Degradation of the inducible cAMP early repressor (ICER) by the ubiquitin–proteasome pathway

Folco, J. Eduardo; Koren, Gideon

doi:10.1042/bj3280037

Cited by 48 publications

(39 citation statements)

References 33 publications

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“…This finding is consistent with the observation that transgenic mice with cardiac specific overexpression of constitutively active PKA developed dilated cardiomyopathy (21). The stability of ICER protein is regulated by the process of proteasome-dependent degradation (22). The precise mechanism by which PKA-regulated ICER protein stability will require further investigation; however, cAMP has been previously shown to attenuate ICER protein ubiquitination and degradation probably via cAMP-dependent inhibition of mitogen-activated protein kinase ERK1͞2 that phosphorylates and targets ICER to ubiquitin-mediated destruction (18).…”

Section: Discussionsupporting

confidence: 81%

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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Section: Discussionsupporting

confidence: 81%

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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“…7A). Wild-type ICER-II␥ was found to be efficiently ubiquitinated and accumulated as shown before (28,29). However, the expression of ubiquitinated intermediates was not altered in two independent AtT20 cell clones expressing different levels of ICER-II␥(Ala-41 Among the CREM isoforms, ICER has been uniquely shown to be a substrate of the ubiquitin-conjugating enzyme CDC34 (29).…”

Section: Phosphorylation At Serine 41 Targets Icer For Degradationmentioning

confidence: 95%

“…by the Ubiquitin-Proteasome Pathway-It was recently shown that the half-life of ICER was regulated by degradation via the proteasome-ubiquitin pathway (28,29). In this study, we found that ICER stability is regulated by phosphorylation.…”

Section: Phosphorylation At Serine 41 Targets Icer For Degradationmentioning

confidence: 99%

Mitogen-activated Protein Kinase Phosphorylates and Targets Inducible cAMP Early Repressor to Ubiquitin-mediated Destruction

Yehia¹,

Schlotter²,

Razavi³

et al. 2001

Journal of Biological Chemistry

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Inducible cAMP early repressor (ICER) is an important mediator of cAMP antiproliferative activity that acts as a putative tumor suppressor gene product. In this study, we examined the regulation of ICER protein by phosphorylation and ubiquitination in human choriocarcinoma JEG-3 and mouse pituitary AtT20 cells. We found that cAMP stabilized ICER protein by inhibiting the mitogen-activated protein kinase (MAPK) cascade. Activation of the MAPK pathway increased ICER phosphorylation. ICER phosphorylation was abrogated by inhibition of the MAPK pathway either by cAMP or directly by the MAPK inhibitor PD098059. The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4 -5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway. These results present a novel cell signaling crosstalk mechanism at the cell nucleus between the MAPK and cAMP pathways, whereby MAPK targets a repressor of the cAMP-dependent gene expression for ubiquitination and proteasomal degradation.The MAPK 1 pathway controls cell growth by regulating gene expression, protein synthesis, nucleotide synthesis, the interaction between cyclins and cyclin-dependent kinases, and protein stability by ubiquitin-mediated proteasomal degradation (Refs. 1 and 2 and references therein). In the classic pathway, activation of MAPK occurs by peptide growth factors that bind to a transmembrane tyrosine kinase receptor. This results in the activation of the small GTP-binding protein Ras that recruits a member of the Raf kinase family (Raf-1, A-Raf, or B-Raf) to the plasma membrane. Raf phosphorylates and activates the MEKs (MEK1 and MEK2), which in turn activates the MAPKs ERK1 and ERK2 by phosphorylation on threonine and tyrosine.

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“…ICER expression depends on CREB/ICER transcriptional activity and its protein degradation rate. 3 CREB is a nuclear protein that regulates gene expression principally through activation of cAMP-dependent cell signal transduction pathways. CREB activity modulation was found to be a result of protein kinase A-dependent phosphorylation of CREB at Serine 133.…”

Section: Introductionmentioning

confidence: 99%

ICER expression inhibits leukemia phenotype and controls tumor progression

et al. 2008

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The inducible cyclic AMP (cAMP) early repressor (ICER) and cAMP response element-binding protein (CREB) are transcriptional regulators of the cAMP-mediated signaling pathway. CREB has been demonstrated to be upregulated in the majority of childhood leukemias contributing to disease progression, whereas ICER, its endogenous repressor, was found to be downregulated. Our research focus has been the function of restored ICER expression. ICER exogenously expressed in cell lines decreases CREB protein level and induces a lowered clonogenic potential in vitro. It decreases the ability of HL60 to invade the extramedullary sites and to promote bone marrow angiogenesis in nonobese diabetic-severe combined immunodeficient mice, demonstrating its potential effects on tumor progression. ICER represses the majority of 96 target genes upregulated by CREB. It binds CRE promoters and controls gene expression restoring the normal regulation of major cellular pathways. ICER is subjected to degradation through a constitutively active form of the extracellular signal-regulated protein kinase, which drives it to the proteasome. We propose that ICER is downregulated in HL60 to preserve CREB overexpression, which disrupts normal myelopoiesis and promotes blast proliferation. These findings define the function of ICER as a tumor suppressor in leukemia. Unbalanced CREB/ICER expression needs to be considered a pathogenetic feature in leukemogenesis. The molecular characterization of this pathway could be useful for novel therapeutic strategies.

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Degradation of the inducible cAMP early repressor (ICER) by the ubiquitin–proteasome pathway

Cited by 48 publications

References 33 publications

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

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

Mitogen-activated Protein Kinase Phosphorylates and Targets Inducible cAMP Early Repressor to Ubiquitin-mediated Destruction

ICER expression inhibits leukemia phenotype and controls tumor progression

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