Here's more HDAC1 on APL:
Fusion proteins of the retinoic acid receptor-alpha recruit histone
deacetylase in promyelocytic leukaemia
The transforming proteins of acute promyelocytic leukaemias (APL) are
fusions of the promyelocytic leukaemia (PML) and the promyelocytic
leukaemia zinc-finger (PLZF) proteins with retinoic acid receptor-alpha
(RAR-alpha). These proteins retain the RAR-alpha DNA- and retinoic acid
(RA)-binding domains, and their ability to block haematopoietic
differentiation depends on the RAR-alpha DNA-binding domain. Thus
RA-target genes are downstream effectors. However, treatment with RA
induces differentiation of leukaemic blast cells and disease remission in
PML-RAR-alpha APLs, whereas PLZF-RAR-alpha APLs are resistant to
RA. Transcriptional regulation by RARs involves modifications of chromatin
by histone deacetylases, which are recruited to RA-target genes by nuclear
co-repressors. Here the authors show that both PML- RAR-alpha and
PLZF-RAR-alpha fusion proteins recruit the nuclear co-repressor (N-CoR)
- histone deacetylase complex through the RAR-alpha CoR box.
PLZF-RAR-alpha contains a second, RA-resistant binding site in the PLZF
amino-terminal region. High doses of RA release histone deacetylase activity
from PML-RAR-alpha, but not from PLZF- RAR-alpha. Mutation of the
N-CoR binding site abolishes the ability of PML-RAR-alpha to block
differentiation, whereas inhibition of histone deacetylase activity switches the
transcriptional and biological effects of PLZF-RAR-alpha from being an
inhibitor to an activator of the RA signalling pathway. Therefore, recruitment
of histone deacetylase is crucial to the transforming potential of APL fusion
proteins, and the different effects of RA on the stability of the
PML-RAR-alpha and PLZF-RAR- alpha co-repressor complexes
determines the differential response of APLs to RA.
F Grignani, S De Matteis, C Nervi, L Tomassoni, V Gelmetti, M Cioce,
M Fanelli, M Ruthardt, F F Ferrara, I Zamir, C Seiser, F Grignani,
M A Lazar, S Minucci & P G Pelicci
Fusion proteins of the retinoic acid receptor-alpha recruit histone
deacetylase in promyelocytic leukaemia (Letter to Nature)
Nature 391, 815 (1998) |
