The N-terminal Set-β Protein Isoform Induces Neuronal Death

Trakhtenberg, Ephraim F.; Morkin, Melina I.; Patel, Kunal; Fernandez, Stephanie; Sang, Alan; Shaw, Peter X.; Liu, Xiongfei; Wang, Yan; Mlacker, Gregory M.; Gao, Han; Velmeshev, Dmitry; Dombrowski, Susan M.; Vitek, Michael P.; Goldberg, Jeffrey L.

doi:10.1074/jbc.m114.633883

Cited by 11 publications

(9 citation statements)

References 38 publications

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“…Half of postnatal RGCs also responded to 5HTR2C agonist in vitro , demonstrating that 5HTR2C is functional in at least a subset of RGCs during early development. Our RGC culture conditions are well‐established for maintaining RGCs health for at least several days (Corredor et al, ; Trakhtenberg et al, ; Trakhtenberg et al, ), arguing against the possibility that deterioration of cell health accounted for half of RGCs' failure to respond to 5HTR2C agonist. Although the 5HTR2C agonist WAY‐161503 used in these studies might have some affinity to the other 5HTR2A and ‐B isoforms, the lack of transcript expression of these isoforms in our RNA‐seq profiling (Table ) suggests that the effect was specifically attributable to the 5HTR2C isoform.…”

Section: Discussionsupporting

confidence: 69%

Serotonin receptor 2C regulates neurite growth and is necessary for normal retinal processing of visual information

Trakhtenberg

Pita-Thomas

Fernandez

et al. 2016

Developmental Neurobiology

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Serotonin (5HT) is present in a subpopulation of amacrine cells, which form synapses with retinal ganglion cells (RGCs), but little is known about the physiological role of retinal serotonergic circuitry. We found that the 5HT receptor 2C (5HTR2C) is upregulated in RGCs after birth. Amacrine cells generate 5HT and about half of RGCs respond to 5HTR2C agonism with calcium elevation. We found that there are on average 83 5HT+ amacrine cells randomly distributed across the adult mouse retina, all negative for choline acetyltransferase and 90% positive for tyrosine hydroxylase. We also investigated whether 5HTR2C and 5HTR5A affect RGC neurite growth. We found that both suppress neurite growth, and that RGCs from the 5HTR2C knockout (KO) mice grow longer neurites. Furthermore, 5HTR2C is subject to post-transcriptional editing, and we found that only the edited isoform's suppressive effect on neurite growth could be reversed by a 5HTR2C inverse agonist. Next, we investigated the physiological role of 5HTR2C in the retina, and found that 5HTR2C KO mice showed increased amplitude on pattern electroretinogram. Finally, RGC transcriptional profiling and pathways analysis suggested partial developmental compensation for 5HTR2C absence. Taken together, our findings demonstrate that 5HTR2C regulates neurite growth and RGC activity and is necessary for normal amplitude of RGC response to physiologic stimuli, and raise the hypothesis that these functions are modulated by a subset of 5HT+/ChAT-/TH+ amacrine cells as part of retinal serotonergic circuitry. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 419-437, 2017.

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Section: Discussionsupporting

confidence: 69%

Serotonin receptor 2C regulates neurite growth and is necessary for normal retinal processing of visual information

Trakhtenberg

Pita-Thomas

Fernandez

et al. 2016

Developmental Neurobiology

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“…SET downregulates CTNNB1 , the gene responsible for AD mental retardation type 19 (MIM# 615075; Almeida et al., ). SET is also a component of the “inhibitor of histone acetyltransferases” (INHAT) protein complex wherein it recognizes mono‐, di‐, or tri‐methylated histone H3K267 residues (Cervoni, Detich, Seo, Chakravarti, & Szyf, ; Karetsou et al., ; Kato, Okuwaki, & Nagata, ; Kim, Kim, Kim, Lee, & Seo, ; Seo et al., ; Trakhtenberg et al., , ). The complex represses transcription via preventing histone acetylation.…”

Section: Discussionmentioning

confidence: 99%

“…SET switches between an active and inactive state via nucleo‐cytoplasmic shuttling and dependent on its cellular localization and phosphorylation status, thereby either promoting or suppressing neurite growth (Lam, Anthony, & Hordijk, ; ten Klooster et al., ). In the cytoplasmic/membranous state, SET may promote axon growth by inhibiting PP2A, which has suppressive effects on neurogenesis (Qu et al., ; Trakhtenberg et al., and ). In early stages of neuronal development, nuclear SET negatively regulates neuronal differentiation by repressing transcription of differentiation markers such synapsin‐1, NFM, MAP1a and by regulating specific Krüppel‐like factors (Kim et al., ; Miyamoto‐Sato et al., ; Trakhtenberg et al., and ).…”

