Tissue Inhibitor of Metalloproteinase-3 Downregulation in Lymphangioleiomyomatosis

Zhe, Xiaoning; Yang, Yan; Jakkaraju, Sandhya; Schuger, Lucia

doi:10.1165/rcmb.2002-0124oc

Cited by 67 publications

(45 citation statements)

References 45 publications

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“…Elevated levels of SRF have been reported in lymphangioleiomyomatosis (LAM), a rare disorder of interstitial pulmonary SMCs. 95 Induced SRF expression resulted in the upregulation of two matrix metalloproteinases (2 and 14) and a reduction in one of the inhibitors of metalloproteinases (TIMP3), all of which are characteristic of LAM. 95 As with other putative targets, whether these effects are directed through SRF-binding CArG elements is unknown.…”

Section: Srf and Pulmonary System Diseasementioning

confidence: 99%

“…95 Induced SRF expression resulted in the upregulation of two matrix metalloproteinases (2 and 14) and a reduction in one of the inhibitors of metalloproteinases (TIMP3), all of which are characteristic of LAM. 95 As with other putative targets, whether these effects are directed through SRF-binding CArG elements is unknown. In hypoplastic lungs of humans, where a stretch signal known to promote alternate SRF splice variants favoring normal pulmonary myogenesis is thought to be missing, the levels of full-length SRF are reduced.…”

Section: Srf and Pulmonary System Diseasementioning

confidence: 99%

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Role of serum response factor in the pathogenesis of disease

Miano

2010

Laboratory Investigation

120

100

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Serum response factor (SRF) is a ubiquitously expressed transcription factor that binds to a DNA cis element known as the CArG box, which is found in the proximal regulatory regions of over 200 experimentally validated target genes. Genetic deletion of SRF is incompatible with life in a variety of animals from different phyla. In mice, loss of SRF throughout the early embryo results in gastrulation defects precluding analyses in individual organ systems. Genetic inactivation studies using conditional or inducible promoters directing the expression of the bacteriophage Cre recombinase have shown a vital role for SRF in such cellular processes as contractility, cell migration, synaptic activity, inflammation, and cell survival. A growing number of experimental and human diseases are associated with changes in SRF expression, suggesting that SRF has a role in the pathogenesis of disease. This review summarizes data from experimental model systems and human pathology where SRF expression is either deliberately or naturally altered. Genomic DNA is a quaternary code comprising proteincoding and non-protein-coding sequences. While the protein-coding sequences are well-defined and increasingly understood, we are only beginning to elucidate the hidden information within the vast landscape of the non-proteincoding sequences. The field of comparative genomics has facilitated the identification of transcription factor-binding sites (TFBS) and microRNAs (miRs), which, aside from repetitive DNA sequences, are among the more easily decipherable non-protein-coding sequences in the human genome. Together, TFBS and miRs have essential roles in cell fate determination and cellular homeostasis of most life forms. Sequence variations (eg, single-nucleotide polymorphisms, SNPs) in the TFBS, miRs, and miR target sequences alter gene/protein expression and thus disturb homeostasis leading to disease. 1-4 A major imperative, therefore, is decoding the non-protein-coding genome relating to gene regulation to gain a full understanding of how DNA-binding transcription factors and the estimated one million or more TFBS direct normal biological processes.Serum response factor (SRF) is the founding member of the MADS-box family of transcription factors 5 and is one of the best understood DNA-binding proteins in the human proteome. The DNA-binding properties of SRF and its molecular cloning were first defined in the laboratory of Richard Treisman. 6,7 SRF has relatively low intrinsic transcriptional activity, but its interaction with over 60 cofactors confers strong transactivation potential in a cell-and context-specific manner. At least two major signaling pathways converge upon SRF to direct the programs of gene expression. 8,9 The classic pathway involves growth factor stimulation and mitogen-activated protein kinase signaling leading to the phosphorylation of the SRF cofactor, ELK1, and the activation of growth-related genes. 10,11 The second regulatory pathway occurs through Rho-dependent changes in actin dynamics. 12 In this pathway, si...

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Section: Srf and Pulmonary System Diseasementioning

confidence: 99%

Section: Srf and Pulmonary System Diseasementioning

confidence: 99%

Role of serum response factor in the pathogenesis of disease

Miano

2010

Laboratory Investigation

120

100

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“…These include expression of MMP-2, 20-22 MMP-2 activator, membrane type (MT) MT-1-MMP or MMP-14, [22][23][24] and MMP9. 21 The tissue inhibitors of metalloproteinase TIMP-1, TIMP À 2, and TIMP À 3 were expressed at low level in LAM cells.…”

Section: Expression Of Metalloproteinases (Mmps) and Circulation Of Lmentioning

confidence: 99%

“…21 The tissue inhibitors of metalloproteinase TIMP-1, TIMP À 2, and TIMP À 3 were expressed at low level in LAM cells. 21,22 Doxycycline treatment to block MMP activity resulted in an improvement in the respiratory function of one patient. 25 A recent study by Lee et al found that cells derived from a LAM-associated angiomyolipoma exhibited higher of MMP2 activity, and that this was not sensitive to rapamycin, suggesting mTORC1-independence.…”

Section: Expression Of Metalloproteinases (Mmps) and Circulation Of Lmentioning

confidence: 99%

mTOR Activation, Lymphangiogenesis, and Estrogen-Mediated Cell Survival: The “Perfect Storm” of Pro-Metastatic Factors in LAM Pathogenesis

