scholarly journals Lamin B1 fluctuations have differential effects on cellular proliferation and senescence

2013 ◽  
Vol 200 (5) ◽  
pp. 605-617 ◽  
Author(s):  
Oliver Dreesen ◽  
Alexandre Chojnowski ◽  
Peh Fern Ong ◽  
Tian Yun Zhao ◽  
John E. Common ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Nuclear Lamina ◽  
Dermal Fibroblasts ◽  
Premature Aging ◽  
Simultaneous Reduction ◽  
Messenger Ribonucleic Acid ◽  
Rna Translation ◽  
Protein Levels ◽  
Lamin B1 ◽  
Premature Aging Syndrome

The nuclear lamina consists of A- and B-type lamins. Mutations in LMNA cause many human diseases, including progeria, a premature aging syndrome, whereas LMNB1 duplication causes adult-onset autosomal dominant leukodystrophy (ADLD). LMNB1 is reduced in cells from progeria patients, but the significance of this reduction is unclear. In this paper, we show that LMNB1 protein levels decline in senescent human dermal fibroblasts and keratinocytes, mediated by reduced transcription and inhibition of LMNB1 messenger ribonucleic acid (RNA) translation by miRNA-23a. This reduction is also observed in chronologically aged human skin tissue. To determine whether altered LMNB1 levels cause senescence, we either increased or reduced LMNB1. Both LMNB1 depletion and overexpression inhibited proliferation, but only LMNB1 overexpression induced senescence, which was prevented by telomerase expression or inactivation of p53. This phenotype was exacerbated by a simultaneous reduction of LMNA/C. Our results demonstrate that altering LMNB1 levels inhibits proliferation and are relevant to understanding the molecular pathology of ADLD.

scholarly journals Concentration-dependent lamin assembly and its roles in the localization of other nuclear proteins

2014 ◽  
Vol 25 (8) ◽  
pp. 1287-1297 ◽  
Author(s):  
Yuxuan Guo ◽  
Youngjo Kim ◽  
Takeshi Shimi ◽  
Robert D. Goldman ◽  
Yixian Zheng
Keyword(s):  
Nuclear Lamina ◽  
Nuclear Pore ◽  
Lamin A ◽  
Nuclear Pore Complexes ◽  
Developmental Defects ◽  
Protein Levels ◽  
Lamin B1 ◽  
Mouse Cells ◽  
Pore Complexes ◽  
And Function

The nuclear lamina (NL) consists of lamin polymers and proteins that bind to the polymers. Disruption of NL proteins such as lamin and emerin leads to developmental defects and human diseases. However, the expression of multiple lamins, including lamin-A/C, lamin-B1, and lamin-B2, in mammals has made it difficult to study the assembly and function of the NL. Consequently, it has been unclear whether different lamins depend on one another for proper NL assembly and which NL functions are shared by all lamins or are specific to one lamin. Using mouse cells deleted of all or different combinations of lamins, we demonstrate that the assembly of each lamin into the NL depends primarily on the lamin concentration present in the nucleus. When expressed at sufficiently high levels, each lamin alone can assemble into an evenly organized NL, which is in turn sufficient to ensure the even distribution of the nuclear pore complexes. By contrast, only lamin-A can ensure the localization of emerin within the NL. Thus, when investigating the role of the NL in development and disease, it is critical to determine the protein levels of relevant lamins and the intricate shared or specific lamin functions in the tissue of interest.

scholarly journals Protein sequestration at the nuclear periphery as a potential regulatory mechanism in premature aging

2017 ◽  
Vol 217 (1) ◽  
pp. 21-37 ◽  
Author(s):  
Leonid Serebryannyy ◽  
Tom Misteli
Keyword(s):  
Nuclear Membrane ◽  
Aging Process ◽  
Regulatory Mechanism ◽  
Biological Process ◽  
Nuclear Periphery ◽  
Nuclear Lamina ◽  
Premature Aging ◽  
Molecular Changes ◽  
Fundamental Biological Process ◽  
Premature Aging Syndrome

Despite the extensive description of numerous molecular changes associated with aging, insights into the driver mechanisms of this fundamental biological process are limited. Based on observations in the premature aging syndrome Hutchinson–Gilford progeria, we explore the possibility that protein regulation at the inner nuclear membrane and the nuclear lamina contributes to the aging process. In support, sequestration of nucleoplasmic proteins to the periphery impacts cell stemness, the response to cytotoxicity, proliferation, changes in chromatin state, and telomere stability. These observations point to the nuclear periphery as a central regulator of the aging phenotype.

scholarly journals Lamin B1 acetylation slows the G1 to S cell cycle transition through inhibition of DNA repair

2021 ◽  
Author(s):  
Laura A Murray-Nerger ◽  
Joshua L Justice ◽  
Pranav Rekapalli ◽  
Josiah E Hutton ◽  
Ileana M Cristea
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Posttranslational Modifications ◽  
Cell Cycle Progression ◽  
Nuclear Periphery ◽  
Virus Production ◽  
Nuclear Lamina ◽  
Regulatory Function ◽  
Herpesvirus Type ◽  
Lamin B1

