Interferons and IRF-1 Induce Expression of the Survival Motor Neuron (SMN) Genes

Baron-Delage, S; Abadie, A; Echaniz‐Laguna, Andoni; Melki, Judith; Beretta, Laura

doi:10.1007/bf03401830

Cited by 51 publications

(25 citation statements)

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“…In the present study, compounds such as forskolin and dibutyryl cAMP were shown to increase the expression of the SMN2 gene. Interferon ␤ and ␥ have been shown to bind to an ISRE element in the SMN promoter and activate SMN expression (31). In some cases, the activation results in a greater increase in the exon⌬7SMN isoform.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of SMN2 in all SMA patients, the ability of more copies of SMN2 to modify the SMA phenotype, and the rescue of SMA mice by multiple copies of SMN2 make it an attractive therapeutic candidate. Molecules capable of inducing SMN2 expression (30,31) or altering the splicing of SMN2 such that more full-length SMN transcript is produced have been identified (32)(33)(34)(35)(36)(37). At the present time, there is limited information on the mode of action of these compounds as well as the protein complexes that interact with the SMN promoter.…”

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confidence: 99%

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Identification of a Novel Cyclic AMP-response Element (CRE-II) and the Role of CREB-1 in the cAMP-induced Expression of the Survival Motor Neuron (SMN) Gene

Majumder

Varadharaj

Ghoshal

et al. 2004

Journal of Biological Chemistry

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Spinal muscular atrophy, an autosomal recessive disorder, is caused by loss of the SMN1 (survival motor neuron) gene while retaining the SMN2 gene. SMN1 produces a majority of full-length SMN transcript, whereas SMN2 generates mostly an isoform lacking exon 7. Here, we demonstrate a novel cAMP-response element, CRE-II, in the SMN promoter that interacts with the cAMP-response element-binding (CREB) family of proteins. In vitro DNase I protection analysis and in vivo genomic footprinting of the SMN promoter using the brain and liver nuclei from SMN2 transgenic mice revealed footprinting at the CRE-II site. Site-directed mutation of the CRE-II element caused a marked reduction in the SMN promoter activity revealed by transient transfection assay. Activation of the cAMP pathway by dibutyryl cAMP (0.5 mM) alone or in combination with forskolin (20 M) caused a 2-5-fold increase in the SMN promoter activity but had no effect on the CRE-II mutated promoter. Electrophoretic mobility shift assay and a UV-induced DNA-protein crosslinking experiment confirmed that CREB1 binds specifically to the CRE-II site. Transient overexpression of CREB1 protein resulted in a 4-fold increase of the SMN promoter activity. Intraperitoneal injection of epinephrine in mice expressing two copies of the human SMN2 gene resulted in a 2-fold increase in full-length SMN transcript in the liver. Combined treatment with dibutyryl cAMP and forskolin significantly increased the level of both the full-length and exon 7-deleted SMN (exon⌬7SMN) transcript in primary hepatocytes from mice expressing two copies of human SMN2 gene. Similar treatments of type I spinal muscular atrophy mouse and human fibroblasts as well as HeLa cells resulted in an augmented level of SMN transcript. These findings suggest that the CRE-II site in SMN promoter positively regulates the expression of the SMN gene, and treatment with cAMP-elevating agents increases expression of both the full-length and exon⌬7SMN transcript.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Identification of a Novel Cyclic AMP-response Element (CRE-II) and the Role of CREB-1 in the cAMP-induced Expression of the Survival Motor Neuron (SMN) Gene

Majumder

Varadharaj

Ghoshal

et al. 2004

Journal of Biological Chemistry

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“…Interferon-stimulated gene expression inducing SMN mRNA has been reported. 15 Moreover, aclarubicin, a tetracyclin derivative, has been shown to increase fl SMN production by modifying the isoform ratio. 16 However, the side effects of interferon treatment and the toxicity of aclarubicin advice against the use of these drugs for therapy of young SMA patients.…”

Section: Introductionmentioning

confidence: 99%

Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy

et al. 2003

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Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, characterized by degeneration of the anterior horn cells of the spinal cord. SMA presents with a highly variable phenotype ranging from very severe to mild (type I-III). No cure for SMA is available at present. All forms of SMA are caused by homozygous loss of the functional survival motor neuron (SMN1) gene. However, all patients have one or more copies of the SMN2 gene, nearly identical to SMN1. Both genes encode the SMN protein but the level produced by SMN2 is insufficient to protect from disease. Increasing SMN2 gene expression could be of considerable therapeutic importance. The aim of this study was to assess whether SMN2 gene expression can be increased by 4-phenylbutyrate (PBA). Fibroblast cell cultures from 16 SMA patients affected by different clinical severities were treated with PBA, and full-length SMN2 transcripts were measured by real-time PCR. In all cell cultures, except one, PBA treatment caused an increase in full-length SMN2 transcripts, ranging from 50 to 160% in type I and from 80 to 400% in type II and III cultures. PBA was found also effective in enhancing SMN protein levels and the number of SMN-containing nuclear structures (gems). These data show that SMN expression is considerably increased by PBA, and suggest that the compound, owing also to its favorable pharmacological properties, could be a good candidate for the treatment of SMA.

