Intron Retention Generates a Novel Id3 Isoform That Inhibits Vascular Lesion Formation

Forrest, Scott T.; Barringhaus, Kurt G.; Perlegas, Demetra; Hammarskjöld, Marie‐Louise; McNamara, Coleen A.

doi:10.1074/jbc.m404882200

Cited by 54 publications

(62 citation statements)

References 25 publications

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“…24 This isoform, in contrast to Id3, seems to attenuate growth of smooth muscle cell during vascular lesion formation by inducing apoptosis. 23,24 Unlike Id3 and Id3a, SOM1 and SOM3 are coexpressed in normal tissues and in primary human EC (Ting et al 6 and this study), but similar to Id3, they have opposing effects. Whereas Id proteins sequester basic helix-loop-helix factors, thereby preventing them from binding to DNA and activating transcription, 25 both SOM-isoforms are active transcription factors on their own.…”

Section: Discussionmentioning

confidence: 99%

“…Id3 can promote cell cycle entry and thereby induce smooth muscle cell proliferation by inhibiting p21 WAF1 and p16 INK4 transcription. 23 An alternatively spliced transcript translates into an isoform with a different C terminus (Id3a), which is not detected in normal rat carotid arteries, but abundantly expressed in the neointimal layer after balloon injury, like its human homolog Id3L in carotid atherosclerotic plaques. 24 This isoform, in contrast to Id3, seems to attenuate growth of smooth muscle cell during vascular lesion formation by inducing apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Two Isoforms of Sister-of-Mammalian Grainyhead Have Opposing Functions in Endothelial Cells and In Vivo

Haendeler

Mlynek²,

Büchner³

et al. 2013

ATVB

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Objective— Sister-of-Mammalian Grainyhead (SOM) is a member of the Grainyhead family of transcription factors. In humans, 3 isoforms are derived from differential first exon usage and alternative splicing and differ only in their N terminal domain. SOM2, the only variant also present in mouse, induces endothelial cell migration and protects against apoptosis. The functions of the human specific isoforms SOM1 and SOM3 have not yet been investigated. Therefore we wanted to elucidate their functions in endothelial cells. Approach and Results— Overexpression of SOM1 in primary human endothelial cells induced migration, phosphorylation of Akt1 and endothelial nitric oxide synthase, and protected against apoptosis, whereas SOM3 had opposite effects; isoform-specific knockdowns confirmed the disparate effects on apoptosis. After reporter assays demonstrated that both are active transcription factors, microarray analyses revealed that they induce different target genes, which could explain the different cellular effects. Overexpression of SOM3 in zebrafish embryos resulted in increased lethality and severe deformations, whereas SOM1 had no deleterious effect. Conclusions— Our data demonstrate that the splice variant–derived isoforms SOM1 and SOM3 induce opposing effects in primary human endothelial cells and in a whole animal model, most likely through the induction of different target genes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Two Isoforms of Sister-of-Mammalian Grainyhead Have Opposing Functions in Endothelial Cells and In Vivo

Haendeler

Mlynek²,

Büchner³

et al. 2013

ATVB

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“…One clearly documented example involves some of the members of the Id family of helix-loop-helix (HLH) transcription factors. Specifically, retention of the single small intron in the Id3 gene after vascular injury results in expression of an alternative protein isoform, which appears to function as a modulator of the protein expressed from the spliced RNA (Matsumura et al 2001;Forrest et al 2004). This may be particularly relevant, since a recent study demonstrated that deletion of the WT1(+KTS) isoform affected the expression of MASH1, an HLH transcription factor required for early neurogenesis (Wagner et al 2005).…”

Section: Discussionmentioning

confidence: 99%

The Wilms’ tumor 1 (WT1) gene (+KTS isoform) functions with a CTE to enhance translation from an unspliced RNA with a retained intron

Bor¹,

Swartz²,

Morrison³

et al. 2006

Genes Dev.

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The Wilms' tumor 1 (WT1) gene plays an important role in mammalian urogenital development, and dysregulation of this gene is observed in many human cancers. Alternative splicing of WT1 RNA leads to the expression of two major protein isoforms, WT1(+KTS) and WT1(−KTS). Whereas WT1(−KTS) acts as a transcriptional regulator, no clear function has been ascribed to WT1(+KTS), despite the fact that this protein is crucial for normal development. Here we show that WT1(+KTS) functions to enhance expression from RNA possessing a retained intron and containing either a cellular or viral constitutive transport element (CTE). WT1(+KTS) expression increases the levels of unspliced RNA containing a CTE and specifically promotes the association of this RNA with polyribosomes. These studies provide further support for links between different steps in RNA metabolism and for the existence of post-transcriptional operons.

