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Original Studies |
Gene
Endocrine Unit (A.P., B.C., P.L., F.C., L.B., M.S.) and Medical Genetics Unit (S.B.-P.), Department of Clinical Physiopathology, University of Florence, 50139 Florence, Italy; and Institute of Endocrine Sciences, Ospedale Maggiore, University of Milan (S.C., E.B., A.S.), 20122 Milan, Italy
Address all correspondence and requests for reprints to: Alessandro Peri, M.D., Ph.D., Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy. E-mail: a.peri{at}dfc.unifi.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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gene, which convert this gene into an
oncogene termed gsp, occur. Gs
mutations have been related to pituitary tumorigenesis. We focused on 2
nuclear transcription factors that are final targets of the
cAMP-dependent pathway and are positively regulated by cAMP signaling,
i.e. the cAMP-responsive element binding protein (CREB)
and the inducible cAMP early repressor (ICER), that derives from
alternative splicing of cAMP-responsive element modulator gene. We
examined 21 GH-secreting adenomas, 8 with
(gsp+) and 13 without
(gsp-) a mutated
Gs. Analysis of CREB and ICER I/II messenger RNA
revealed that the levels of both transcripts were higher in
gsp+ than in
gsp- tumors
(CREB/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mean optical
density ± SE, 2.34 ± 0.36 in
gsp+ vs. 0.99 ± 0.22 in
gsp-, P = 0.003;
ICER I/GAPDH, 0.53 ± 0.15 in gsp+
vs. 0.14 ± 0.07 in
gsp-, P = 0.01;
ICER II/GAPDH, 1.5 ± 0.21 in gsp+
vs. 0.83 ± 0.13 in
gsp-, P = 0.01),
although a few cases in both groups did not display this pattern of
expression. Moreover, no positive correlation between the levels of
CREB and ICER transcripts was observed, suggesting the possible
presence of alterations in the mechanisms by which cAMP signaling
directs the expression of CREB and/or ICER genes. Our results indicate
a complex pattern of expression of nuclear transcription factors that
mediate cAMP action in both gsp+ and
gsp- tumors, suggesting that, beside
Gs gene mutations, different and partially unknown
molecular events may contribute to the pathogenesis of these tumors. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subunit of the Gs protein in a subset (30–40%) of GH-secreting
adenomas (2, 3, 4, 5, 6, 7). These mutations convert the
Gs gene into an oncogene, termed gsp (for Gs
protein) (3). In recent studies, the cellular phenotype
resulting from the expression of mutant Gs has been
investigated and the presence of counterregulatory mechanisms, such as
increased activity of phosphodiesterases (PDEs) and low levels
of mutated protein, has been identified (8, 9).
Most of the effects of cAMP are mediated by the activation of
cAMP-dependent protein kinase A (PKA). PKA activates, upon
phosphorylation at specific serine sites, two members of the family of
transcription factors containing the basic domain leucine zipper
(bZIP), i.e. cAMP-responsive element modulator (CREM) and
cAMP-responsive element binding protein (CREB) (reviewed in Ref.
10). Phosphorylated CREB and CREM bind as dimers to
palindromic cAMP response element (CRE) sequences, thus modulating the
expression of cAMP-dependent genes. The peculiar aspect of CREB and
CREM genes resides in the fact that they can encode different isoforms
by mechanisms of alternative exon splicing, alternative promoter usage
and autoregulation of promoters (11, 12). Some of CREB and
CREM isoforms stimulate gene expression, whereas others act as
repressors (11, 12). The promoter of CREB gene is
autoregulated by cAMP signaling (13), whereas the promoter
of CREM gene is not. Instead, an alternative internal promoter of CREM
gene directs the expression of repressor isoforms indicated as
inducible cAMP early repressors (ICER) in response to cAMP signaling
(14). Four ICERs isoforms, i.e. ICER I, I
,
II, and II have been described (14). Several targets of
CREB are related to mitogenesis, including the early immediate genes
c-fos, c-jun, and jun B,
(15) and cyclin D1 (16). Interestingly,
overexpression of a transcriptionally inactive CREB transgene in
pituitary somatotrophs led to dwarfism in transgenic mice
(17). In a series of 15 human GH-secreting tumors elevated
levels of phosphorylated, hence activated, CREB have been consistently
detected, independently of the presence or not of Gs gene
mutations (18). This observation prompted us to further
investigate on the final targets of the intracellular signaling
pathways, in particular by focusing on the expression of both CREB and
ICER in GH-secreting adenomas either with or without Gs
mutations.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Twenty-one patients (11 males and 10 females) affected by acromegaly and undergoing transphenoidal surgery were included in the study, after obtaining informed consent. The age ranged from 18–69 yr (41.6 ± 3.5, mean ± SE), GH levels were between 3.8 and 65.3 µg/L (28.2 ± 4.5, mean ± SE; normal value <3 µg/L), insulin-like growth factor I (IGF-I) levels ranged from 55.4–227.2 nmol/L (130.97 ± 12.7, mean ± SE), and the size of the tumors (maximum diameter) ranged from 12–43 mm (23 ± 2.1, mean ± SE). In 13 cases the tumors extended beyond the sella turcica. At the time of surgery, a sample from the adenoma was obtained for each patient, frozen, and stored at -80 C.
