Sumoylation regulates nuclear localization of repressor DREAM

Palczewska, Małgorzata; Casafont, Íñigo; Ghimire, Kedar; Rojas, Ana M.; Valencia, Alfonso; Lafarga, Miguel; Mellström, Britt; Naranjo, José R.

doi:10.1016/j.bbamcr.2010.11.001

Cited by 28 publications

(32 citation statements)

References 40 publications

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“…In this regard, we have recently shown that sumoylation regulates the nuclear localization of DREAM in differentiated neurons (27). Single Lys-to-Arg mutations at Lys-26 and Lys-90 reduce DREAM nuclear localization and transcriptional activity, although sumoylation mutants retain the ability to bind to the DRE sequence in vitro (27). Interestingly, it has been reported that the sumoylation process can be enhanced by phosphorylation of specific residues near the sumoylation site (28).…”

Section: Regulation Of Voltage-gated Calcium Channelsmentioning

confidence: 99%

“…However, this study did not specify where CaMKII phosphorylates DREAM and did not analyze which other post-translational modifications in the DREAM protein may be also present in cardiomyocytes. In this regard, we have recently shown that sumoylation regulates the nuclear localization of DREAM in differentiated neurons (27). Single Lys-to-Arg mutations at Lys-26 and Lys-90 reduce DREAM nuclear localization and transcriptional activity, although sumoylation mutants retain the ability to bind to the DRE sequence in vitro (27).…”

Section: Regulation Of Voltage-gated Calcium Channelsmentioning

confidence: 99%

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Ca2+-dependent Transcriptional Control of Ca2+ Homeostasis

Naranjo

Mellström

2012

Journal of Biological Chemistry

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Intracellular free Ca2؉ ions regulate many cellular functions, and in turn, the cell devotes many genes/proteins to keep tight control of the level of intracellular free Ca 2؉ . Here, we review recent work on Ca 2؉ -dependent mechanisms and effectors that regulate the transcription of genes encoding proteins involved in the maintenance of the homeostasis of Ca 2؉ in the cell.Control of intracellular free calcium is a delicate balance between mechanisms that provide the ion, including extracellular membrane calcium channels (voltage-, ligand-, and storeoperated types) and intracellular calcium release channels (ryanodine (RyR) 2 and inositol 1,4,5-trisphosphate (IP 3 R) receptors), and mechanisms that clear the ion from the cytosol, including calcium pumps and exchangers that are localized both in extra-and intracellular membranes (1, 2). Consolidated evidence, as well as recent evidence, indicates that this group of proteins, with the mission to keep tight control of free Ca 2ϩ concentration, is in turn subjected to regulation by several mechanisms controlled by changes in free Ca 2ϩ concentration. In some cases, these self-regulatory processes involve parallel compensatory changes in several Ca 2ϩ regulatory proteins so that increases or decreases in intracellular stores and cytosolic Ca 2ϩ levels slowly adjust the concentrations of key signaling pathway components (3). In other cases, components of the homeostasis machinery are coordinately modified to respond to chronic pathological conditions as in end stages of heart failure (4, 5) or in neurodegenerative processes. Thus, in Huntington disease striatal neurons accumulate changes in the expression of most, if not all, genes related to Ca 2ϩ homeostasis (6). Also, in Alzheimer disease (AD), changes in the expression of RyRs and STIM (stromal interacting molecule) have been observed in the hippocampus of presymptomatic AD mouse models (7) and post-mortem human brain samples (8) and in B lymphocytes from patients with familial AD mutations in the presenilin-1 gene (9), respectively. Of the different control mechanisms, here we will review those that control Ca 2ϩ homeostasis at the transcriptional level and that are directly regulated by Ca 2ϩ . A review of the transcriptional control of calcium homeostasis, with particular emphasis on the roles of members of the Egr (early growth response) family of zinc finger immediate-early transcription factors and the closely related protein WT1 (Wilms tumor suppressor 1), has been published recently (10).Control of the activity of specific transcriptional networks by Ca 2ϩ is regulated by cytosolic and nuclear mechanisms that decode the calcium signal specificity in terms of frequency and spatial properties. Thus, the Ca 2ϩ entry site (synaptic versus extrasynaptic) or its intracellular source (mitochondria, endoplasmic reticulum (ER), or Golgi apparatus) makes the Ca 2ϩ ions face different microdomains that are composed of specific sets of proteins and determines the biological outcome of the Ca 2ϩ signal by inducing t...

