Leiomodin and tropomodulin in smooth muscle

Conley, Catharine A.

doi:10.1152/ajpcell.2001.280.6.c1645

Cited by 49 publications

(53 citation statements)

References 56 publications

(72 reference statements)

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“…In vitro studies in human microvascular endothelial cells-1 suggest that TMOD3 overexpression results in cell depolarization that is associated with decreased cell motility (17). Since TMOD3 is expressed in smooth muscle cells (12) and plexiform lesions in PAH are formed in part by migrating smooth muscle cells (67), we suggest that decreased expression of TMOD3 might have a role in regulating migration of smooth muscle cells in PAH. CHL1 encodes neural cell adhesion molecules required for migration and differentiation of neuronal cells.…”

Section: Resultsmentioning

confidence: 90%

Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hypertension

Rajkumar

Konishi²,

Richards³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

163

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Idiopathic pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by pulmonary arteriolar remodeling. This investigation aimed to identify genes involved specifically in the pathogenesis of PAH and not other forms of pulmonary hypertension (PH). Using genomewide microarray analysis, we generated the largest data set to date of RNA expression profiles from lung tissue specimens from 1) 18 PAH subjects and 2) 8 subjects with PH secondary to idiopathic pulmonary fibrosis (IPF) and 3) 13 normal subjects. A molecular signature of 4,734 genes discriminated among these three cohorts. We identified significant novel biological changes that were likely to contribute to the pathogenesis of PAH, including regulation of actin-based motility, protein ubiquitination, and cAMP, transforming growth factor-␤, MAPK, estrogen receptor, nitric oxide, and PDGF signaling. Bone morphogenic protein receptor type II expression was downregulated, even in subjects without a mutation in this gene. Women with PAH had higher expression levels of estrogen receptor 1 than normal women. Real-time quantitative PCR confirmed differential expression of the following genes in PAH relative to both normal controls and PH secondary to IPF: a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9, cell adhesion molecule with homology to L1CAM, cytochrome b558 and ␤-polypeptide, coagulation factor II receptor-like 3, A-myb myeloblastosis viral oncogene homolog 1, nuclear receptor coactivator 2, purinergic receptor P2Y, platelet factor 4, phospholamban, and tropomodulin 3. This study shows that PAH and PH secondary to IPF are characterized by distinct gene expression signatures, implying distinct pathophysiological mechanisms. bone morphogenic protein receptor type II; estrogen; idiopathic pulmonary fibrosis; microarrays; mitogen-activated protein kinase; nitric oxide; platelet-derived growth factor PULMONARY ARTERIAL HYPERTENSION (PAH) is a disease characterized by elevated mean pulmonary arterial pressures (Ն25 mmHg at rest or Ն30 mmHg during exercise) (56) and subsequent right ventricular hypertrophy and failure. Vascular remodeling, manifested by excessive proliferation of vascular endothelium, smooth muscle cells, and fibroblasts, resulting in thickening of the walls of the pulmonary arterioles and formation of plexiform lesions, is the underlying cause of the increased vascular resistance (65). The mean survival time without treatment is ϳ2.8 yr, and the ratio of affected women to men is up to 3:1 (38, 46). PAH is termed idiopathic when sporadic, and familial in the 6% of cases with a positive family history. Both forms appear to share the same pathophysiological processes (16).Bone morphogenic protein (BMP) receptor type II (BMPR2) mutations, including exon duplications and deletions and gene

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Section: Resultsmentioning

confidence: 90%

Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hypertension

Rajkumar

Konishi²,

Richards³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

163

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“…LMOD1 was originally cloned from a human thyroid cDNA library (21) and subsequently was shown to be enriched in smooth muscle-containing tissues (22). An early report showed that the amino terminus of LMOD1 binds tropomyosins in an isoform-specific manner (23).…”

Section: Discussionmentioning

confidence: 99%

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Halim

Wilson

Oliver

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

108

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Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital visceral myopathy characterized by severe dilation of the urinary bladder and defective intestinal motility. The genetic basis of MMIHS has been ascribed to spontaneous and autosomal dominant mutations in actin gamma 2 (ACTG2), a smooth muscle contractile gene. However, evidence suggesting a recessive origin of the disease also exists. Using combined homozygosity mapping and whole exome sequencing, a genetically isolated family was found to carry a premature termination codon in Leiomodin1 (LMOD1), a gene preferentially expressed in vascular and visceral smooth muscle cells. Parents heterozygous for the mutation exhibited no abnormalities, but a child homozygous for the premature termination codon displayed symptoms consistent with MMIHS. We used CRISPR-Cas9 (CRISPR-associated protein) genome editing of Lmod1 to generate a similar premature termination codon. Mice homozygous for the mutation showed loss of LMOD1 protein and pathology consistent with MMIHS, including late gestation expansion of the bladder, hydronephrosis, and rapid demise after parturition. Loss of LMOD1 resulted in a reduction of filamentous actin, elongated cytoskeletal dense bodies, and impaired intestinal smooth muscle contractility. These results define LMOD1 as a disease gene for MMIHS and suggest its role in establishing normal smooth muscle cytoskeletal–contractile coupling.

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“…Lmod2 has been proposed to be the long sought-after muscle actin nucleator because it: (1) is only expressed in striated muscle; (2) efficiently nucleates actin filaments in vitro; and (3) is required for proper sarcomere assembly in cultured cardiomyocytes (Chereau et al, 2008;Conley, 2001). If Lmod2 were indeed the primary nucleator of thin filaments in the heart, it would be expected to be present very early in development, just as the first thin filaments are forming.…”

Section: Discussionmentioning

confidence: 99%

Leiomodin-2 is an antagonist of tropomodulin-1 at the pointed end of the thin filaments in cardiac muscle

Tsukada

Pappas

Moroz

et al. 2010

Journal of Cell Science

202

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SummaryRegulation of actin filament assembly is essential for efficient contractile activity in striated muscle. Leiomodin is an actin-binding protein and homolog of the pointed-end capping protein, tropomodulin. These proteins are structurally similar, sharing a common domain organization that includes two actin-binding sites. Leiomodin also contains a unique C-terminal extension that has a third actinbinding WH2 domain. Recently, the striated-muscle-specific isoform of leiomodin (Lmod2) was reported to be an actin nucleator in cardiomyocytes. Here, we have identified a function of Lmod2 in the regulation of thin filament lengths. We show that Lmod2 localizes to the pointed ends of thin filaments, where it competes for binding with tropomodulin-1 (Tmod1). Overexpression of Lmod2 results in loss of Tmod1 assembly and elongation of the thin filaments from their pointed ends. The Lmod2 WH2 domain is required for lengthening because its removal results in a molecule that caps the pointed ends similarly to Tmod1. Furthermore, Lmod2 transcripts are first detected in the heart after it has begun to beat, suggesting that the primary function of Lmod2 is to maintain thin filament lengths in the mature heart. Thus, Lmod2 antagonizes the function of Tmod1, and together, these molecules might fine-tune thin filament lengths.

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Leiomodin and tropomodulin in smooth muscle

Cited by 49 publications

References 56 publications

Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hypertension

Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hypertension

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Leiomodin-2 is an antagonist of tropomodulin-1 at the pointed end of the thin filaments in cardiac muscle

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