Analysis of Gs gene mutations
DNA was extracted from tissue homogenate at the same time of RNA
extraction, by using a commercial kit (Tri-Reagent; Molecular Research Center, Inc., Cincinnati, OH). Analysis of mutations in
the Gs gene was performed as described previously
(8). Briefly, 100 ng DNA were amplified in a 50-µL
reaction mixture containing 2 U Taq polymerase
(Perkin-Elmer Corp./Cetus, Norwalk, CT), 0.5
µM of each primer, 0.2 mM
2-deoxy-nucleoside-5'-triphosphate, 10 mM
Tris-HCl (pH 8.3), 1.5 mM
MgCl2, 50 mM KCl, and
0.001% (wt/vol) gelatin. The following amplification program was used:
1 min at 94 C, 1 min at 56 C (for codon 201 of the Gs
gene) or at 54 C (for codon 227 of the Gs gene), and 1
min at 72 C. The oligonucleotides used as primers for the amplification
of codon 201 were: 5'-CCAAACTACTCCAGACCTTT-3' and
5'-TGGAAGTTGACTTTGTCCAC-3'. For the amplification of codon 227 the
following oligonucleotides were used: 5'-ACAGAGATCATGGTTTCTTG-3' and
5'-TTAACCAAAGAGAGCAAAGC-3'. Amplified fragments were purified and
directly sequenced using the AmpliCycle Sequencing Kit
(Perkin-Elmer Corp., Branchburg, NY).
RT-PCR
RT-PCR was performed on total RNAs (0.5 µg for each reaction)
extracted from tissue homogenates by acid guanidine
thyocianate-phenol-chloroform extraction using a commercial kit
(Tri-Reagent; Molecular Research Center, Inc.). A
commercially available kit (SuperScript One Step RT-PCR System;
Stratagene, La Jolla, CA) was used to prepare the mixture
for RT-PCR. For the detection of CREB transcripts, a pair of specific
primers spanning sequences at the 5' and 3' end of CREB messenger RNA
(mRNA) and previously described (19) were used. The
sequence of the sense primer (CREB-L) was 5'-ATGACCATGGAATCTGGAGC-3'.
The sequence of the antisense primer (CREB-R) was
5'-TTAATCTGATTTGTGGCAGT-3'. For the analysis of ICER transcripts, a
pair of primers was designed by using the computer program OLIGO 4.0.
The sequence of the sense primer (ICER-L), which spanned sequences of
the internal promoter and exon of CREM gene, was
5'-CTGATGAGGAAACTGAACTTG-3'. The sequence of the antisense primer
(ICER-R), spanning sequences of exon Ib of CREM gene, was 5'-
TCGGCTCTCCAGACATTTTAC-3'. The primers were synthesized by
Roche Diagnostics (Monza, Italy). RT-PCR was performed by
using the Programmable Thermal Controller PTC-100 (MJ Research, Inc., Watertown, MA). Retrotranscription was performed at 50 C
for 30 min. For complementary DNA (cDNA) amplification the
following conditions were established: 1 min at 94 C (denaturation); 1
min at 60 C (for CREB) or at 56 C (for ICER) (annealing); and 1
min at 70 C (extension). Preliminary experiments were performed to
determine the PCR cycles corresponding to the exponential phase of
amplification. Thereafter, the PCR were always stopped in the
exponential phase. The quality of RNAs was assessed by performing
additional RT-PCR using primers specific for the
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene, as described
previously (20). Finally, in each RT-PCR experiment a no
RNA reaction was added as a negative control.
