A mechanism of AP-1 suppression through interaction of c-Fos with lamin A/C

Ivorra, Carmen; Kubicek, Markus; González, José María González; Sanz-González, Silvia M.; Álvarez-Barrientos, Alberto; O’Connor, José-Enrique; Burke, Brian; Andrés, Vicente

doi:10.1101/gad.349506

Cited by 200 publications

(191 citation statements)

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“…Lamin A/C binds c-Fos, an interaction that correlates with decreased AP-1 DNA binding and transcriptional activation (45). Here the negative effect on gene expression is attributed to lamin A/C-mediated c-Fos sequestration, which reduces c-Fos/c-Jun heterodimer formation.…”

Section: Discussionmentioning

confidence: 97%

Inner Nuclear Membrane Proteins Asi1, Asi2, and Asi3 Function in Concert to Maintain the Latent Properties of Transcription Factors Stp1 and Stp2

Zargari

Boban

Heessen

et al. 2007

Journal of Biological Chemistry

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In yeast the homologous transcription factors Stp1 and Stp2 are synthesized as latent cytoplasmic precursors with N-terminal regulatory domains. In response to extracellular amino acids the regulatory domains are endoproteolytically excised by the plasma membrane-localized SPS sensor. The processed forms of Stp1 and Stp2 efficiently enter the nucleus and induce expression of amino acid permease genes. We recently reported that the inner nuclear membrane protein Asi1 is required to prevent unprocessed forms of Stp1 and Stp2, which ectopically enter the nucleus, from binding SPS sensor-regulated promoters. Here we show that Asi3, an Asi1 homolog, and Asi2 are integral proteins of the inner nuclear membrane that function in concert with Asi1. In cells lacking any of the three Asi proteins, unprocessed full-length forms of Stp1 and Stp2 constitutively induce SPS sensor-regulated genes. Our results demonstrate that the Asi proteins ensure the fidelity of SPS sensor signaling by maintaining the dormant, or repressed state, of gene expression in the absence of inducing signals. This study documents additional components of a novel mechanism controlling transcription in eukaryotic cells.In eukaryotes the nucleoplasm and cytoplasm are separated by the nuclear envelope. The nuclear envelope consists of two closely aligned bilayers, the inner and outer membranes, each with a unique set of resident proteins. The two nuclear membranes are joined at nuclear pore complexes, which function as channels that provide selective entry and exit routes across the nuclear envelope. Aside from rather detailed knowledge regarding the structure of nuclear pores, there is markedly little known regarding non-pore nuclear proteins (1). However, accumulating data indicate that nuclear envelope proteins participate in a variety of important processes including maintenance of nuclear architecture, chromatin organization, signaling, and gene expression (1-3). Significantly, mutations in genes encoding nuclear envelope proteins are linked to at least 15 inherited human diseases and syndromes (4, 5).In mammalian cells, nuclear lamins are involved in an extensive network of protein-protein interactions, including inner nuclear membrane proteins and transcriptional regulators, some of which bind DNA (3, 6). Although yeast cells lack lamin homologs (7), processes associated with the inner nuclear membrane have been shown to influence patterns of gene expression. For example, although silencing is not obligatorily linked to perinuclear anchoring (8), recruitment of chromatin to the nuclear periphery can facilitate gene repression (9). Evidence obtained using genome-wide approaches suggest that transcriptionally active regions of chromosomes localize to nuclear pore complexes (10, 11). Consistently, a number of actively expressed genes have been found to interact with the nucleoporin Nup2; the interactions occur at the promoter region of genes and appear to correlate with early events of gene expression (12, 13). Together findings in yeast and metazoan...

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Section: Discussionmentioning

confidence: 97%

Inner Nuclear Membrane Proteins Asi1, Asi2, and Asi3 Function in Concert to Maintain the Latent Properties of Transcription Factors Stp1 and Stp2

Zargari

Boban

Heessen

et al. 2007

Journal of Biological Chemistry

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“…Interestingly it has been reported that c-fos is sequestered in the nuclear envelope in a Lamin A/Cdependent manner, which effectively reduces AP-1 factor DNA binding activity. 33 It is tempting to speculate that continued AP-1-mediated transcription in the nuclear remnants is necessary for the increased BMP2 expression; 34 and that parakeratosis itself can alter keratinocyte terminal differentiation.…”

Section: Discussionmentioning

confidence: 99%

AKT1-mediated Lamin A/C degradation is required for nuclear degradation and normal epidermal terminal differentiation