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Section: Regulation Of Voltage-gated Calcium Channelsmentioning

confidence: 99%

Section: Regulation Of Voltage-gated Calcium Channelsmentioning

confidence: 99%

Ca2+-dependent Transcriptional Control of Ca2+ Homeostasis

Naranjo

Mellström

2012

Journal of Biological Chemistry

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“…Single K-to-R mutations at positions K26 and K90 prevent in vitro sumoylation of recombinant DREAM and reduce nuclear localization of DREAM [29]. These results suggested that sumoylation regulates the nuclear localization of DREAM and thereby determines its transcriptional repressor activity.…”

Section: + -Dependent Interactions Revealed By Yeast Two-hybridmentioning

confidence: 67%

“…These results suggested that sumoylation regulates the nuclear localization of DREAM and thereby determines its transcriptional repressor activity. Indeed, it was shown that in PC12 cells, sumoylated DREAM is present exclusively in the nucleus, and accordingly, in fully differentiated trigeminal neurons, DREAM and SUMO-1 colocalize in nuclear domains associated with transcription [29]. Sequence analysis of the four members of the KChIP family (Figure 1) shows that the sumoylation consensus site K26, located in the DREAM-specific N-terminal region, is not present in the other three members, while the sumoylation site at K90 is conserved in KChIP 1 and 2 but not in KChIP4.…”

Section: + -Dependent Interactions Revealed By Yeast Two-hybridmentioning

confidence: 99%

Building the DREAM interactome

Rivas

Villar²,

González³

et al. 2011

Sci. China Life Sci.

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DREAM/calsenilin/KChIP3 is a calcium binding protein of the neuronal calcium sensor superfamily. DREAM interacts with DRE (downstream regulatory element) sites in the DNA to regulate transcription and with many proteins to exert specialized functions in different subcellular compartments. Work from different laboratories has identified a growing list of interacting proteins that constitutes the DREAM interactome. The knowledge of these interactions has greatly contributed to the understanding of the various physiological functions of DREAM. 1 DREAM, a multifunctional protein DREAM (Antagonist Modulator of DRE sites) was cloned in a functional screening of a cDNA library from human striatum as a transcriptional repressor able to form tetramers and bind to the DRE site in the proximal promoter of the human prodynorphin gene [1,2]. DREAM is expressed in brain, thyroid gland, immune system, heart and gonads and is one of four highly conserved members of the KChIP (potassium channel interacting protein) subfamily of neuronal calcium sensors [3,4]. DREAM, also known as calsenilin [5] or KChIP3 [3], is a calcium binding protein that contains three functional EF-hand motifs (Figure 1) and interacts with DRE (downstream regulatory element) sites in the DNA and with many proteins to exert specialized functions in different subcellular compartments [6]. Binding of calcium induces a structural change in DREAM that precludes binding to DNA and modifies the interaction with some proteins but not with others. For instance, Ca 2+ -bound DREAM does not interact with CREB [7] or with the PSD-95 protein [8], while the interaction of DREAM with presenilins [5], with potassium channels of the Kv4 class [3] or with the TSH receptor [9], is not affected by calcium.A key property of DREAM is the ability to form homomers or heterotetramers with other KChIP proteins, which results in different affinities for DNA binding to DRE sites proximal to the transcription start site, leading to transcriptional repression of target genes [2,4,10,11]. The DRE sequence was defined as the element responsible for basal and induced expression of the prodynorphin gene, encoding a protein involved in nociception as well as in learning and memory [12,13]. More recent studies, however, have shown that many other genes also contain DRE sites and are regulated by DREAM. For instance, DRE sites contribute to basal and induced expression of a number of immediate early transcription factors including c-fos, c-jun and ICER [2,4]. In addition to its regulation by calcium, binding of DREAM to DNA is hampered by its interaction with phosphoCREM [14], while interaction with other transcription