Abstract The integrity and regulation of the nuclear lamina is essential for nuclear organization and chromatin stability, with its dysregulation being linked to laminopathy diseases and cancer. Although numerous posttranslational modifications have been identified on lamins, few have been ascribed a regulatory function. Here, we establish that lamin B1 (LMNB1) acetylation at K134 is a molecular toggle that controls nuclear periphery stability, cell cycle progression, and DNA repair. LMNB1 acetylation prevents lamina disruption during herpesvirus type 1 (HSV-1) infection, thereby inhibiting virus production. We also demonstrate the broad impact of this site on laminar processes in uninfected cells. LMNB1 acetylation negatively regulates canonical nonhomologous end joining by impairing the recruitment of 53BP1 to damaged DNA. This defect causes a delay in DNA damage resolution and a persistent activation of the G1/S checkpoint. Altogether, we reveal LMNB1 acetylation as a mechanism for controlling DNA repair pathway choice and stabilizing the nuclear periphery.

scholarly journals IL6 sensitizes prostate cancer to the antiproliferative effect of IFNα2 through IRF9

2013 ◽  
Vol 20 (5) ◽  
pp. 677-689 ◽  
Author(s):  
Holger H H Erb ◽  
Regina V Langlechner ◽  
Patrizia L Moser ◽  
Florian Handle ◽  
Tineke Casneuf ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Tissue Expression ◽  
Type I ◽  
Regulatory Factor ◽  
Quantitative Real Time Pcr ◽  
Antiproliferative Effects ◽  
Protein Levels

Development and progression of prostate cancer (PCa) are associated with chronic inflammation. The cytokine interleukin 6 (IL6) can influence progression, differentiation, survival, and angiogenesis of PCa. To identify novel pathways that are triggered by IL6, we performed a gene expression profiling of two PCa cell lines, LNCaP and MDA PCa 2b, treated with 5 ng/ml IL6. Interferon (IFN) regulatory factor 9 (IRF9) was identified as one of the most prevalent IL6-regulated genes in both cell lines. IRF9 is a mediator of type I IFN signaling and acts together with STAT1 and 2 to activate transcription of IFN-responsive genes. The IL6 regulation of IRF9 was confirmed at mRNA and protein levels by quantitative real-time PCR and western blot respectively in both cell lines and could be blocked by the anti-IL6 antibody Siltuximab. Three PCa cell lines, PC3, Du-145, and LNCaP-IL6+, with an autocrine IL6 loop displayed high expression of IRF9. A tissue microarray with 36 PCa tissues showed that IRF9 protein expression is moderately elevated in malignant areas and positively correlates with the tissue expression of IL6. Downregulation and overexpression of IRF9 provided evidence for an IFN-independent role of IRF9 in cellular proliferation of different PCa cell lines. Furthermore, expression of IRF9 was essential to mediate the antiproliferative effects of IFNα2. We concluded that IL6 is an inducer of IRF9 expression in PCa and a sensitizer for the antiproliferative effects of IFNα2.

scholarly journals Podiatric complications during a premature aging syndrome: Rare case

2016 ◽  
Vol 59 ◽  
pp. e28-e29
Author(s):  
Siham Zahi ◽  
Laila Mahir ◽  
Soumia Meftah ◽  
Fatima Lmidmani ◽  
Abdellatif El fatimi
Keyword(s):  
Rare Case ◽  
Premature Aging ◽  
Premature Aging Syndrome

scholarly journals Lamin B1 and lamin B2 are long-lived proteins with distinct functions in retinal development

2016 ◽  
Vol 27 (12) ◽  
pp. 1928-1937 ◽  
Author(s):  
David Razafsky ◽  
Candace Ward ◽  
Chloe Potter ◽  
Wanqiu Zhu ◽  
Yunlu Xue ◽  
...  
Keyword(s):  
Nuclear Lamina ◽  
Building Blocks ◽  
Postnatal Life ◽  
Cone Photoreceptors ◽  
Obvious Effect ◽  
Lamin B1 ◽  
Embryonic Neurogenesis ◽  
And Function ◽  
Embryonic Retina ◽  
Rod And Cone Photoreceptors

Lamin B1 and lamin B2 are essential building blocks of the nuclear lamina, a filamentous meshwork lining the nucleoplasmic side of the inner nuclear membrane. Deficiencies in lamin B1 and lamin B2 impair neurodevelopment, but distinct functions for the two proteins in the development and homeostasis of the CNS have been elusive. Here we show that embryonic depletion of lamin B1 in retinal progenitors and postmitotic neurons affects nuclear integrity, leads to the collapse of the laminB2 meshwork, impairs neuronal survival, and markedly reduces the cellularity of adult retinas. In stark contrast, a deficiency of lamin B2 in the embryonic retina has no obvious effect on lamin B1 localization or nuclear integrity in embryonic retinas, suggesting that lamin B1, but not lamin B2, is strictly required for nucleokinesis during embryonic neurogenesis. However, the absence of lamin B2 prevents proper lamination of adult retinal neurons, impairs synaptogenesis, and reduces cone photoreceptor survival. We also show that lamin B1 and lamin B2 are extremely long-lived proteins in rod and cone photoreceptors. OF interest, a complete absence of both proteins during postnatal life has little or no effect on the survival and function of cone photoreceptors.

