respectively, resulting in the pr oduction of PML-RAR alpha and Tif1 alpha-B-Raf (T18) oncoproteins. Here we show that PML, Tif1 alpha and RXR alpha/RAR alpha function together in a tr anscription complex that is dependent on retinoic acid (RA). We found that PML acts as a ligand-dependent coactivator of RXR alpha/RAR alpha. PML inte racts with Tif1 alpha and CBP. In Pml(-/-) cells, the RA-dependent inductio n of genes such as RARB2 and the ability of Tif1 alpha and CBP to act as tr anscriptional coactivators on RA are impaired. We show that both PML and Ti f1 alpha are growth suppressors required for the growth-inhibitory activity of RA. T18, similar to PML-RAR alpha, disrupts the RA-dependent activity o f this complex in a dominant-negative manner resulting in a growth advantag e. Our data define a new pathway for the control of cell growth and tumorig enesis, and provide a new model for the pathogenesis of acute promyelocytic leukaemia (APL).