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“…Thus, under normal conditions, endogenous DREAM has a permissive effect on the early activation of a set of genes, some of which will be further activated by parallel pathways involving the nuclear calcium/calmodulin complex. Importantly, it has been shown that posttranslational modifications of DREAM, such as sumoylation or a change in the redox state, which are associated with increased nuclear localization and repressor capability, respectively (36,47), could render a DREAM protein with increased repressor activity to block to a greater extent activity-dependent learning and memory formation. In this scenario, it is tempting to speculate that changes in the posttranslational processing of DREAM could participate in the cognitive decline associated with aging or pathological conditions of the brain.…”

Section: Discussionmentioning

confidence: 99%

DREAM Controls the On/Off Switch of Specific Activity-Dependent Transcription Pathways

Mellström

Sahún

Ruiz‐Nuño

et al. 2014

Molecular and Cellular Biology

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h Changes in nuclear Ca 2؉ homeostasis activate specific gene expression programs and are central to the acquisition and storage of information in the brain. DREAM (downstream regulatory element antagonist modulator), also known as calsenilin/KChIP-3 (K ؉ channel interacting protein 3), is a Ca 2؉ -binding protein that binds DNA and represses transcription in a Ca 2؉ -dependent manner. To study the function of DREAM in the brain, we used transgenic mice expressing a Ca 2؉ -insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Using genome-wide analysis, we show that DREAM regulates the expression of specific activity-dependent transcription factors in the hippocampus, including Npas4, Nr4a1, Mef2c, JunB, and c-Fos. Furthermore, DREAM regulates its own expression, establishing an autoinhibitory feedback loop to terminate activity-dependent transcription. Ablation of DREAM does not modify activity-dependent transcription because of gene compensation by the other KChIP family members. The expression of daDREAM in the forebrain resulted in a complex phenotype characterized by loss of recurrent inhibition and enhanced long-term potentiation (LTP) in the dentate gyrus and impaired learning and memory. Our results indicate that DREAM is a major master switch transcription factor that regulates the on/off status of specific activitydependent gene expression programs that control synaptic plasticity, learning, and memory.A major challenge for neuroscience is to identify the regulatory molecules underpinning the storage of information in neurons. Activity-dependent gene expression underlies neuronal plasticity and adaptive responses to different environmental stimuli in the central nervous system (CNS) and is determinant in the formation and storage of memories. Diverse signaling pathways participate in these processes. Among them, changes in intracellular free calcium concentration are the most universal signal, and the final output, in terms of adapted gene expression, is given by a specific set of proteins that decode the calcium signal according to its frequency, subcellular location, and intensity (1-3). A nuclear tool kit of Ca 2ϩ -dependent effectors modifies the activity or the properties of specific transcription factors to regulate gene expression in response to the Ca 2ϩ signal (for reviews, see references 4 and 5). Despite extensive investigation, a detailed mechanistic description of Ca 2ϩ -dependent signaling in the expression of the late, transcription-dependent component of long-term potentiation (LTP) is far from been complete (reviewed in reference 6). Here, we examine the role of the Ca 2ϩ -dependent transcriptional repressor DREAM (downstream regulatory element antagonist modulator) in the control of activity-dependent transcription and the expression of LTP, as well as in learning and memory.The DREAM/calsenilin/KChIP-3 gene belongs to a group of four genes (encoding K ϩ channel interacting proteins 1 to 4 [KChIP-1 to -4]) that regulate the membrane expression and gating of Kv4 potassiu...

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Sumoylation regulates nuclear localization of repressor DREAM

Cited by 28 publications

References 40 publications

Ca2+-dependent Transcriptional Control of Ca2+ Homeostasis

Ca2+-dependent Transcriptional Control of Ca2+ Homeostasis

Building the DREAM interactome

DREAM Controls the On/Off Switch of Specific Activity-Dependent Transcription Pathways

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