ABSTRACT
The
transcriptional repressor PLZF was identified by its translocation with
retinoic acid receptor alpha in t(11;17) acute promyelocytic leukemia
(APL). Ectopic expression of PLZF leads to cell cycle arrest and growth
suppression, while disruption of normal PLZF function is implicated in
the development of APL. To clarify the function of PLZF in cell growth
and survival, we used an inducible PLZF cell line in a microarray
analysis to identify the target genes repressed by PLZF. One prominent
gene identified was c-myc. The array analysis demonstrated
that repression of c-myc by PLZF led to a reduction in
c-myc-activated transcripts and an increase in
c-myc-repressed transcripts. Regulation of c-myc
by PLZF was shown to be both direct and reversible. An interaction
between PLZF and the c-myc promoter could be detected both in
vitro and in vivo. PLZF repressed the wild-type c-myc promoter
in a reporter assay, dependent on the integrity of the binding site
identified in vitro. PLZF binding in vivo was coincident with a
decrease in RNA polymerase occupation of the c-myc promoter,
indicating that repression occurred via a reduction in the initiation
of transcription. Finally, expression of c-myc reversed the
cell cycle arrest induced by PLZF. These data suggest that PLZF
expression maintains a cell in a quiescent state by repressing
c-myc expression and preventing cell cycle progression. Loss
of this repression through the translocation that occurs in t(11;17)
would have serious consequences for cell growth
control.
Correlating In Vitro Splice Switching Activity With Systemic In Vivo Delivery Using Novel ZEN-modified Oligonucleotides