c-Myc Regulates
Transcriptional Pause
Release
The Myc family of
transcription factors
are well-known
oncoproteins, and the c-Myc
oncogene is expressed in
both embryonic stem
cells and cancer cells.
It is also a key
regulator of cellular
proliferation. A new
study published in Cell
contributes important
insights to the
mechanisms of MYC
regulation. Rahl and
colleagues demonstrate
that MYC plays a key
role in regulating
transcriptional
elongation by RNA
polymerase II (Pol II).
RNA polymerase II is
detected in the
promoter-proximal region
of most genes, and the
recruitment of the Pol
II transcription
initiation apparatus to
promoters by specific
DNA-binding
transcription factors is
well recognized as a key
regulatory step in gene
expression. MYC
participates in positive
elongation factor b (P-TEFb)-dependent
release of paused Pol
II, as MYC can bind P-TEFb
and stimulate
transcriptional
elongation in cancer
cells.
Rahl and co-workers
found that MYC and its
heterodimer partner MAX
bind to P-TEFb in
embryonic stem (ES)
cells. To directly test
whether MYC regulates
pause release, they
treated ES cells with an
inhibitor of MYC–MAX
dimerization, 10058-F4.
This decreased the
expression of most MYC
target genes and reduced
the levels of the Pol II
form associated with
elongation, but the
levels of the form of
Pol II associated with
transcriptional
initiation were
unaffected. Moreover,
reduction of MYC
activity by 10058-F4 or
by short hairpin RNA
knockdown reduced the
levels of Pol II across
transcribed regions of
MYC target genes, but
had little effect on the
levels of
promoter-proximal Pol
II. The researchers
suggest that combined
targeting of MYC and P-TEFb
could be an effective
therapeutic strategy in
tumor cells that
overexpress MYC.
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