Detection of RT-PCR products
The detection of RT-PCR products was performed as described previously (21). Briefly, cDNAs were subjected to agarose gel electrophoresis and subsequent Southern blot on nylon membranes (Roche Diagnostics). Immobilized cDNAs were hybridized to CREB- and ICER-specific oligonucleotide probes, synthesized by Roche Diagnostics. The sequence of the probes was completely different from the sequence of the primers. The sequences of CREB probe, ICER probe, and GAPDH probe were, respectively, 5'-GTACAGGGCCTGCAAACATTA-3', 5'-GGAGTGGTGATGGCTGCATCG-3', and 5'-CTAAGCAGTTGGTGGTGCA-3'. The hybridization temperatures were, respectively, 57, 63, and 57 C. The hybridized cDNAs were detected by using an immunochemiluminescent method (Roche Diagnostics), as described previously (21).
The levels of CREB, ICER I, and ICER II mRNA were evaluated by calculating the ratio between the optical densities of the signals representing CREB or ICER I/II RT-PCR products on x-ray films and those corresponding to GAPDH, as described for comparative PCR (9, 22, 23). To compare the results qualitatively, the time of exposure to x-ray films was kept constant.
Sequence analysis of ICER I and II isoforms
RT-PCR for the determination of ICER transcripts originated
signals of different length. The specificity of the putative signals
corresponding to ICER I and II isoforms was validated by additional
sequence analysis. After gel electrophoresis, the ICER I (657 bp) and
ICER II putative signals (257 bp) were excised from the agarose and
purified by means of a commercially available kit (Agarose Gel DNA
Extraction Kit; Roche Diagnostics). Sequence analysis was
performed by using the AmpliCycle Sequencing Kit (Perkin-Elmer Corp.), according to the manufacturer’s instructions. For ICER
II sequencing, ICER-L and ICER-R primers were radiolabeled with
[-32P]ATP. For ICER I sequencing, 2
additional [-32P]ATP-radiolabeled primers
were used. The sequence of these primers that was internal to the
sequence spanned by ICER-L and ICER-R was: ICERSEQ-R (used together
with ICER-L), 5'-GATCTTTGAGGGCCTTGAGTT-3'; and ICERSEQ-L (used together
with ICER-R), 5'-GAACTCAAGGCCCTCAAAGAT-3'. The Programmable Thermal
Controller PTC-100 (MJ Research, Inc.) was used for direct
sequencing, using the following conditions, after an initial
2-min denaturation step at 95 C: 30 sec at 95 C (denaturation)
and 30 sec at 70 C (annealing and extension), for a total of 30 cycles.
Amplified products were electrophoresed on acrilamide gel (6%) in the
presence of 7 M urea. The gels were then blotted on
Whatman 3-M filters (Whatman
International Ltd., Maidstone, UK). After drying, the filters were
transferred to an x-ray cassette and exposed to x-ray films for 12
h.
Statistical analysis
Linear regression analysis was performed to search a correlation between the levels of CREB and ICER I or II expression. GH and IGF-I levels, the size of the tumors, CREB and ICER I/II expression in gsp+ and gsp- tumors were compared by Student’s t test. Differences were considered as statistically significant at the 0.05 level.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene mutations
GH-secreting adenomas were submitted to mutation analysis for
Gs gene (n = 21). Eight tumors (38.1%) harbored
point mutations of Gs gene. In all cases the mutation was
located at codon 201 (CGT > TGT/Arg > Cys, tumors 1, 3, 10,
11, and 17; CGT > CAT/Arg > His, tumors 2 and 19; CAG
> CTG/Gln > Leu, tumor 18). The numbers indicating the tumors
refer to the numeration used in Fig. 1
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These mutations are known to constitutively activate adenylyl cyclase.
No significant difference in serum GH levels (30.3 ± 8.4 µg/L
in gsp+ vs. 26.9 ±
5.5 µg/L in gsp-, mean ±
SE, P > 0.05) between patients
with or without Gs mutations was found. Similarly, IGF-I
levels did not significantly differ between
gsp+ and
gsp- adenomas (137.7 ± 21.1 nmol/L
in gsp+ vs. 124.4 ±
13.4 nmol/L in gsp-, mean ±
SE, P > 0.05). Conversely, in
our series of patients tumor size appeared statistically higher in
gsp- than in
gsp+ tumors (17.62 ± 2.2 mm in
gsp+ vs. 26.3 ± 2.8
mm in gsp-, mean ±
SE, P = 0.04).
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Because the amount of tumoral tissue was too limited to perform
Northern blot analysis or RNase protection assay, the presence of CREB
transcripts in GH-secreting adenomas was determined by RT-PCR, using
specific primers spanning sequences at the 5' and 3' end of CREB mRNA.
