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
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).