A possible general mechanism of the signal transfer switching on the Α//3-interferons expression. 2. The role of the cAMP in the process of the interferon induction
The author carries out an analysis of available data concerning the participation of cyclic adenosine 3',5'-monophosphate (cAMP) in the signal transduction pathway on the α/β-inierferons (IFN) expression during the induction process. The cAMP is known to participate in the activation of pr...
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| Cite this: | A possible general mechanism of the signal transfer switching on the Α//3-interferons expression. 2. The role of the cAMP in the process of the interferon induction / A.V. Karpov // Биополимеры и клетка. — 1999. — Т. 15, № 1. — С. 83-87. — Бібліогр.: 47 назв. — англ. |
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Karpov, A.V. 2019-06-17T16:50:05Z 2019-06-17T16:50:05Z 1999 A possible general mechanism of the signal transfer switching on the Α//3-interferons expression. 2. The role of the cAMP in the process of the interferon induction / A.V. Karpov // Биополимеры и клетка. — 1999. — Т. 15, № 1. — С. 83-87. — Бібліогр.: 47 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00050A https://nasplib.isofts.kiev.ua/handle/123456789/156005 578.245.577.113.7 The author carries out an analysis of available data concerning the participation of cyclic adenosine 3',5'-monophosphate (cAMP) in the signal transduction pathway on the α/β-inierferons (IFN) expression during the induction process. The cAMP is known to participate in the activation of protein kinasev during the interferon induction as well as of nuclear factors activating specifically the regulating domains, of IFN genes. The cAMP is thought to be a secondary key messenger mediating the signal, for α/β-lFN induction, the first stage of this induction being the local cell membrane deformation caused by diffirent inducers. Проаналізовано літературні дані стосовно участі циклічного аденозин-3' ,5'-монофосфату (cAMP) при передачі сигналу до експресії α/β-інтерферонів (ІФН) у процесі індукції. Описано участь сАМР в активації протеїнкіназ, які беруть участь в індукції, а також ядерних факторів, що специфічно активують регуляторні домени генів ІФН. Висунуто припущення, що сAMP виступає в ролі ключового вторинного месепджера, який опосередковує сигнал до індукції α/β-ІФН, початковим етапом якого є специфічна деформація клітинної мембрани під дією різних індукторів. Проанализированы литературные данные относительно участия циклического аденозин-3',5-монофосфата (сAMP) при передаче сигнала к экспрессии α/β-интерферонов (ИФН) в процессе индукции. Описано участие сАМР в активации протеинкиназ, участвующих в индукции, а также ядерных факторов, специфически активирующих регуляторные домены генов ИФН. Выдвинуто предположение о том., что с AMP выступает в роли ключевогом вторичного мессенджера, опосредующего сигнал к индукции α/β-ИФН, начальным этапом которого является специфическая деформация клеточной мембраны под воздействием различных индукторов. en Інститут молекулярної біології і генетики НАН України Биополимеры и клетка Дискуссии A possible general mechanism of the signal transfer switching on the Α//3-interferons expression. 2. The role of the cAMP in the process of the interferon induction Можливий універсальний механізм передачі сигналу до експресії α/β-інтерферонів, 2. Роль сАМР при індукції Возможный универсальный механизм передачи сигнала к экспрессии α/β-интерферонов. 2. Роль сАМР при индукции Article published earlier |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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| title |
A possible general mechanism of the signal transfer switching on the Α//3-interferons expression. 2. The role of the cAMP in the process of the interferon induction |
| spellingShingle |
A possible general mechanism of the signal transfer switching on the Α//3-interferons expression. 2. The role of the cAMP in the process of the interferon induction Karpov, A.V. Дискуссии |
| title_short |
A possible general mechanism of the signal transfer switching on the Α//3-interferons expression. 2. The role of the cAMP in the process of the interferon induction |
| title_full |
A possible general mechanism of the signal transfer switching on the Α//3-interferons expression. 2. The role of the cAMP in the process of the interferon induction |