Each RNA was retro-transcribed and amplified in three different
experiments, to assess the reproducibility of the results. After
agarose gel electrophoresis, Southern blotting, and hybridization to a
CREB-specific probe, a major signal of 1026 bp, corresponding to the
full-length transcript of CREB gene and acting as an activator of gene
transcription, was consistently detected by chemiluminescence in the
tumors, with the exclusion of two
gsp- cases (6, 13). In Fig. 1A
the
results of a typical experiment are reported; the results were
virtually identical in all the experiments that were performed. In all
cases the quality of RNAs was assessed by the analysis of GAPDH
transcripts. A GAPDH-specific signal was found in all RNA samples (Fig. 1C), indicating that the failure to detect CREB signals in tumors 6 and
13 was not due to RNA degradation. The levels of expression of CREB
gene were determined by densitometric analysis as the CREB/GAPDH ratio,
as previously described for Gs expression
(9). By this analysis, the levels of CREB transcript were
significantly higher in tumors with a mutated Gs than in
those with wild-type Gs (CREB/GAPDH ratio, 2.34 ±
0.36 in gsp+ vs. 0.99
± 0.22 in gsp-, mean optical
density ± SE, P = 0.003).
The exclusion of the tumors in which CREB mRNA was not detectable did
not result in loss of statistically significant difference among
gsp+ and
gsp- tumors (P = 0.01).
However, individual variations in each of the two groups were observed,
as shown in Fig. 2. Among tumors showing
the highest levels of expression of CREB gene there were for instance
two gsp- tumors (4, 21). Conversely,
in a gsp+ tumor (tumor 19) one of the
lowest levels of CREB mRNA was detected (Fig. 2).
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The expression of ICER was also assessed by RT-PCR, using specific
primers, in three different experiments for each RNA sample. The RT-PCR
products were hybridized to a specific probe and detected by
chemiluminescence. A predominant signal of 257 bp (Fig. 1B),
corresponding to the isoform ICER II, as determined by sequence
analysis (Fig. 3), was detected in
all cases except for three gsp- tumors
(7, 8, 9). As already mentioned, a signal corresponding to GAPDH
transcript was detected in all samples (Fig. 1C). We analyzed the
levels of ICER II transcript, which resulted to be significantly higher
in gsp+ than in
gsp- tumors (ICER II/GAPDH ratio,
1.5 ± 0.21 in gsp+
vs. 0.83 ± 0.13 in gsp-,
mean optical density ± SE,
P = 0.01; the difference remained significant even
after exclusion of the tumors not showing detectable levels of ICER II
mRNA, P = 0.04), despite the tumor-to-tumor variations
(Fig. 4). In particular, among tumors in
which ICER II mRNA could be detected, the lowest level was consistently
found in a gsp+ adenoma (1; Fig. 4).
An additional RT-PCR product (657 bp), present in the majority of cases
(Fig. 1B), was subjected to sequence analysis and was found to
correspond to the isoform ICER I (Fig. 3). According to ICER II, the
levels of ICER I mRNA, despite sporadic individual variations
(i.e. no detectable signal in a
gsp+ tumor, patient 18, Fig. 1B), were
also significantly higher in gsp+ than
in gsp- adenomas (ICER I/GAPDH ratio,
0.53 ± 0.15 in gsp+
vs. 0.14 ± 0.07 in gsp-,
mean optical density ± SE,
P = 0.01) (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene (2, 3, 4, 5, 6, 7), in the last few years
mutation analyses of other key components of the cAMP-dependent pathway
have been carried out in GH-secreting pituitary adenomas, generally
with negative results. Indeed, no mutations in GHRH receptor and PKA
catalytic subunit genes have been reported so far (24, 25); the pathogenesis of GH-secreting adenomas harboring a
wild-type Gs remains elusive. Moreover, in
gsp+ tumors multiple processes
probably contribute to determine the oncogenic potential of
Gs mutations, as cellular mechanisms able to contrast the
consequence of the constitutive activation of the cAMP-dependent
pathway have been identified (8, 9).
In the present study, we examined by RT-PCR the expression of two
members of the cAMP-dependent nuclear transcription factors family,
i.e. CREB and ICER, in 21 GH-secreting adenomas
harboring either a wild-type or a mutated Gs gene. mRNA
measurements were performed by comparing the optical density of the
specific CREB and ICER (i.e. the isoforms I and II) signals
with that corresponding to the GAPDH signal obtained from the same RNA.
