Silencing of ICERs (Inducible cAMP Early Repressors) results in partial protection of neurons from programmed cell death

Bieganska, K.; Figiel, Izabela; Gierej, Dorota; Kaczmarek, Leszek; Klejman, Agata

doi:10.1016/j.nbd.2011.10.015

Cited by 5 publications

(5 citation statements)

References 41 publications

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“…PKA-induced phosphorylation of cAMP response element-binding (CREB) protein is known to promote neuronal survival and counteract the pro-apoptotic effects of TNF by eliciting expression of several genes including brain derived neurotrophic factor and bcl-2 (Bieganska et al 2011; Krakstad et al 2004; Mueller et al 2005). We investigated whether pharmacological inhibition of PKA-CREB signaling could ablate the protective effects of RGS10 WT over-expression in MN9D cells by pre-treating cells with H89, a specific PKA inhibitor, prior to TNF exposure.…”

Section: Resultsmentioning

confidence: 99%

RGS10 exerts a neuroprotective role through the PKA/c‐AMP response‐element (CREB) pathway in dopaminergic neuron‐like cells

Lee

Chung

Druey

et al. 2012

Journal of Neurochemistry

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Regulator of G-protein signaling-10 (RGS10) is a GTPase activating protein (GAP) for Gαi/q/z subunits that is highly expressed in the immune system and in a broad range of brain regions including the hippocampus, striatum, dorsal raphe, and ventral midbrain. Previously, we reported that RGS10-null mice display increased vulnerability to chronic systemic inflammation-induced degeneration of nigral dopaminergic (DA) neurons. Given that RGS10 is expressed in DA neurons, we investigated the extent to which RGS10 regulates cell survival under conditions of inflammatory stress. Because of the inherent limitations associated with use of primary DA neurons for biochemical analyses, we employed a well-characterized ventral mesencephalon DA neuroblastoma cell line (MN9D) for our studies. We found that stable over-expression of RGS10 rendered them resistant to TNF-induced cytotoxicity; whereas MN9D cells expressing mutant RGS10-S168A (which is resistant to phosphorylation by protein kinase A (PKA) at a serine residue that promotes its nuclear translocation) showed similar sensitivity to TNF as the parental MN9D cells. Using biochemical and pharmacological approaches, we identified protein kinase A (PKA) and the downstream phospho-cAMP response element-binding (CREB) signaling pathway (and ruled out ERK 1/2, JNK, and NFkB) as key mediators of the neuroprotective effect of RGS10 against inflammatory stress.

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Section: Resultsmentioning

confidence: 99%

RGS10 exerts a neuroprotective role through the PKA/c‐AMP response‐element (CREB) pathway in dopaminergic neuron‐like cells

Lee

Chung

Druey

et al. 2012

Journal of Neurochemistry

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“…ICER induction and expression were linked to apoptosis and cell death in various tissues, e.g., cardiomyocytes (41, 42), neurons (26, 43, 44), pancreatic β cells (45), and vascular smooth muscle cells (46). Accordingly, expression of ICER or smICER increased the sensitivity of HT‐29 and HT‐1080 cells to proapoptotic stimuli.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, ICER suppresses CREB‐dependent expression of the antiapoptotic protein Bcl‐2 and, thereby, confers induction of apoptosis on elevation of intracellular cAMP levels (24, 25). Silencing of endogenous ICER proteins, in contrast, has been reported to protect neurons against programmed cell death (26).…”

mentioning

confidence: 99%

A novel intronic promoter of theCremgene induces small ICER (smICER) isoforms

et al. 2013

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The transcription factors cAMP-responsive element binding protein (CREB) and cAMP-responsive element modulator (CREM) regulate gene transcription in response to elevated cAMP levels. The Crem isoform inducible cAMP early repressor (Icer) is transcribed by the internal promoter P2 as a critical regulator of multiple cellular processes. Here, we describe a novel inducible Crem isoform, small Icer (smIcer), regulated by a newly identified promoter (P6). ChIP revealed binding of CREB to P6 in human and mouse myocardium. P6 activity was induced by constitutively active CREB or stimulation of adenylyl cyclase. In mice, smIcer mRNA was ubiquitously expressed and transiently induced by β-adrenoceptor stimulation e.g., in heart and lung. SmICER repressed both basal and cAMP-induced activities of P6 and P2 promoters. Stimulation of adenylyl cyclase induced P2 and P6 in cell type-specific manner. Alternative translational start sites resulted in three different smICER proteins, linked to increased apoptosis sensitivity. In conclusion, the Crem gene provides two distinct and mutually controlled mechanisms of a cAMP-dependent induction of transcriptional repressors. Our results suggest not only that smICER is a novel regulator of cAMP-mediated gene regulation, but also emphasize that biological effects that have been ascribed solely to ICER, should be revised with regard to smICER.

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“…Numerous studies have manipulated the activity of CREB and demonstrated its role in memory formation (Balschun et al 2003, Barco et al 2003, Bourtchuladze et al 1994, Bernabeu et al 1997. However, interpretations of the role of CREB in plasticity are complicated because CREB deficiency also leads to cell death, a reduction of neuronal excitability, and a consequent deficit in synaptic plasticity (Benito and Barco 2014, Bieganska et al 2012, Jancic et al 2009, Jaworski et al 2003. In contrast to CREB, SRF deletion does not influence the viability of neurons, but it produces deficiencies in hippocampal synaptic plasticity and learning (Etkin et al 2006, Kuzniewska et al 2016, Losing et al 2017, Ramanan et al 2005.…”

Section: Involvement Of Other Transcription Factors In Synaptic Plasticity Learning and Memorymentioning

confidence: 99%

c-Fos and neuronal plasticity: the aftermath of Kaczmarek’s theory

Jaworski¹,

Kalita²,

Knapska³

2018

Acta Neurobiologiae Experimentalis

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The development of molecular biology methods in the early 1980s led to a better understanding of the role of transcription factors in mammalian cells. The discovery that some transcription factors are critically important for cells to switch between different functional states was fundamental for modern molecular neurobiology. In the 1980s Leszek Kaczmarek proposed that, analogically to the cell cycle or to cell differentiation, long-term synaptic plasticity, learning, and memory should also require the activity of transcription factors. To test his hypothesis, he focused on c-Fos. His team showed that the c-Fos proto-oncogene is activated by synaptic plasticity and learning, and is required for these phenomena to occur. Subsequent studies showed that timp-1 and mmp-9 are c-Fos effector genes that are required for plasticity. The present review summarizes Kaczmarek's hypothesis and the major evidence that supports it. We also describe the ways in which knowledge of the molecular neurobiology of learning and memory advanced because of Kaczmarek's theory. Finally, we briefly discuss the degree to which his hypothesis holds true today after the discovery of non-coding RNAs, a novel class of regulatory molecules that were not taken into account by Leszek Kaczmarek in the 1980s.

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Silencing of ICERs (Inducible cAMP Early Repressors) results in partial protection of neurons from programmed cell death

Cited by 5 publications

References 41 publications

RGS10 exerts a neuroprotective role through the PKA/c‐AMP response‐element (CREB) pathway in dopaminergic neuron‐like cells

RGS10 exerts a neuroprotective role through the PKA/c‐AMP response‐element (CREB) pathway in dopaminergic neuron‐like cells

A novel intronic promoter of theCremgene induces small ICER (smICER) isoforms

c-Fos and neuronal plasticity: the aftermath of Kaczmarek’s theory

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