| title_fullStr |
A possible general mechanism of the signal transfer switching on the Α//3-interferons expression. 2. The role of the cAMP in the process of the interferon induction |
| title_full_unstemmed |
A possible general mechanism of the signal transfer switching on the Α//3-interferons expression. 2. The role of the cAMP in the process of the interferon induction |
| title_sort |
possible general mechanism of the signal transfer switching on the α//3-interferons expression. 2. the role of the camp in the process of the interferon induction |
| author |
Karpov, A.V. |
| author_facet |
Karpov, A.V. |
| topic |
Дискуссии |
| topic_facet |
Дискуссии |
| publishDate |
1999 |
| language |
English |
| container_title |
Биополимеры и клетка |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| format |
Article |
| title_alt |
Можливий універсальний механізм передачі сигналу до експресії α/β-інтерферонів, 2. Роль сАМР при індукції Возможный универсальный механизм передачи сигнала к экспрессии α/β-интерферонов. 2. Роль сАМР при индукции |
| description |
The author carries out an analysis of available data concerning the participation of cyclic adenosine 3',5'-monophosphate (cAMP) in the signal transduction pathway on the α/β-inierferons (IFN) expression during the induction process. The cAMP is known to participate in the activation of protein kinasev during the interferon induction as well as of nuclear factors activating specifically the regulating domains, of IFN genes. The cAMP is thought to be a secondary key messenger mediating the signal, for α/β-lFN induction, the first stage of this induction being the local cell membrane deformation caused by diffirent inducers.
Проаналізовано літературні дані стосовно участі циклічного аденозин-3' ,5'-монофосфату (cAMP) при передачі сигналу до експресії α/β-інтерферонів (ІФН) у процесі індукції. Описано участь сАМР в активації протеїнкіназ, які беруть участь в індукції, а також ядерних факторів, що специфічно активують регуляторні домени генів ІФН. Висунуто припущення, що сAMP виступає в ролі ключового вторинного месепджера, який опосередковує сигнал до індукції α/β-ІФН, початковим етапом якого є специфічна деформація клітинної мембрани під дією різних індукторів.
Проанализированы литературные данные относительно участия циклического аденозин-3',5-монофосфата (сAMP) при передаче сигнала к экспрессии α/β-интерферонов (ИФН) в процессе индукции. Описано участие сАМР в активации протеинкиназ, участвующих в индукции, а также ядерных факторов, специфически активирующих регуляторные домены генов ИФН. Выдвинуто предположение о том., что с AMP выступает в роли ключевогом вторичного мессенджера, опосредующего сигнал к индукции α/β-ИФН, начальным этапом которого является специфическая деформация клеточной мембраны под воздействием различных индукторов.
|
| issn |
0233-7657 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/156005 |
| citation_txt |
A possible general mechanism of the signal transfer switching on the Α//3-interferons expression. 2. The role of the cAMP in the process of the interferon induction / A.V. Karpov // Биополимеры и клетка. — 1999. — Т. 15, № 1. — С. 83-87. — Бібліогр.: 47 назв. — англ. |
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ISSN 0233-7657. Биополимеры и клетка. 1999. Т. 15. Ns 1
ДИСКУССИИ
A possible general mechanism of the signal
transfer switching on the Α / / 3 - i n t e r f e r o n s expression.
2. The role of the cAMP in the process of the
interferon induction
Alexander V. Karpov
Danylo Zabolotnoho Institute of Microbiology and Virology, National Academy of Sciences of Ukraine
1.54 Zaboiotny str., Kyiv, 252143, Ukraine
The author carries out an analysis of available data concerning the participation of cyclic adenosine
3',5'-monophosphate (cAMP) in the signal transduction pathway on the a/β-interferons (IFN ) expression
during the induction process. The cAMP is known to participate in the activation of protein kinases during
the interferon induction as well as of nuclear factors activating specifically the regulating domains of IFN
genes. The cAMP is thought to be a secondary key messenger mediating the signal for α/β-IFN induction,
the first stage of this induction being the local cell membrane deformation caused by diffirent inducers.
