Inducible cAMP early repressor (ICER) in the nervous system – a transcriptional regulator of neuronal plasticity and programmed cell death

Mioduszewska, Barbara; Jaworski, Jacek; Kaczmarek, Leszek

doi:10.1046/j.1471-4159.2003.02116.x

Cited by 69 publications

(67 citation statements)

References 58 publications

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“…23 and AP1 ref. 24 inhibiting their transcriptional activity. Here, we report NF-κB as a new class of transcriptional factors that are negatively regulated by ICER, further expanding our fundamental understanding of this repressor.…”

Section: Discussionmentioning

confidence: 99%

A negative feedback loop of ICER and NF-κB regulates TLR signaling in innate immune responses

Qiu

et al. 2016

Cell Death Differ

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The NF-κB pathway has important roles in innate immune responses and its regulation is critical to maintain immune homeostasis. Here, we report a newly discovered feedback mechanism for the regulation of this pathway by TLR ligands in macrophages. Lipopolysaccharide (LPS) induced the expression of ICER via p38-mediated activation of CREB in macrophages. ICER, in turn, inhibited the transcriptional activity of NF-κB by direct interaction with the p65 subunit of NF-κB. Deficiency in ICER elevated binding of NF-κB to promoters of pro-inflammatory genes and their subsequent gene expression. Mice deficient in ICER were hypersensitive to LPS-induced endotoxic shock and showed propagated inflammation. Whereas ICER expression in ICER KO bone marrow transplanted mice rescued the ultra-inflammation phenotype, expression of a p65 binding-deficient ICER mutant failed to do so. Our results thus establish p38-CREB-ICER as key components of a negative feedback mechanism necessary to regulate TLR-driven inflammation. Cell Death and Differentiation (2017) 24, 492-499; doi:10.1038/cdd.2016; published online 23 December 2016Activation of TLR4, a pattern recognition receptor used in the innate immune system, by lipopolysaccharide (LPS) leads to the transcription of pro-inflammatory mediators that promote innate immune responses.1 One critical pathway triggered by TLR4 is the NF-κB pathway.2 TLR4 initiates a signaling cascade through adapter molecules MyD88 and TRIF, resulting in TRAF6 activation. TRAF6 in turn triggers the phosphorylation of IκB by IKK and proteosomal degradation of IκB. Subsequently, NF-κB disassociates from IκB and translocates to the nucleus where it promotes the transcription of genes involved in pro-inflammatory responses.3,4 Activation of TRAF6 also leads to downstream activation of the MAPK cascade, including JNKs and p38 isoforms. 5 The p38 pathway has attracted considerable interest as a possible target for antiinflammatory drugs. Activation of p38 results in the activation of CREB, a transcription factor that regulates diverse cellular responses including proliferation, survival and immune responses. CREB is phosphorylated and activated by MSK1/2, a downstream kinase of p38, and subsequently mediates the transcription of genes containing a cAMP-responsive element. Several anti-inflammatory genes possess this cAMPresponsive element, including Dusp1 and IL-10. 6 In addition, phosphorylated CREB has been proposed to directly inhibit NF-κB activation by blocking the binding of CREB binding protein to the NF-κB complex, thereby limiting proinflammatory responses. 7Inducible cAMP early repressors (ICERs) are members of the cAMP-response element (CRE) modulator family and are induced by CREB.8 ICER is transcribed via an alternative internal promoter in the CREM gene and consists of four different isoforms generated by alternative splicing of its transcript (ICERI, ICERIγ, ICERII, ICERIIγ). 9 The isoforms encode either CREB-like (ICERI) or CREM-like (ICERII) DNA-binding domains (DBDs) with or without the alternat...

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Section: Discussionmentioning

confidence: 99%

A negative feedback loop of ICER and NF-κB regulates TLR signaling in innate immune responses

Qiu

et al. 2016

Cell Death Differ

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“…Under normal physiological conditions, ICER induction is transient because of negative down-regulation of its expression by competing with CREB for CRE-binding sequences in the ICER promoter (10,20). This negative feedback mechanism is responsible for returning stimulated cells to the steady-state level and allows cAMP-dependent signaling to be activated in a cyclic fashion.…”

Section: Discussionmentioning

confidence: 99%

“…To determine the molecular mechanism responsible for PDE3 inhibition-induced down-regulation of PDE3A expression, we focused on PKA, CREB, and ICER because a decrease in PDE3A activity causes elevation of cAMP (12,17), which may stimulate PKA and subsequent CREB activation, then induce ICER expression (10). To determine the roles of PKA, CREB, and ICER, we used adenovirus-mediated expression of PKI (a 75-aa endogenous PKA inhibitor), DN-CREB (a dominant negative form of CREB, with phosphorylation site serine133 mutated to alanine), and ICER-AS (antisense ICER-II␥).…”