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“…The consequence of differential transcription start site usage remains unclear. A small number of transcription factors regulating the core SMN promoter have been identified including IFNg and IFNb [Baron-Delage et al, 2000], the CRE binding protein CREB-1 [Majumder et al, 2004] as well Sp and Ets family members [Rouget et al, 2005]. Finally, core SMN promoter activity can be modulated by a number of upstream enhancer and silencer elements [Echaniz-Laguna et al, 1999;Monani et al, 1999;Boda et al, 2004]; however, aside from their location, little else is known about their function.…”

Section: Are Smn1 and Smn2 As Identical As They Appear To Be?mentioning

confidence: 99%

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

Tiziano

Melki

Simard

2013

American J of Med Genetics Pt A

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Spinal muscular atrophy (SMA) is an autosomal recessive, lower motor neuron disease. Clinical heterogeneity is pervasive: three infantile (type I-III) and one adult-onset (type IV) forms are recognized. Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA. Most forms of SMA are caused by mutations of the survival motor neuron (SMN1) gene. A second gene that is 99% identical to SMN1 (SMN2) is located in the same region. The only functionally relevant difference between the two genes identified to date is a C ! T transition in exon 7 of SMN2, which determines an alternative spliced isoform that predominantly excludes exon 7. Thus, SMN2 genes do not produce sufficient full length SMN protein to prevent the onset of the disease. Since the identification of the causative mutation, biomedical research of SMA has progressed by leaps and bounds: from clues on the function of SMN protein, to the development of different models of the disease, to the identification of potential treatments, some of which are currently in human trials. The aim of this review is to elucidate the current state of knowledge, emphasizing how close we are to the solution of the puzzle that is SMA, and, more importantly, to highlight the missing pieces of this puzzle. Filling in these gaps in our knowledge will likely accelerate the development and delivery of efficient treatments for SMA patients and be a prerequisite towards achieving our final goal, the cure of SMA. Ó 2013 Wiley Periodicals, Inc. Key words: spinal muscular atrophy; SMN INTRODUCTIONSpinal muscular atrophy (SMA) is a lower motor neuron disease that predominantly affects spinal cord anterior horn cells and brain stem nuclei [Dubowitz, 1995; reviewed in Hamilton and Gillingwater, 2013]. Alpha-motor neuron cell degeneration results in progressive, symmetrical skeletal muscle atrophy of limbs and trunk, spreading proximal to distal [Crawford and Pardo, 1996]. Clinical heterogeneity is pervasive: based on the age of onset and on the maximum motor achievement of patients, three infantile (type I-III) and one adult-onset (type IV) forms are commonly recognized. Classification criteria are summarized in Table I. However, this rigid classification does not accurately depict the range of SMA clinical phenotypes, which display a more continuous spectrum, ranging from prenatal onset to almost asymptomatic patients. SMA is a common autosomal recessive disorder (incidence is $1 in 6,000 in most ethnicities). Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA [Crawford and Pardo, 1996;Prior, 2010].Most forms of SMA are caused by mutations in the survival motor neuron (SMN) gene, which was isolated in 1995 in chromosome 5q13 harboring a segmental duplication [Lefebvre et al., 1995]. Mutations in SMN1 are responsible for the four forms of SMA [Wirth, 2000;Alías et al., 2009]. A second gene that is 99% identical to SMN1, the SMN2 gene, is located in the same region [Le...

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Interferons and IRF-1 Induce Expression of the Survival Motor Neuron (SMN) Genes

Cited by 51 publications

References 30 publications

Identification of a Novel Cyclic AMP-response Element (CRE-II) and the Role of CREB-1 in the cAMP-induced Expression of the Survival Motor Neuron (SMN) Gene

Identification of a Novel Cyclic AMP-response Element (CRE-II) and the Role of CREB-1 in the cAMP-induced Expression of the Survival Motor Neuron (SMN) Gene

Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

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