The regulation of the interferon (IFN) genes ex-
pression as well as the expression of a lot of other
ones is usually realized by the induction mechanism,
i. e. by the extracellular activation [1]. The IFN
induction is now known to be realized both by viruses
and by many compounds of high and low molecular
weight [I—4]. The induction process is thought to be
a multi-stage and perhaps a branched one beginning
from any inductor interaction with the cell surface
and completing by the initiation of the JFN genes
transcription. It must be noted that no generally
accepted up-to-date conception has been elaborated
concerning the IFN induction mechanism as well the
nature of intermediate signal carriers assuring the
IFN-ccding genes activation following the action of
multilateral inducers.
A great body of experimental data accumulated
during several last years shows the genes coding both
and a- and /Ї-IFN to contain multiple positive and
negative as-acting elements necessary for induction.
These elements are mostly able to bind with different
protein factors also influencing the transcription [5,
© Α. V. KARPOV, 1999
6 |. It is also noteworthy the activation of both a - and
Д-IFN genes needs no new protein synthesis. So it is
clear the cell to possess some «latent» («silent»)
factors necessary for the effective IFN genes expres-
sion, these factors being activated by the induction
process [6, 7 J.
I have earlier proposed a hypolhesis postulating
the first a- and /S-IFN induction stage to be a rather
common phenomenon — the local cellular membrane
deformation taking place as a result of any IFN-
inducing agent action [8 ]. In this paper I would like
to discuss some possible events on the level of
molecular processes developing after such membrane
deformation.
The interaction of some biologically active sub-
stances with the cellular membrane as well as some
other processes cause the activation of many enzymes
including also adenylate cyclase — an enzyme res-
ponsible for the cyclic adenosine-3',5'-monopho:>phate
(cAMP) synthesis. Due to such activation the intra-
cellular cAMP level increases [9]. A similar pheno-
menon is also found following local artificial mecha-
nical effect on the cell membrane [10—12], The
cAMP is known to belong Io a group of so called
«secondary messengers» — ubiquitous intracellular
83
KARfOV Α. V.
substances activating a lot of genes [13], hormones
[14], and also protein factors regulating the exp-
ression of many genes [15]. The transcription ini-
tiation is realized due to the activation of a specific
cAMP-dependent protein kinase — protein kinase A
(PKA) activating a corresponding transcription factor
[16] by a phosphorylation process. The inactive PKA
holoenzyme consists of two regulatory subunits pos-
sessing two cAMP-binding sites and two catalytic
ones. There are two types of regulatory subunits, the
catalytic ones being identical. The binding of four
cAMP molecules to regulatory subunits causes the
release of catalytic monomer subunits pliosphorylating
cell proteins.
The participation of different protein kinases
including also the cAMP-deperident one in the IFN
induction process is known for a rather long time
[17]. Tv/o inter-independent types of transductive
lFN-activating signals are now thought to be set in
motion following extracellular stimulus. Protein kina-
ses are found to participate directly in the signal
development of both types. The first IFN-activating
process needs the Ca2i-Calmodulin system partici-
pation, the second one includes the activity of the
Ca"'-dependent diacylglycerol protein kinase C [18].
Some experiments with different inhibitors of this
enzyme have shown the poly (I) -poly (C)-induced IFN
synthesis, contrary to the virus-induced one, is de-
pendent on this enzyme activity [19]. The inhibition
of the dsRNA- and virus-induced /J-IFN synthesis by
2-aminopurine proves the role of the dsRNA-clepend-
cnt protein Idnase in the /?-IFN induction. This
anomalous nucleoside is found to be a potential
inhibitor of some protein kinases including also
dsRNA-dependent and heme-reguiated protein kinase
eIF-2 [20, 21 ]. The data given above confirm the
importance and significance of this type enzymes in
he IFN induction. The cAMP participation in this
process, except its direct role in the PKA activation
discussed above, includes also several stages of the
protein ldnases mediated signal transfer which is
impossible without the cAMP. For example, this
secondary messenger has been demonstrated to sti
mulate the PKC penetration into the nucleus [22 ]. At
the same time the cAMP increases the activity of ionic
channels permitting Ca2+-Ions introduction into the
cell followed by the PKC activation [23]. In its turn,
this process is also known to be negatively regulated,
an adenylate cyclase subunit being inactivated by the
PKC [24 ] and the intracellular Ca2+-excess leading
t he cAMP-spliitting phosphodiesterase activation [25].