Henske

2010

Lymphatic Research and Biology

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Research interest in lymphangioleiomyomatosis (LAM) has grown dramatically in the past decade, particularly among cancer biologists. There are at least two reasons for this: first, the discovery in the year 2000 that LAM cells carry TSC2 gene mutations, linking LAM with cellular pathways including the PI3K=Akt=mTOR axis, and allowing the Tuberous Sclerosis Complex (TSC)-regulated pathways that are believed to underlie LAM pathogenesis to be studied in cells, yeast, Drosophila, and mice. A second reason for the rising interest in LAM is the discovery that LAM cells can travel to the lung, including repopulating a donor lung after lung transplantation, despite the fact that LAM cells are histologically benign. This ''benign metastasis'' underpinning suggests that elucidating LAM pathogenesis will unlock a set of fundamental mechanisms that underlie metastatic potential in the context of a cell that has not yet undergone malignant transformation. Here, we will outline the data supporting the metastatic model of LAM, consider the biochemical and cellular mechanisms that may enable LAM cells to metastasize, including both cell autonomous and non-cell autonomous factors, and highlight a mouse model in which estrogen promotes the metastasis and survival of TSC2-deficient cells in a MEKdependent manner. We propose a multistep model of LAM cell metastasis that highlights multiple opportunities for therapeutic intervention. Taken together, the metastatic behavior of LAM cells and the involvement of tumorrelated signaling pathways lead to optimism that cancer-related paradigms for diagnosis, staging, and therapy will lead to therapeutic breakthroughs for women living with LAM.

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“…LAM cells are smooth muscle-like, express melanocytic proteins, and grow in a diffuse pattern throughout both lungs (4)(5)(6). The relationship between the LAM cells and the regions of cystic lung degeneration is unknown, although it is believed that secretion of proteases by LAM cells is a contributing factor (6)(7)(8)(9)(10)(11)(12).…”

Section: Lymphangioleiomyomatosis and The Tuberous Sclerosis Complex mentioning

confidence: 99%

Mammalian Target of Rapamycin Signaling and Autophagy: Roles in Lymphangioleiomyomatosis Therapy

Yu¹,

Parkhitko²,

Henske³

2010

Proceedings of the American Thoracic Society

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The pace of progress in lymphangioleiomyomatosis (LAM) is remarkable. In the year 2000, TSC2 gene mutations were found in LAM cells; in 2001 the tuberous sclerosis complex (TSC) genes were discovered to regulate cell size in Drosophila via the kinase TOR (target of rapamycin); and in 2008 the results were published of a clinical trial of rapamycin, a specific inhibitor of TOR, in patients with TSC and LAM with renal angiomyolipomas. This interval of just 8 years between a genetic discovery for which the relevant signaling pathway was as yet unknown, to the initiation, completion, and publication of a clinical trial, is an almost unparalleled accomplishment in modern biomedical research. This robust foundation of basic, translational, and clinical research in TOR, TSC, and LAM is now poised to optimize and validate effective therapeutic strategies for LAM. An immediate challenge is to deduce the mechanisms underlying the partial response of renal angiomyolipomas to rapamycin, and thereby guide the design of combinatorial approaches. TOR complex 1 (TORC1), which is known to be active in LAM cells, is a key inhibitor of autophagy. One hypothesis, which will be explored here, is that low levels of autophagy in TSC2-null LAM cells limits their survival under conditions of bioenergetic stress. A corollary of this hypothesis is that rapamycin, by inducing autophagy, promotes the survival of LAM cells, while simultaneously arresting their growth. If this hypothesis proves to be correct, then combining TORC1 inhibition with autophagy inhibition may represent an effective clinical strategy for LAM.Keywords: tuberin; rapamycin; chloroquine; Rheb; tuberous sclerosis LYMPHANGIOLEIOMYOMATOSIS AND THE TUBEROUS SCLEROSIS COMPLEX GENESLymphangioleiomyomatosis (LAM) is a rare lung disease affecting women, with onset typically during the childbearing years (1-3). Pathologically, LAM is characterized by two distinct components: LAM cells and cystic areas of alveolar destruction. LAM cells are smooth muscle-like, express melanocytic proteins, and grow in a diffuse pattern throughout both lungs (4-6). The relationship between the LAM cells and the regions of cystic lung degeneration is unknown, although it is believed that secretion of proteases by LAM cells is a contributing factor (6-12).LAM can occur in women with tuberous sclerosis complex (TSC), an autosomal dominant disease characterized by neurologic disease (seizures, intellectual disability, autism) and benign tumors of the brain, skin, heart, and kidneys (13). About 30% of women with TSC have evidence of cystic lung disease on CT scans and are believed to have LAM, although many of these women have mild symptoms or are asymptomatic and have not had biopsy to determine whether the cystic lesions are accompanied by LAM cells (14,15). For reasons that are not yet understood, LAM affects almost exclusively women, although a small number of men with TSC and histologically confirmed LAM have been reported (16-21).The cloning of the TSC1 and TSC2 genes in 1996 and 1993, respective...

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Tissue Inhibitor of Metalloproteinase-3 Downregulation in Lymphangioleiomyomatosis

Cited by 67 publications

References 45 publications

Role of serum response factor in the pathogenesis of disease

Role of serum response factor in the pathogenesis of disease

mTOR Activation, Lymphangiogenesis, and Estrogen-Mediated Cell Survival: The “Perfect Storm” of Pro-Metastatic Factors in LAM Pathogenesis

Mammalian Target of Rapamycin Signaling and Autophagy: Roles in Lymphangioleiomyomatosis Therapy

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