Naeem¹,

Zhu²,

Di³

et al. 2015

Cell Death Differ

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Nuclear degradation is a key stage in keratinocyte terminal differentiation and the formation of the cornified envelope that comprises the majority of epidermal barrier function. Parakeratosis, the retention of nuclear material in the cornified layer of the epidermis, is a common histological observation in many skin diseases, notably in atopic dermatitis and psoriasis. Keratinocyte nuclear degradation is not well characterised, and it is unclear whether the retained nuclei contribute to the altered epidermal differentiation seen in eczema and psoriasis. Loss of AKT1 function strongly correlated with parakeratosis both in eczema samples and in organotypic culture models. Although levels of DNAses, including DNase1L2, were unchanged, proteomic analysis revealed an increase in Lamin A/C. AKT phosphorylates Lamin A/C, targeting it for degradation. Consistent with this, Lamin A/C degradation was inhibited and Lamin A/C was observed in the cornified layer of AKT1 knockdown organotypic cultures, surrounding retained nuclear material. Using AKT-phosphorylation-dead Lamin A constructs we show that the retention of nuclear material is sufficient to cause profound changes in epidermal terminal differentiation, specifically a reduction in Loricrin, Keratin 1, Keratin 10, and filaggrin expression. We show that preventing nuclear degradation upregulates BMP2 expression and SMAD1 signalling. Consistent with these data, we observe both parakeratosis and evidence of increased SMAD1 signalling in atopic dermatitis. We therefore present a model that, in the absence of AKT1-mediated Lamin A/C degradation, DNA degradation processes, such as those mediated by DNAse 1L2, are prevented, leading to parakeratosis and changes in epidermal differentiation. Nuclear degradation is a key stage in keratinocyte terminal differentiation and the formation of the cornified envelope that comprises the majority of epidermal barrier function. [1][2][3] Parakeratosis, the retention of nuclear material in the cornified layer of the epidermis, is a common histological observation in many skin diseases, but most notably in the epidermal barrierdefective diseases eczema and psoriasis. 4,5 Mechanisms of nuclear degradation in the epidermis have not yet been well characterised and it is not known whether the retained nuclei contribute to the altered epidermal differentiation programmes seen in these skin diseases. 6,7 It is surprising that, for such a critical component of epidermal terminal differentiation, relatively few molecular mechanisms inducing parakeratosis have been investigated. The caspase-14 knockout mouse develops parakeratotic plaques upon chemical barrier disruption 8 and has subtle defects in epidermal terminal differentiation, including filaggrin processing, 9 whereas the DNAse 1L2 knockout mouse showed constitutive nuclear retention in hair and nails, which led to structural abnormalities in the hair shaft. 10,11 Parakeratosis also occurs during wound healing. 12 Nuclei are retained in the scab of healing wounds, and this correlates with...

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“…However, as part of the inner nuclear membrane, lamin A/C possesses additional properties such as interaction with transcription factors [3], distinct from other structural proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Because lamin A/C sequesters cFos at the nuclear envelope of fibroblasts and suppresses the DNA binding activity of transcription activator protein-1 (AP-1) by affecting cFos and cJun dimerization [3], reduced levels of lamin protein could have consequences on downstream transcription. If AV nodal myocytes, like other excitable neural cells, are particularly sensitive to AP-1 mediated transcriptional regulation, including caspase activation and stress-induced apoptosis [41], mutations that reduce lamin A/C levels could activate pro-cell death signals selectively in these specialized myocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Lamin A and C are widely expressed intermediate filament proteins within the inner nuclear membrane(1) where they provide mechanical support (2) and interact with other proteins, including tissue-specific transcription factors (3). Mutations in the human lamin A/C (LMNA) gene cause 16 different diseases with considerable clinical variability, ranging from cardiac and skeletal myopathies to lipodystrophy, peripheral neuropathy, and premature aging(4), (5).…”

Section: Introductionmentioning

confidence: 99%

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Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

Wolf

Wang

Alcalai

et al. 2008

Journal of Molecular and Cellular Cardiology

153

147

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Mutations in the lamin A/C (LMNA) gene, which encodes nuclear membrane proteins, cause a variety of human conditions including dilated cardiomyopathy (DCM) with associated cardiac conduction system disease. To investigate mechanisms responsible for electrophysiologic and myocardial phenotypes caused by dominant human LMNA mutations, we performed longitudinal evaluations in heterozygous Lmna +/-mice. Despite one normal allele, Lmna +/-mice had 50% of normal cardiac lamin A/C levels and developed cardiac abnormalities. Conduction system function was normal in neonatal Lmna +/-mice but by 4 weeks of age AV nodal myocytes had abnormally shaped nuclei and active apoptosis. Telemetric and in vivo electrophysiologic studies in 10 week-old Lmna +/-mice showed atrioventricular (AV) conduction defects and both atrial and ventricular arrhythmias, analogous to those observed in humans with heterozygous LMNA mutations. Isolated myocytes from 12-month old Lmna +/-mice exhibited impaired contractility. In vivo cardiac studies of aged Lmna +/-mice revealed DCM; in some mice this occurred without Contact address: Charles I. Berul, M.D., Department of Cardiology -Children's Hospital, 300 Longwood Ave., Boston, MA 02115 USA, Phone: 617 355-6432, Fax: 617 566-5671, charles.berul@cardio.chboston.org. * These authors contributed equally to this publication. Disclosures: NonePublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public AccessAuthor Manuscript J Mol Cell Cardiol. Author manuscript; available in PMC 2010 December 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript overt conduction system disease. However, neither histopathology nor serum CK levels indicated skeletal muscle pathology. These data demonstrate cardiac pathology due to heterozygous Lmna mutations reflecting a 50% reduction in lamin protein levels. Lamin haploinsufficiency caused early-onset programmed cell death of AV nodal myocytes and progressive electrophysiologic disease. While lamin haploinsufficiency was better tolerated by non-conducting myocytes, ultimately these too succumbed to diminished lamin levels leading to dilated cardiomyopathy, which presumably arose independently from conduction system disease.

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A mechanism of AP-1 suppression through interaction of c-Fos with lamin A/C

Cited by 200 publications

References 50 publications

Inner Nuclear Membrane Proteins Asi1, Asi2, and Asi3 Function in Concert to Maintain the Latent Properties of Transcription Factors Stp1 and Stp2

Inner Nuclear Membrane Proteins Asi1, Asi2, and Asi3 Function in Concert to Maintain the Latent Properties of Transcription Factors Stp1 and Stp2

AKT1-mediated Lamin A/C degradation is required for nuclear degradation and normal epidermal terminal differentiation

Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

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