The addition of the PKA activating cAMP analogs
decreases the cAMP level in hepatocytes [26 ]. All
Ihese data suggest the existence of numerous negative
feed back regulation pathways in the system of
secondary messengers; the negative regulation is tho-
ught to prevent the excessive cell stimulation. I think
such regulation is to play the determinative crucial
role for the choice of any signal transduction pathway
necessary for the IFN induction in any concrete case
of interactions between any IFN inducer and the cell.
My conception correlates completely with the conclu-
sion concerning any concrete case of the secondary
messengers participation in the IFN synthesis follo-
wed by viral and non-viral IFN induction [19].
To discuss the cAMP role at the final stages of
the IFN genes expression, it is necessary to remem-
ber some experimental results. PRDIV, one of the
four positive /S-IFN regulatory elements, contains a
site binding transcription factors of the ATF/CREB
family [27—29], the CPEB factor assuring the
cAMP-dependen t induct ion [30]. The multiple
PRDIV copies have been also demonstrated to realize
both virus- and cAMP-dependent IFN induction with
heterologous promoters [29].
At the same time the cAMP has been shown to
participate in the virus-directed IFN gene induction
which is dependent on PRDII, another positive regu-
lating domain of this gene promoter [31 ]. Such
induction is usually realized with the help of a specific
nuclear protein — NF-лВ. This protein has been
shown to bind the лВ-site of the A-chain (NF-κΒ) in
the immunoglobulin enhancer [32, 33 ]. The NF-лВ is
demonstrated to be present in the cytoplasm of many
cells forming a complex with an inhibitor protein, IKB
[34]. The cell treatment by several agents, such as
phorbol ethers, lypopolysaccharides, and cAMP, the
last case being especially noteworthy, causes the
dissociation of the NFWCB/IKB complex and the
development of a nuclear NF-A'B-binding activity
[35]. Besides, some in vitro experiments suggest the
activation of a NF-л'В precursor followed by its
conversion into an active DNA-binding form is rea-
lized with the participation both of the PKC and the
cAMP dependent PKA [36].
The NF-AB is found to bind specifically the
PRDII site of the /S-IFN promoter, the PRDlI muta-
tions decreasing the virus-directed IFN induction in
vivo reduce also the NF-κΒ affinity to the PRDII in
vitro [37, 38 ]. It is noteworthy the NF-/cB binding
and its transfer to the nucleus are activated both by
viruses and by poly (I)-poly (C) preparations [31,
37—39]. The NF-κΒ is also known to activate the
PKC and the heme-regulated kinase eIF-2 as well as
the cAMP-dependent PKA. At the same time, the LcB
is demonstrated to become phosphorylated and inac-
tivated in the presence of the PKC and of the
elF-kinase, but not in the presence of the PKA [35 ].
84
All these data including especially the very fact
of the cAMP-mediated α/β-lFN induction [5 | as well
as the experiments suggesting the intracellular cAMP
concentration increasing directed by the dsRNA [401
and synthetic nucleotides [41 [ prove the cAMP being
the secondary messenger to make the principal contri-
bution into the developing of several signal transfer
pathways leading from the cellular membrane to the
α/β-lFN coding genes activation.
Besides, I would like to discuss a problem of the
cAMP-mediated signal; I think this term to concern
not only the α/β-lFN expression, but also the exp-
ression of many other genes activated following the
virus/dsRNAs interactions with any cell [42 ]. It i.;
noteworthy a similar situation is found following any
mechanical deformation of the cell membrane [11,
12]. Unfortunately, the data concerning this last case
have been never discussed in connection with the IFN
induction.
