|Uncontrollable cell proliferation and suppressed apoptosis are
hallmarks of tumorigenic transformation [1-3]. Deregulation of genes
controlling cell proliferation and survival plays an important role in the
process. For instance, apoptotic genes are frequently down-regulated
while anti-apoptotic genes are highly expressed in a number of cancer
cell types; artificial down regulation of anti-apoptotic genes or up
regulation of apoptotic genes are often sufficient to eradicate those
cancer cells. The activating transcription factor 5 (ATF5 or ATFx) is
a member of the ATF/CREB transcription factor family. Although
ATF5 is known to regulate cell cycle progression [4-7], cell survival
[5-13], autophagy , cell fate determination [15-17] and cellular
stress response [13-19], and it is likely involved in the development
of schizophrenia [20-22] and chronic lymphocytic leukemia , only
a few of its targets have been reported and the mechanism of ATF5
function remains largely unknown and occasionally controversial. For
instance, previous reports have shown that ATF5 enhances cell survival
and proliferation of glioma, breast cancer cells and neuroprogenitor
cells [5-24] while eliciting a G2/M blockade in hepatocellular
carcinoma cells [4,6]. ATF5 acts as a pro-survival factor in HeLa and
hematopoietic FL5.12 cells  but may also increase cisplatin-induced
apoptosis through up-regulation of cyclin D3 in HeLa cells .
Transactivation of Mcl-1 by ATF5 was found to be essential for the
survival of GL261 glioma cells  but Bcl-2 was activated by ATF5 in
C6 glioma and MCF-7 breast cancer cells . ATF5 is essential for the
survival of HeLa , glioma [5-24], breast cancer cells [5-12], but seems
to be dispensable in HEK293, PC12, astrocytes, mouse embryonic
stem cells and breast epithelial cells [11-16]. ATF5 expression blocks
neuronal and glial differentiation of neuroprogenitor cells [15-17] while
promoting intestinal differentiation of the Caco-2 cells . These
findings highlight the cell type-dependent function of ATF5. ATF5 may
interact with several distinct DNA regulatory elements to modulate
the expression of genes whose promoters contain them. It suppresses
CREB-responsive element (CRE)-dependent gene transcription [6,15]
but activates amino acid responsive element (AARE)-dependent
gene transcription [18,27]. We found that ATF5 can also recognize
an ATF5-specific responsive element (ARE) and stimulate AREcontaining
promoters [5-28]. Significant downstream targets known to
be regulated by ATF5 include stress-related genes asparagine synthase
[29,30], CHOP , CYP2B6 , HSP27 ; apoptotic regulators
Mcl-1  and Bcl-2 ; and cell proliferation regulators Egr-1
 and ID1 . ATF5 expression is induced in response to various
forms of cellular stress including Endoplasmic Reticulum (ER) stress
[33,34], arsenite exposure [18,34], and amino acid limitation [18,27],
among others. ATF5 is known to subject to multilayered regulation
that includes transcriptional regulation by EBF1 , translational
regulation that is controlled by phosphorylated eIF2 [19,34], and posttranslational
regulation that involves phosphorylation , acetylation
, and ubiquitin-mediated [6-37] and caspase-mediated proteolysis
[6,13]. We found that ATF5 is an extremely unstable protein with
a half-life of about 1 h in HeLa, C6 and MCF-7 cells and that both
chaperone proteins HSP70 and NPM1 are involved in regulating ATF5
protein stability [6,13].
|Current research indicates that ATF5 plays important roles in
diverse biological processes including cell proliferation, cell survival,
cellular stress response, cell fate determination, and is involved in the
development of several human diseases such as cancer and neurological
disorders. Our understanding of the mechanism by which ATF5
functions is very limited and many questions remain unanswered.
There are a number of urgent questions need to be addressed. For
instance, what are the causes for the seemingly varied and sometimes
opposing effects exerted by ATF5 in different cell types? How is ATF5
involved in so many critical biological functions while at the same time
it displays remarkable cell type-dependent regulation? Are there more
vital downstream transcriptional targets of ATF5 that have yet to be
discovered? Only a few binding partners have been identified for ATF5,
are there others that hold the secrets of ATF5 function? Although we
had found that ATF5 acetylation of K29 affects ATF5 interaction
with p300 and the transcriptional activity of ATF5 , are there other
post-translational modifications on ATF5, such as phosphorylation
and glycosylation, that may regulate ATF5 function? Under what
conditions are these modifications critical? With the increasing pace of
the ATF5 research, we can anticipate significant progress in answering
these important questions in the next few years. These advances will
not only elevate our understanding of ATF5 mechanism to a new level
but also help uncover novel therapeutic targets for the treatment of the
various human diseases in which ATF5 plays a role.
|Work by the authors is supported by grants from the American Cancer Society
and from the U.S. Department of Defense.
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