Section: Role Of Pde3a Enzymatic Activity In the Regulation Of Icer Ementioning

confidence: 99%

“…Inducible cAMP early repressors (ICERs) are members of the cAMP-response element (CRE) modulator family and are induced by CRE-binding protein (CREB) (10). ICER proteins contain DNA binding and leucine zipper domains but not the N-terminal transactivation domain, which make them function as endogenous inhibitors of gene transcription driven by its cognates such as CREB, including its own expression by competing with CREB in binding CRE sequences (10).…”

mentioning

confidence: 99%

“…ICER proteins contain DNA binding and leucine zipper domains but not the N-terminal transactivation domain, which make them function as endogenous inhibitors of gene transcription driven by its cognates such as CREB, including its own expression by competing with CREB in binding CRE sequences (10). Hence, under physiological conditions, ICER induction is a transient phenomenon that allows cAMP signaling to return to the basal state (10).…”

mentioning

confidence: 99%

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A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis

Ding

Abe

Heng

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

113

124

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cAMP plays crucial roles in cardiac remodeling and the progression of heart failure. Recently, we found that expression of cAMP hydrolyzing phosphodiesterase 3A (PDE3A) was significantly reduced in human failing hearts, accompanied by up-regulation of inducible cAMP early repressor (ICER) expression. Angiotensin II (Ang II) and the ␤-adrenergic receptor agonist isoproterenol (ISO) also induced persistent PDE3A down-regulation and concomitant ICER up-regulation in vitro, which is important in Ang II-and ISO-induced cardiomyocyte apoptosis. We hypothesized that interactions between PDE3A and ICER may constitute an autoregulatory positive feedback loop (PDE3A-ICER feedback loop), and this loop would cause persistent PDE3A down-regulation and ICER up-regulation. Here, we demonstrate that ICER induction repressed PDE3A gene transcription. PDE3A down-regulation activated cAMP͞PKA signaling, leading to ICER up-regulation via PKAdependent stabilization of ICER. With respect to Ang II, the initiation of the PDE3A-ICER feedback loop depends on activation of Ang II type 1 receptor (AT1R), classical PKC(s), and CREB (cAMP response element binding protein). We further show that the PDE3A-ICER feedback loop is essential for Ang II-induced cardiomyocyte apoptosis. ISO and PDE3 inhibitors also induced the PDE3A-ICER feedback loop and subsequent cardiomyocyte apoptosis, highlighting the importance of this PDE3A-ICER feedback loop and cAMP signaling in cardiomyocyte apoptosis. Our findings may provide a therapeutic paradigm to prevent cardiomyocyte apoptosis and the progression of heart failure by inhibiting the PDE3A-ICER feedback loop.angiotension II ͉ ␤-andrenergic receptor ͉ PKC ͉ heart failure C ardiac remodeling including dysregulated myocyte apoptosis contributes to the development and progression of myocardial remodeling and the transition from cardiac hypertrophy to chronic heart failure (1-3). Stimulation of the renin-angiotensin and ␤-adrenergic receptor (␤-AR) systems are broadly involved in contraction, growth control, and cell death (3, 4). Both systems are subject to counterregulatory balances under normal physiological circumstances, which are overridden by chronic activation in heart failure. For example, chronic exposure to angiotensin II (Ang II) and ISO promote cardiac dysfunction resulting from cardiac remodeling including hypertrophy and apoptosis (4-7). Many clinical trials have indicated that angiotensinconverting enzyme inhibitors and ␤-AR blockers significantly improve the survival rates of heart failure patients by decreasing cardiac remodeling (8). However, the exact mechanisms of myocyte apoptosis, especially those mediated by angiotensin II, remain unclear.cAMP signaling plays important roles in both physiologic and pathologic regulation of cardiac performance (9). cAMP is one of the most well characterized signaling molecules in ␤-AR signaling, but its contribution to Ang II signaling in cardiomyocytes is not fully understood. Clinical and experimental studies indicate that acute stimulation of ␤-AR...

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Distribution of transcription factor inducible cyclicAMP early repressor (ICER) in rodent brain and pituitary

Kell

Dehghani

Wicht

et al. 2004

J of Comparative Neurology

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In morphogenetic dynamics of neurons, and in adaptive physiology of brain function, transcription factors of the cyclicAMP signaling pathway, such as activator cyclicAMP responsive element binding protein (CREB) and inhibitor inducible cyclicAMP early repressor (ICER), play an important role. In particular, the presence of the transcription factor ICER in neurons or neuroendocrine cells suggests the need for the gating of an up-regulated gene expression. Little is known, however, about the natural distribution of the inhibitory transcription factor ICER. We, therefore, mapped the rodent brain and pituitary for an ICER immunoreaction and found a nuclear staining for this transcription factor. ICER-positive glial cells were found throughout the brain. ICER-positive neurons were found in sensory input centers, like the olfactory bulb, or sensory brain stem nuclei, and in hypothalamic nuclei involved in central neuroendocrine control. In addition, neuroendocrine/endocrine transducers, like the pituitary and the pineal gland showed a high basal presence of ICER. Our data show that a basic ICER level is required by many cell systems and can be seen as an anticipatory and/or a protective measure in systems with superior reactive dynamics.

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Inducible cAMP early repressor (ICER) in the nervous system – a transcriptional regulator of neuronal plasticity and programmed cell death

Cited by 69 publications

References 58 publications

A negative feedback loop of ICER and NF-κB regulates TLR signaling in innate immune responses

A negative feedback loop of ICER and NF-κB regulates TLR signaling in innate immune responses

A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis

Distribution of transcription factor inducible cyclicAMP early repressor (ICER) in rodent brain and pituitary

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