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“…In vivo, Id3 expression is induced during vascular lesion formation in response to injury. 26,27,41 Herein, we provide evidence that elevated 12/15LO expression at baseline resulted in increased postinjury Id3 expression. Moreover, loss of Id3 attenuated the increased neointimal Ki-67-positive staining in the injured 12/15LO-tg animals, providing evidence that Id3 is essential for 12/15LO-induced vascular wall proliferation.…”

Section: Discussionmentioning

confidence: 88%

Increased 12/15-Lipoxygenase Enhances Cell Growth, Fibronectin Deposition, and Neointimal Formation in Response to Carotid Injury

Deliri

Meller

Kadakkal

et al. 2011

ATVB

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Objective-To determine whether increased 12/15-lipoxygenase (12/15LO) expression in vivo enhances neointimal formation in response to injury. Methods and Results-12/15LO expression in the vessel wall is increased in animal models of metabolic syndrome and diabetes mellitus. Increased expression of 12/15LO enhances cultured vascular smooth muscle cell (VSMC) proliferation, an effect mediated by the helix-loop-helix factor inhibitor of differentiation 3 (Id3). Carotid endothelial denudation was performed on apolipoprotein (Apo) E Ϫ/Ϫ , ApoE Ϫ/Ϫ /12/15LO Ϫ/Ϫ , C57BL/6, and 12/15LO-overexpressing transgenic mice. ApoE Ϫ/Ϫ /12/15LO Ϫ/Ϫ mice had attenuated and 12/15LO-overexpressing transgenic mice had enhanced neointimal formation compared with control mice. 12/15LO-overexpressing transgenic mice had greater postinjury carotid Id3 and Ki-67 expression, cell number, and fibronectin deposition compared with C57BL/6 mice. Loss of 12/15LO attenuated proliferation of cultured ApoE Ϫ/Ϫ VSMCs, whereas 12/15LO overexpression induced VSMC proliferation. Loss of Id3 enhanced immunoglobulin trascription factor (ITF)-2b binding to and activation of the p21 cip1 promoter and abrogated 12/15LO-induced VSMC proliferation. Conclusion-To our knowledge, these data are the first demonstration that increased expression of 12/15LO in the vessel wall enhances Id3-dependent cell proliferation, fibronectin deposition, and neointimal formation in response to injury. Key Words: vascular biology Ⅲ fibronectin Ⅲ helix-loop-helix motifs Ⅲ lipoxygenase Ⅲ neointima Ⅲ smooth muscle cell I ndividuals with type 2 diabetes mellitus have increased rates of restenosis after vascular interventional procedures. 1,2 Vascular smooth muscle cell (VSMC) proliferation and matrix production are key events in the process of neointimal formation (NIF) after percutaneous interventions. 3,4 Identifying the molecular mechanisms that mediate acceleration of these processes may provide important insight into strategies to attenuate restenosis in high-risk populations, such as those with type 2 diabetes.Previous studies have implicated 12/15-lipoxygenase (12/ 15LO) in the vascular response to injury. 12/15LO products of arachidonic acid, such as 12S-hydroxyeicosatetrenoic acid (HETE), 15S-HETE, and 13S-hydroperoxyoctadecadienoic acid (HPODE), are produced in VSMCs and have hypertrophic effects. 5,6 In vitro, 12/15LO inhibition attenuates hypertrophic effects of angiotensin II in VSMCs, mitogenic effects of cytokines, and chemotactic effects of platelet-derived growth factor. 5,7,8 Compared with VSMCs from C57BL/6 (BL-6) mice, VSMCs from 12/15LO-overexpressing transgenic (12/15LO-tg) mice grow faster, and VSMCs from 12/15LO Ϫ/Ϫ mice grow slower and display decreased S-phase entry in culture. 9,10 12/15LO and its products are increased in the vascular wall of animal models of atherosclerosis and injury-induced restenosis. 11 Compared with uninjured carotids, 12/15LO expression is significantly increased in rat carotids on day 12 after injury. 12 Moreover, pharmacological...

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Intron Retention Generates a Novel Id3 Isoform That Inhibits Vascular Lesion Formation

Cited by 54 publications

References 25 publications

Two Isoforms of Sister-of-Mammalian Grainyhead Have Opposing Functions in Endothelial Cells and In Vivo

Two Isoforms of Sister-of-Mammalian Grainyhead Have Opposing Functions in Endothelial Cells and In Vivo

The Wilms’ tumor 1 (WT1) gene (+KTS isoform) functions with a CTE to enhance translation from an unspliced RNA with a retained intron

Increased 12/15-Lipoxygenase Enhances Cell Growth, Fibronectin Deposition, and Neointimal Formation in Response to Carotid Injury

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