In principle, RT-PCR does not provide a direct measurement of specific
transcripts (requiring both retrotranscription of RNA and subsequent
amplification of the obtained cDNA), and it is dependent on the
appropriate setting of the experimental conditions, such as the
temperature of annealing of the primers and the cycle number. However,
especially when the starting material is not sufficient to perform
direct measurements of RNA by Northern blot analysis or by RNase
protection assay, as in our case, semiquantitative RT-PCR is largely
used to determine the levels of a specific transcript, provided that it
is performed correctly (9, 22, 23). Quantitative RT-PCR
applications, such as competitive PCR, are not possible in the case of
CREB and ICER, as well as in the case of genes with similar
characteristics, as the coexistence of various isoforms represents a
major problem for constructing specific competitors. Indeed, the
structure of both CREB and ICER gene makes virtually impossible to
design specific primers for only one isoform. It is noteworthy that, to
our knowledge, there have been no reports on competitive PCR for CREB
and/or ICER mRNA measurements so far. In our hands, semiquantitative
RT-PCR was validated by adding the same amount of RNA to each reaction,
by stopping the amplification in the exponential phase and by using the
same time of exposure of the films. Furthermore, the reproducibility of
the results was confirmed in different experiments.
The analysis of CREB and ICER I/II expression revealed in most cases
the presence of specific transcripts in GH-secreting adenomas. We found
that in gsp+ tumors the levels of
either CREB or ICER I/II mRNA were significantly higher than in
gsp- tumors. This finding confirms that
the presence of a mutated Gs appears to be associated to
the activation of the cAMP-dependent pathway. In particular, it is
likely that increased PKA-mediated phosphorylation of CREB represents
the key regulator in directing high levels of expression of CREB itself
and ICER. In fact, both the promoter of CREB and the internal promoter
of CREM that regulates ICER expression contain CREs (13, 14), through which activated, i.e. phosphorylated,
CREB stimulates mRNA transcription and protein synthesis
(26). Therefore, CREB and ICER mRNA levels may indirectly
provide information about the amount of phosphorylated
CREB.
An interesting aspect of our study is represented by the fact that,
although CREB and ICER transcripts were found to be higher in
gsp+ tumors, nonetheless variable
levels of expression were detected in a few tumors, irrespective of the
Gs status. In particular, in a minority of cases, despite
a mutated Gs, low levels of CREB or ICER mRNA were found,
suggesting the presence of mechanisms able to counteract the increase
in cAMP production induced by Gs mutations, such as PDE
overactivity or other counterregulatory mechanisms (8, 9).
Admittedly, in these tumors the oncogenic pathway activated by
Gs mutations remains to be clarified.
In a few more cases, high levels of CREB mRNA were found in tumors not
harboring gain-of-function mutations of the Gs gene. In
these tumors high CREB expression might be targeted as the primary
alteration leading to cell proliferation. Although the presence of
activating mutations of CREB gene in pituitary adenomas has not been
reported so far, this could be a possibility to be investigated.
Alternatively, the high levels of CREB expression occurring in some
gsp- adenomas might be regarded as
secondary to increased phosphorylation of CREB, resulting for instance
from reduced PDE activity or to augmented kinase(s) activity. Although
gain-of-function mutations of PKA have not been so far identified
(25), CREB can be the substrate of other non
cAMP-dependent protein kinases, such as protein kinase C, casein kinase
II, mitogen-activated protein kinase and
Ca2+/calmodulin-dependent kinase IV (reviewed in
Ref. 10). Because CREB should be considered as a point to
which different pathways converge and from which signals ultimately
modulating gene expression depart, it is tempting to speculate that,
besides the cAMP-dependent cascade, other signaling pathways may be
activated in gsp- tumors with high CREB
expression.
Our data, showing that CREB/ICER levels in
gsp+ tumors are higher than in
gsp- tumors, are partially at variance
with those by Bertherat et al. (18). Even
taking into account the variability we observed in some cases, the
results of these authors differ from ours, in that they consistently
found elevated levels of Ser133-phosphorylated
CREB in a series of GH-secreting adenomas, independently of the
presence or not of Gs gene mutations (18).
However, although CREB phosphorylation usually occurs at
Ser133 and causes activation of the protein, the
additional phosphorylation at Ser142 determines
loss of transcriptional activation (27, 28). Therefore,
data reporting high levels of phosphorylated CREB in
gsp- tumors (18) should be
reconsidered taking into account that
Ser133-phosphorylated CREB does not unequivocally
represent activated CREB.