At the same time, any similar cAMP-mediated
signal is to be a rather specific one, the IFN induction
process being found to take place following the
suppression of the general cellular protein synthesis
[1—4]. This process specificity is possible to be due
to two additional ones. Firstly, the cAMP together
with a lot of cAMP-dependent kinases and some other
proteins is now thought to form a rather complex
coordinated system of secondary messengers pos-
sessing several entries for extracellular signals and
having numerous feed back factors [25 ]. Such system
is able to adapt its possibilities for any concrete case
to realize such a general cell response as the IFN
induction. Secondly, some cAMP-independent factors
have been also shown to regulate the INF synthesis
[5 ]. The additive action of all these factors parti-
cipating in the IFN induction is to increase the
specificity level.
During a rather long time some synthetic poly-
nucleotides belonging to an important group of IFN-
inducing substances are known to be compounds
stimulating the synthesis of antibodies. Such a stri-
king property of such compounds is thought to be
correlated with their ability to increase the adenylate
cyclase activity in immunocompetent cells followed by
the increased intracellular cAMP concentration [43].
The accelerated immune response has been demon-
strated not only as a result of polynucleotide-induced
increasing of the adenylate cyclase activity, but also
as a consequence of the phosphodiesterase inhibitors
effect, such as theophilline and caffeine [44]. It is
clear such immune responses to be correlated with or
directly due to the IFN-inducing activity. There are
direct evidences that such compounds as methyl-
xanthines (purines) and a lot of their derivatives
A MECHANISM OF THE SIGNAL ON THE INTERFERON EX PRESSION
including theophilline and caffeine mentioned above
as well as theobromine, papaverine and some other
ones are also cAMP phosphodiesterase inhibitors [45,
46 ] possessing some marked IFN-inducing properties
[47]. At the same time I think the direct IFN-
inducing cytotropic effect of the cAMP is not a
probable one, this compound being inable to penetrate
through the cell membrane [13].
I think all these data permit to assume the cAMP
to be the crucial factor participating in 1he IFN-
inducing signal transfer developed earlier according to
the postulated mechanism due to the specific cell
membrane deformation [8 ]. Such a situation does not
exclude the synergistic contribution of some other
IFN-inducing factors leading finally to the process of
the genes expression coding the I type IFN (i. e.
α/β-lFN). So I think the further investigations con-
cerning all the details of the IFN regulation and IFN
expression mentioned above will disclose the picture
of the cAMP participation in this process as well as
some variations concerning this compound concen-
trations at different IFN induction stages; these data
are to be of great value and to help us to solve the
general problem of the IFN induction. The expe-
riments with many different inducers and inhibitors
of the IFN synthesis participating in the cAMP
metabolism are to be especially useful.
О. В. Карпов
Можливий універсальний механізм передачі сигналу до
експресії «//{-інтерферонів. 2. Роль сАМР при індукції
Резюме
Проаналізовано літературні дані стосовно участі циклічного
аденозин-3',.5'-монофосфату (cAMP) при передачі сигналу до
експресії а/β-інтерферонів (ІФН) у процесі індукції. Описано
участь сАМР в активації протеїнкіназ, які беруть участь в
індукції, а також ядерних факторів, що специфічно активу-
ють регуляторні домени генів ІФН. Висунуто припущення, що
сАМР виступає в ролі ключового вторинного месенджера,
який опосередковує сигнал до індукції α/β-ΙΦΗ, початковим
етапом якого є специфічна деформація клітинної мембрани
під дією різних індукторів.
А. В. Карпов
Возможный универсальный механизм передачи сигнала к
экспрессии а//?-интерферонов. 2. Роль сАМР при индукции
Резюме
Проанализированы литературные данные относительно уча-
стия циклического аденозин-3',5'-моно(росфапш (сАМР) при
передаче сигнала к экспрессии α/β-интерферонов (ИФН) в
процессе индукции. Описано участие сАМР в активации чроте-
инкиназ, участвующих в индукціш, а также ядерных факто-
ров, специфически активирующих регуляторные домены генов
ИФН. Выдвинуто предіюложение о том, что сАМР выступа-
ет в роли ключсвогом вторичного мессенджера, опосредующе-
85
KARFOV А V.
го сигнал к индукции α/β-ИФН, начальным .этапом которого
является специфическая деформация клеточной мембраны под
воздействием различных индукторов.
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УДК 578.245.577.113.7
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