Abstract 2681: Mutations in Smooth Muscle-Specific Contractile Proteins Cause Familial Thoracic Aortic Aneurysms and Dissections and Lead to Increased IGF-1 Expression

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Christina L Papke ◽  
Hariyadarshi Pannu ◽  
Dong-Chuan Guo ◽  
Nili Avidan ◽  
Van Tran-Fadulu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Contractile Proteins ◽  
Dermal Fibroblasts ◽  
Aortic Aneurysms ◽  
Trophic Factors ◽  
Aortic Tissue ◽  
Thoracic Aortic Aneurysms ◽  
Protein Levels ◽  
Tgf Β1

Aortic aneurysms and dissections are the most common disorders affecting the aorta, and are a major cause of morbidity and mortality in the United States. Familial thoracic aortic aneurysms and dissections (FTAAD) are inherited in an autosomal dominant manner with variable expression and decreased penetrance. The disorder is genetically heterogeneous with four loci and three genes identified. Mutations in either TGFBR2 , encoding the transforming growth factor β (TGF-β) type II receptor, or MYH11 , encoding the smooth muscle cell (SMC)-specific β-myosin heavy chain, were previously found to cause FTAAD. Recently, positional cloning identified smooth muscle α-actin ( ACTA2 ) mutations as a novel cause in 10% of FTAAD. Mutations in ACTC and MYH7 cause hypertrophic cardiomyopathy (HCM), characterized by myocyte disarray and upregulation of mitotic and trophic factors. Histologic examination of aortic tissue from patients with ACTA2 (n = 6) and MYH11 (n = 2) mutations revealed SMC disarray in the aortic media similar to that seen in HCM. Furthermore, we hypothesized that mutations in ACTA2 and MYH11 cause a similar increase of mitotic and trophic factors in SMCs. The expression of two factors known to be increased in HCM, TGF-β1 and insulin-like growth factor 1 (IGF-1), were analyzed in patients’ aortic SMCs and dermal myofibroblasts. No changes in TGF-β1 were found; however, both mRNA, as measured by Q-PCR (p<0.05), and protein levels, as assessed by immunostaining, of IGF-1 were markedly increased in MYH11 and two ACTA2 mutant SMCs and aortic tissue compared with control SMCs and tissue. Differentiation of dermal fibroblasts into myofibroblasts was accomplished using TGF-β1 treatment; myofibroblast differentiation was confirmed by assessing α-actin mRNA and protein levels in untreated vs. TGF-β1-treated fibroblasts. Upon differentiation, patients’ myofibroblasts (n = 3) demonstrated increased IGF-1 expression compared with controls (p<0.05), similar to the increased IGF-1 expression by SMCs. In conclusion, IGF-1 secretion is increased in response to defects in SMC contractile proteins in SMCs and myofibroblasts. Future studies will clarify the role of IGF-1 in FTAAD and identify the pathways leading to increased IGF-1 expression.

scholarly journals Ten Representative Saponins on Tissue Factor Expression in Human Monocytes: Structure–Activity Relationships and Molecular Docking

2020 ◽  
Vol 15 (3) ◽  
pp. 1934578X2091368
Author(s):  
Yongjiang Zeng ◽  
Xuhua He ◽  
Wenwen Jiang ◽  
Junping Kou ◽  
Boyang Yu
Keyword(s):  
Cardiovascular Disease ◽  
Molecular Docking ◽  
Tissue Factor ◽  
Inhibitory Effect ◽  
Coagulation Cascade ◽  
Human Monocytes ◽  
Messenger Ribonucleic Acid ◽  
Structure Activity Relationships ◽  
Protein Levels ◽  
Structure Activity

Saponins have significant bioactivities in treating cardiovascular disease. Whereas there is a lack of in-depth knowledge about how saponins prevent cardiovascular disease. Tissue factor (TF) is the major initiator of the coagulation cascade and plays an important role in hemostasis and thrombosis. However structure–activity relationships (SARs) of saponins inhibiting TF activity have not been discussed in detail at present. To further clarify the relationships between saponins and TF, in this study, 10 representative saponins were selected to study the inhibitory effect on TF procoagulant activity of monocytes by an improved chromogenic substrate method, and the possible SARs were preliminarily analyzed. Furthermore, molecular docking analysis suggested that 4 representative saponins had a good affinity with TF/FVIIa. In addition, a representative saponin, ruscogenin, decreased both messenger ribonucleic acid and protein levels of TF in human monocytes partly due to its downregulation of nuclear factor kappa-light-chain-enhancer of activated B cells and c-Jun N-terminal kinase pathways. In conclusion, this study provides further explanation for the cardiovascular protection of saponins, and the analysis of SARs between inhibiting TF activity and saponins will be helpful to explore the therapeutic TF inhibitors.

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