Biomedical Engineering Reference
In-Depth Information
Figure 10.1
Molecular pathogenesis of APL and mechanisms of action of
ATRA and arsenic trioxide. Top panel: PML/RAR
α
binds to
DNA as a homodimer or as a heterotetradimer with RXR to
canonical or atypical RARE or indirectly via protein-protein
interaction with other transcription factors, e.g. PU.1, recruits
repressive chromatin-modifiers and blocks transcription of
RA-target genes and other sequences. Middle panel: ATRA
causes conformational change of the PML/RAR
α
molecule
allowing for the recruitment of HATs that mediate acetylation
of histones and open the chromatin structure leading to de-
repression of blocked transcription. In addition, the presence
of ATRA causes the degradation of PML/RAR
α
via cleavage
and proteasomal destruction detaching PML/RAR
α
from
the atypical RAREs. Bottom panel: Arsenic binds to the PML
portion of PML/RAR
α
and causes its SUMOylation followed
by poly-ubiquitination and proteasomal destruction. Some
transcriptional re-activation is present.
