| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
Department of Biochemistry and Molecular Biology University of Texas Houston Medical School Houston, Texas 77030
Address all correspondence and requests for reprints to: Barbara M. Sanborn, Department of Biochemistry and Molecular Biology, University of Texas Houston Medical School, Houston, Texas 77030.
 |
Introduction |
|---|
 Top Introduction References |
|---|
),
and basic region Leu zipper (bZIP) domains responsible for dimerization
and interaction with DNA (Fig. 1
). The
complexity of transcriptional responses to cAMP signals in a given cell
is compounded by the expression of multiple isoforms, particularly of
CREM. These result from the use of alternate promoters and
transcription initiation sites, intron/exon junction splicing choices,
poly-A sites affecting message stability, and translation initiation
sites.
|
forms are determined, at least
in part, by changes in mRNA stability (1, 4). An important
alternative promoter (P2) contains multiple CREs (3). The
products of transcription from this promoter, inducible cAMP early
repressors (ICERs), are truncated molecules that retain the ability to
bind to the CRE but not to activate transcription. Because the
transcription of ICERs is enhanced by cAMP, the resulting proteins
provide a potent negative feedback loop for CREM action that has been
demonstrated to be important in a number of cell types
(1).
In an article in this issue by Daniel et al.
(11), evidence is presented for use in the testis of two
new promoters and two new exons containing translation initiation
codons within the CREM gene. Both of these promoter regions (P3 and P4)
and the respective exons 
1 and 2 were mapped on genomic DNA
between the exon containing a previously described translation start
codon (Exon B in Fig. 1
) and the exon containing most of the first
transactivation domain (Exon C). In reporter assays, both rat P3 and P4
promoters were found to be cAMP responsive. Thus CREM mRNA forms
potentially up-regulated by cAMP now include CREM 1 and CREM 2,
as well as the ICERs.
The data are consistent with significant expression of CREM 1 and
CREM 2 mRNA in testis and in few or no other places. In testis, CREM
gene transcripts undergo cell-specific, stage-dependent alternative
splicing in the germ cells (1, 2, 12), and crem
null mice exhibit an arrest in spermiogenesis (13, 14).
Available data are consistent with the expression of limited amounts of
truncated repressor forms of CREM mRNA generated from the P1 promoter
in early germ cells and large amounts of the activator forms of CREM
(CREMs) in haploid germ cells (2). The coactivator
protein ACT, which facilitates CREM action without the requirement
for phosphorylation, is expressed concomitantly with CREM
(15). ICERs, generated from the cAMP-regulated P2
promoter, are not present in significant amounts in germ cells. The
article by Daniel et al. provides evidence for differential
expression of CREM 1 and CREM 2 mRNAs as a function of the stage
of the seminiferous tubule cycle and during the first wave of
spermatogenesis in testicular maturation. These data, while consistent
with expression of CREM 2 and CREM 1 mRNA primarily in premeiotic
and postmeiotic germ cells, respectively, await more direct
confirmation.
These studies expand the possibilities for regulation of CREM
expression and raise some interesting questions. If both P3 and P4
promoters are cAMP-responsive, what accounts for the apparent
differential expression of the two respective products? Daniel et
al. suggest that the P3 promoter (CREM 1) is more sensitive to
cAMP regulation than the P4 promoter (CREM 2). Expression of CREM
1 mRNA in postmeiotic germ cells would be consistent with the
potential for regulation of P3 by CREM, which is highest in these
cells. Other elements may be more important for P4. Clearly, there is
much more to be learned about the regulation of the P3 and P4 CREM
promoters.
Assuming that CREM 1 and CREM 2 proteins are expressed in
significant amounts, what could be their functions? Exons 1 and 2
both contain translation initiation codons. Full-length complementary
DNAs that use these ATGs and contain transactivation and bZIP
domains were prepared from testis mRNA. The resulting proteins
presumably would activate CRE-directed transcription. Furthermore,
inclusion of exon 1 introduces additional potential phosphorylation
sites that may impart unique regulation. It is also possible that
structural changes related to the inclusion of either exon or the
absence of the N-terminal region present in CREM forms derived from the
use of the P1 promoter may alter interactions with other proteins in
the transcriptional initiation complex. Potentially, CREM 1 and CREM
2 proteins could compete as homodimers or hetereodimers with other
CRE binding proteins in a given cell type. In this case, responses
would reflect the relative concentrations of the various activator and
inhibitor isoforms and the properties of the dimers formed (8, 16).
The molecular mechanisms regulating alternative choices of CREM
promoters and splicing sites and the basis for cell-specific expression
of specific CREM isoforms remain poorly understood. The unique features
of CREM 1 and CREM 2 may relate to their potential up-regulation
by cAMP or to some special regulatory element or interaction imparted
by their structure. In the end, the importance of CREM 1 and CREM
2 will be determined by the degree of expression of the respective
proteins in specific cells, relative to the expression of other CREM
forms and other regulators of CRE-regulated transcription. The
observations of Daniel et al. add an additional dimension to
this important area of investigation and reemphasize the importance of
cellular context in understanding the influences of CREM on gene
function.
Received August 24, 2000.
|
References |
|---|
|
TopIntroductionReferences |
|---|
isoforms expressed by two newly identified cAMP-responsive promoters
active in the testis. Endocrinology 141:3923–3930
heterodimers depends on CREM
phosphorylation. J Biol Chem 269:28839–28843This article has been cited by other articles:
 |
|
 |
|
  A. J. Tyson-Capper, J. Bailey, A. R. Krainer, S. C. Robson, and G. N. Europe-Finner The Switch in Alternative Splicing of Cyclic AMP-response Element Modulator Protein CREM{tau}2{alpha} (Activator) to CREM{alpha} (Repressor) in Human Myometrial Cells Is Mediated by SRp40 J. Biol. Chem., October 14, 2005; 280(41): 34521 - 34529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Bailey, A. J Tyson-Capper, K. Gilmore, S. C Robson, and G N. Europe-Finner Identification of human myometrial target genes of the cAMP pathway: the role of cAMP-response element binding (CREB) and modulator (CREM{alpha} and CREM{tau}2{alpha}) proteins J. Mol. Endocrinol., February 1, 2005; 34(1): 1 - 17. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Gellersen, R. Kempf, R. Sandhowe, G. F. Weinbauer, and R. Behr Novel leader exons of the cyclic adenosine 3',5'-monophosphate response element modulator (CREM) gene, transcribed from promoters P3 and P4, are highly testis-specific in primates Mol. Hum. Reprod., November 1, 2002; 8(11): 965 - 976. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
