Transcriptional enhanced (32). This direct feedback mechanism represents a

Transcriptional regulation of Arf

 

Transcriptional
control is the most important mechanism of Arf
regulation since it has a relatively long half-life of 6 hrs (23; Arf reviewed
in refs. 1-3, 10, 13, 24).  A number of
transcription factors regulate Arf,
either positively or negatively (Fig. 1).  The E2F1 transcription factor induces Arf
transcription by directly binding to its consensus sequences (25, 26) and also
the Sp1 sites (27) which are located in the upstream of the exon 1?, thus
activating cell growth arrest or apoptosis to avoid the emergence of incipient
cancer cells (1, 2).  E2F2 and E2F3a also
transactivates the Arf promoter (26),
however, this process is modulated differently by the various E2F isoforms.  For instance, E2F3b, a splice isoform of E2F3a
that is not regulated by E2Fs, represses Arf
transcription and stimulates cellular growth (28, 29).  The observation that the loss of Arf can rescue E2F3b depletion-mediated
cell cycle arrest suggests anti-reciprocal correlation between these two proteins
(29).  To prevent hyperproliferation of
cells with oncogenic stress, c-Myc activates fail-safe programs such as apoptosis
and cellular senescence by inducing Arf
transcription (30).  Thus, Myc-induced Arf
activates the p53 signaling, preventing immortalization of the murine embryonic
fibroblasts (MEFs).  Bouchard et al.
reported that c-Myc signaling increases nuclear FoxO, which, in turn, binds to
the Arf promoter to suppresses c-Myc-driven
lymphomagenesis (31).

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Qi et al. showed that Arf inhibits
c-Myc through physical interaction that is
independent of p53 (32).  When c-Myc increases, Arf binds to
c-Myc to block c-its
ability to activate transcription, induce hyperproliferation, and
transformation.  In contrast, c-Myc’s ability to repress transcription is unaffected by
Arf, and c-Myc-mediated
cell death is rather enhanced (32).  This
direct feedback mechanism represents a p53-independent checkpoint to prevent c-Myc-mediated tumorigenesis.  The differential effects of Arf on c-Myc function indicate
that independent molecular mechanisms mediate c-Myc-induced
hyperproliferation and apoptosis.  The
same group later showed that Egr1 mediates p53-independent c-Myc-induced apoptosis via an Arf-dependent transcriptional
mechanism (33).  Therefore, c-Myc-Arf-binding
switches the inherent activity of c-Myc from a
proliferative to apoptotic protein without p53 through a unique, non-canonical
transcriptional mechanism.

 

A
cyclin D-binding Myb-like protein Dmp1 (also named Dmtf1) also transactivates
the Arf promoter 25).  Inoue et al. demonstrated that Dmp1 binds to
the Ets consensus (CCCGGATGC) of the mouse Arf
promoter and activates its transcription in murine embryonic fibroblasts (MEFs),
which results in Arf/p53-dependent cell cycle arrest (25, 34-49; Dmp1 reviewed
in 50-53).  DMP1? regulates the human ARF promoter, the activity of which is antagonized
its splice variant DMP1? (48, 49).  E2F1
collaborates the Dmp1 to transactivate the Arf
promoter to remove early stage neoplastic cells (25).  Similar mechanisms must be present in human ARF promoter (27) since both E2F and
DMP1-consensus sequences are found in the human version.

 

Arf
is actively involved in TGF? signaling. 
Zheng et al. reported that TGF? increases the Arf mRNA levels through Smad2/3 and p38MAPKs in MEFs (54).  Smad2/3 binds to the Arf promoter on stimulation by TGF?.  Chromatin
immunoprecipitation revealed that TGF? rapidly induces Smad2/3 binding and
histone H3 acetylation at the genomic DNA proximal to exon 1? of Arf, followed by increased RNA
polymerase II binding, increased Arf transcripts, and tumor suppression (54).  Then the same group showed that TGF?-mediated
induction of Arf correlated with
decreased DNA-binding of C/EBP? to the Arf promoter (55).  In short, their results indicate that C/EBP?
and SP1 are negative and positive Arf regulators that are affected by TGF?.

 

Both
human and mouse ARF promoters have multiple
binding sites for acute myeloid leukemia-1 (AML1), which activates its
transcription causing cellular senescence in MEFs.  Interestingly, the t(8;21) fusion protein
AML1-ETO, which is frequently expressed in acute leukemia with low ARF
expression (56).  Consistently, Shikami
et al. showed that the mRNA expression of p14ARF in t(8;21) AML cells
was found to be lower than those without t(8;21) translocation (57).  Since p14ARF
has been shown to inhibit p53 degradation by binding to MDM2 (1, 2), repression
of p14ARF expression in t(8;21) AML may
accelerate the degradation of p53 by MDM2 explaining why genotoxic damage
caused by ionizing radiation does not induce p53 response in t(8;21) AML cells.

 

Repressors
of Arf transcription have been
reported and reviewed (50; Fig. 2).  The
polycomb group gene Bmi1 suppresses cellular senescence through repression of Arf transcription (58).  Bmi1-deficient
MEFs shows decreased cell cycle progression and increased premature senescence,
which are rescued by Arf/Ink4a depletion
(59).  Bmi1 also requires the EZH2-containing
Polycomb-Repressive Complex 2 (PRC2) to repress ARF/INK4a transcription.  PRC2 maintains the levels of H3K27Me3 as well
as the Bmi1/PRC1 complex at the locus.  The
polycomb group gene, CBX7, increases
the lifespan of normal human cells and MEFs through suppression of Arf/Ink4a expression, independent of Bmi1
(60).  TBX2 immortalizes MEFs and
decreases senescence in normal human cells by repression of Arf transcription (61; Fig. 2).  The basic helix-loop-helix transcription
factor Twist1 activates the recruitment of EZH2 to the Arf transcription start site.  Thus, it increases the levels of H3K27Me3 on
the ARF/INK4a locus, followed by
repression of Arf transcription (62, 63).
 In general, the relative importance of
the Arf gene far exceeds that of p16Ink4a in repression of the
Arf/Ink4a locus in mice reflecting
the strong tumor-prone tendency of Arf-deficient
mice (7, 64) than p16Ink4a-deficient
mice (8, 9) leaving an open question in human cases since in vivo assays are not possible in the latter.

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