Because activated CREB binds to consensus CREs in the promoter of CREB and the internal promoter of CREM that regulates ICER expression, activation of the cAMP-dependent pathway is expected in principle to cause a parallel increase of both these transcription factors. Activation of the cAMP-dependent signaling pathway, resulting in increased levels of phosphorylated CREB, has been shown to cause also increased ICER expression in different cell systems such as thyroid (29), Sertoli (30), and ovarian granulosa cells (31, 32). Accordingly, in thyroid hyperfunctioning adenomas, we have observed a positive correlation between CREB and ICER mRNA levels (Peri, A., unpublished observations). Interestingly, this correlation did not occur in GH-secreting adenomas, implicating the existence of different and complex mechanisms regulating the expression of CREB and ICER. It is known for instance that ICER, which is properly a marker of early cAMP stimulation, can compete with the binding of CREB to CREs, thus inhibiting further expression of its own gene as well as of CREB gene (13, 14). Alternatively, the presence of alterations in the mechanisms by which cAMP directs the expression of CREB and/or ICER, ultimately contributing to determine the oncogenic potential of somatotrophs, might be hypothesized.
In conclusion, in the present study we have correlated for the first
time the levels of mRNA of the nuclear transcription factors CREB and
ICER to the presence or absence of a mutated Gs in
GH-secreting adenomas. Both the expression of CREB and ICER (I-II)
appeared significantly higher in gsp+
tumors. Moreover, the finding that in a few cases CREB and/or ICER
expression did not correlate to the Gs status, suggests
that the pathogenesis of these tumors may involve, in addition to the
cAMP-dependent pathway, other signaling cascades.
Received October 2, 2000.
Revised January 22, 2001.
Accepted January 26, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain
of Gs and stimulate adenylyl cyclase in human pituitary tumors. Nature. 340:692–696.[CrossRef][Medline]
is
associated with an increased phosphodiesterase activity in human growth
hormone-secreting adenomas. J Clin Endocrinol Metab. 83:1624–1628. gene are associated with low levels of Gs protein
in growth hormone-secreting tumors. J Clin Endocrinol Metab. 83:4386–4390.s: chronic
transcriptional activation of c-fos protooncogene in
endocrine cells. J Biol Chem. 36:22663–22671.
subunit gene expression. Mol Endocrinol. 12:785–800.This article has been cited by other articles:
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  D. Romano, K. Magalon, M. Pertuit, R. Rasolonjanahary, A. Barlier, A. Enjalbert, and C. Gerard Conditional Overexpression of the Wild-Type Gs{alpha} as the gsp Oncogene Initiates Chronic Extracellularly Regulated Kinase 1/2 Activation and Hormone Hypersecretion in Pituitary Cell Lines Endocrinology, June 1, 2007; 148(6): 2973 - 2983. [Abstract] [Full Text] [PDF]
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 A. Lania, G. Mantovani, and A. Spada Genetics of Pituitary Tumors: Focus on G-Protein Mutations Experimental Biology and Medicine, October 1, 2003; 228(9): 1004 - 1017. [Abstract] [Full Text] [PDF]
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 J. R. Mead, T. R. Hughes, S. A. Irvine, N. N. Singh, and D. P. Ramji Interferon-gamma Stimulates the Expression of the Inducible cAMP Early Repressor in Macrophages through the Activation of Casein Kinase 2. A POTENTIALLY NOVEL PATHWAY FOR INTERFERON-gamma -MEDIATED INHIBITION OF GENE TRANSCRIPTION J. Biol. Chem., May 9, 2003; 278(20): 17741 - 17751. [Abstract] [Full Text] [PDF]
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 D. ROSENBERG, L. GROUSSIN, E. JULLIAN, K. PERLEMOINE, X. BERTAGNA, and J. BERTHERAT Role of the PKA-Regulated Transcription Factor CREB in Development and Tumorigenesis of Endocrine Tissues Ann. N.Y. Acad. Sci., June 1, 2002; 968(1): 65 - 74. [Abstract] [Full Text] [PDF]
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A. Peri, P. Luciani, B. Conforti, S. Baglioni-Peri, F. Cioppi, C. Crescioli, P. Ferruzzi, S. Gelmini, G. Arnaldi, G. Nesi, et al. Variable Expression of the Transcription Factors cAMP Response Element-Binding Protein and Inducible cAMP Early Repressor in the Normal Adrenal Cortex and in Adrenocortical Adenomas and Carcinomas J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5443 - 5449. [Abstract] [Full Text] [PDF]
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