Section: Discussionmentioning

confidence: 99%

“…In the cytoplasmic/membranous state, SET may promote axon growth by inhibiting PP2A, which has suppressive effects on neurogenesis (Qu et al., ; Trakhtenberg et al., and ). In early stages of neuronal development, nuclear SET negatively regulates neuronal differentiation by repressing transcription of differentiation markers such synapsin‐1, NFM, MAP1a and by regulating specific Krüppel‐like factors (Kim et al., ; Miyamoto‐Sato et al., ; Trakhtenberg et al., and ). It modulates neuronal apoptosis via its cleavage by granzymes and asparaginyl endopeptidases (Liu et al., ; Madeira, Pommet, Prochiantz, & Allinquant, ).…”

Section: Discussionmentioning

confidence: 99%

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De novo mutations in theSETnuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability

et al. 2018

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The role of disturbed chromatin remodeling in the pathogenesis of intellectual disability (ID) is well established and illustrated by de novo mutations found in a plethora of genes encoding for proteins of the epigenetic regulatory machinery. We describe mutations in the "SET nuclear proto-oncogene" (SET), encoding a component of the "inhibitor of histone acetyltransferases" (INHAT) complex, involved in transcriptional silencing. Using whole exome sequencing, four patients were identified with de novo mutations in the SET gene. Additionally, an affected mother and child were detected who carried a frameshift variant in SET. Four patients were found in literature. The de novo mutations in patients affected all four known SET mRNA transcripts. LoF mutations in SET are exceedingly rare in the normal population and, if present, affect only one transcript. The pivotal role of SET in neurogenesis is evident from in vitro and animal models. SET interacts with numerous proteins involved in histone modification, including proteins encoded by known autosomal dominant ID genes, that is, EP300, CREBBP, SETBP1, KMT2A, RAC1, and CTCF. Our study identifies SET as a new component of epigenetic regulatory modules underlying human cognitive disorders, and as a first member of the Nucleosome Assembly Protein (NAP) family implicated in ID.

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“…PP2A is the major enzyme that accounts for 71 % of the total tau phosphatase activity [26], and the activity of PP2A is tightly regulated by the inhibitor protein SET/I2PP2A whose C-terminal region is responsible for the binding to PP2A sub-unit PP2Ac [16]. Inactivation of nuclear localization signal (NLS) in the Cterminal region or cleavage lead to N-and C-terminal peptides causes cytoplasm retention of SET/I2PP2A and leads to abnormal tau pathology and neuronal death [18,27]. Thus, studying regulation of SET promoter activity could provide new insights into the disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Regulation of SET Gene Expression by NFkB

Feng

Zhou

et al. 2016

Mol Neurobiol

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SET is elevated and mislocalized in the neuronal cytoplasm in brains of Alzheimer's disease (AD) and Down syndrome (DS) patients. Cytoplasm SET leads to inhibition of protein phosphatase 2A and is involved in the tau pathology. However, the regulation of SET gene expression remains elusive. In the present study, we cloned a 1399-bp segment of the 5' flanking region of the human SET gene and identified that the transcription start site (TSS) of SET transcript 1 is located at 123 bp upstream of the translation start site ATG in exon 1. Sequence analysis reveals several putative regulatory elements including NFkB, Sp1, and HSE. Luciferase assay and electrophoretic mobility shift assay (EMSA) identified a functional cis-acting NFkB-responsive element in the SET gene promoter. Overexpression and activation of NFkB upregulate transcription of SET isoform 1 but not isoform 2, indicating that the expression of these two isoforms is differentially regulated. The results demonstrate that NFkB plays an important role in regulation of the human SET gene expression. Our findings suggest that oxidative stress and inflammatory responses could result in abnormal SET gene expression, contributing to the tauopathy in AD pathogenesis.

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The N-terminal Set-β Protein Isoform Induces Neuronal Death

Cited by 11 publications

References 38 publications

Serotonin receptor 2C regulates neurite growth and is necessary for normal retinal processing of visual information

Serotonin receptor 2C regulates neurite growth and is necessary for normal retinal processing of visual information

De novo mutations in theSETnuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability

Regulation of SET Gene Expression by NFkB

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