Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice

Pj, McLaughlin; Bakall, Benjamin; Choi, Ji-Won; Liu, Zhonglin; Sasaki, Takako; Davis, Elaine C.; Marmorstein, Alan D.; Marmorstein, Lihua Y.

doi:10.1093/hmg/ddm264

Cited by 149 publications

(163 citation statements)

References 43 publications

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“…In mutated EFEMP1, an up-regulation of vascular endothelial growth factor (VEGF) expression is created by a protein misfolding that activates the unfolded protein response signaling pathway (14,15). Loss of EFEMP1, however, does not result in macular degeneration but in the appearance of hernias as a consequence of a reduction of elastic fibers of fascial connective tissue (16). Interestingly, when originally isolated in senescent fibroblasts, EFEMP1 was observed to be decreased by mitogenic culture conditions; however, when microinjected into fibroblasts, DNA synthesis was stimulated consistently in an autocrine and paracrine manner (17).…”

Section: Introductionmentioning

confidence: 99%

EFEMP1 Expression Promotes In vivo Tumor Growth in Human Pancreatic Adenocarcinoma

Seeliger¹,

Čamaj²,

Ischenko³

et al. 2009

Molecular Cancer Research

100

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The progression of pancreatic cancer is dependent on local tumor growth, angiogenesis, and metastasis. EFEMP1, a recently discovered member of the fibulin family, was characterized with regard to these key elements of pancreatic cancer progression. Differential gene expression was assessed by mRNA microarray hybridization in FG human pancreatic adenocarcinoma cells and L3.6pl cells, a highly metastatic variant of FG. In vivo orthotopic tumor growth of EFEMP1-transfected FG cells was examined in nude mice. To assess the angiogenic properties of EFEMP1, vascular endothelial growth factor (VEGF) production of tumor cells, endothelial cell proliferation and migration, and tumor microvessel density were analyzed in response to EFEMP1. Further, tumor cell apoptosis, cell cycle progression, and resistance to cytotoxic agents were quantitated by propidium iodide staining and flow cytometry. In microarray hybridization, EFEMP1 was shown to be significantly up-regulated in L3.6pl cells compared with FG cells. Concordantly, EFEMP1 transfection of FG cells stimulated orthotopic and metastatic tumor growth in vivo. EFEMP1 expression resulted in a stimulation of VEGF production by tumor cells and an increased number of CD31-positive microvessels. Endothelial cell proliferation and migration were not altered by EFEMP1, indicating an indirect angiogenic effect. Further, EFEMP1 expression decreased apoptosis and promoted cell cycle progression in response to serum starvation or exposure to gemcitabine, 5-fluorouracil, and irinotecan. EFEMP1 has protumorigenic effects on pancreatic cancer in vivo and in vitro mediated by VEGF-driven angiogenesis and antiapoptotic mechanisms. Hence, EFEMP1 is a promising candidate for assessing prognosis and individualizing therapy in a clinical tumor setting. (Mol Cancer Res 2009;7(2):189-98)

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Section: Introductionmentioning

confidence: 99%

EFEMP1 Expression Promotes In vivo Tumor Growth in Human Pancreatic Adenocarcinoma

Seeliger¹,

Čamaj²,

Ischenko³

et al. 2009

Molecular Cancer Research

100

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“…Mutations in the human FBLN3 gene are associated with the eye diseases Doyne honeycomb retinal dystrophy and Malattia Leventinese (21). Fbln3-deficient mice show defective elastogenesis mainly in connective tissue fascia, leading to inguinal hernias and protrusion of xiphoid process without obvious manifestation in the vascular system (22). Developmental arteries and neural crest EGF-like protein (DANCE, also called FBLN5) is another member of the FBLN family, abundantly present in developing arteries (19,23).…”

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confidence: 99%

Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase

Horiguchi¹,

Inoue

Ohbayashi

et al. 2009

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

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Great arteries, as well as lungs and skin, contain elastic fibers as important components to maintain their physiological functions. Although recent studies have revealed that a glycoprotein fibulin-4 (FBLN4) is indispensable for the assembly of mature elastic fibers, it remains to be elucidated how FBLN4 takes part in elastogenesis. Here, we report a dose-dependent requirement for FBLN4 in the development of the elastic fibers in arteries, and a specific role of FBLN4 in recruiting the elastin-cross-linking enzyme, lysyl oxidase (LOX). Reduced expression of Fbln4, which was achieved with a smooth muscle-specific Cre-mediated gene deletion, caused arterial stiffness. Electron-microscopic examination revealed disorganized thick elastic laminae with aberrant deposition of elastin. Aneurysmal dilation of the ascending aorta was found when the Fbln4 expression level was reduced to an even lower level, whereas systemic Fbln4 null mice died perinatally from rupture of the diaphragm. We also found a specific interaction between FBLN4 and the propeptide of LOX, which efficiently promotes assembly of LOX onto tropoelastin. These data suggest a mechanism of elastogenesis, in which a sufficient amount of FBLN4 is essential for tethering LOX to tropoelastin to facilitate cross-linking.development ͉ elastin ͉ extracellular matrix

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“…Among the seven known fibulins, fibulin-3 shares highest homology with fibulin-4 and -5. 19 -22 Recently, McLaughlin and colleagues 23 reported that fibulin-3 has a specific effect on the integrity of elastic fibers in fascial connective tissues. Fbln3 Ϫ/Ϫ mice develop early aging and herniation of the abdominal wall that increases progressively with age.…”

mentioning

confidence: 99%

“…Fbln3 Ϫ/Ϫ mice develop early aging and herniation of the abdominal wall that increases progressively with age. 23 In this study, we report the potential role of fibulin-3 in pelvic organ support by characterizing the gross and ultrastructural changes in the vaginal muscularis of mice deficient in fibulin-3 (Fbln3 Ϫ/Ϫ ). Further, studies were conducted to lend insight into potential mechanisms by which the lack of fibulin-3 led to pelvic organ prolapse.…”

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confidence: 99%

Failure of Pelvic Organ Support in Mice Deficient In Fibulin-3

Rahn

Acevedo

Roshanravan

et al. 2009

The American Journal of Pathology

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Fibulin-5 is crucial for normal elastic fiber synthesis in the vaginal wall; more than 90% of fibulin-5-knockout mice develop pelvic organ prolapse by 20 weeks of age. In contrast, fibulin-1 and -2 deficiencies do not result in similar pathologies, and fibulin-4-knockout mice die shortly after birth. EFEMP1 encodes fibulin-3, an extracellular matrix protein important in the maintenance of abdominal fascia. Herein, we evaluated the role of fibulin-3 in pelvic organ support. Pelvic organ support was impaired significantly in female Efemp1 knockout mice (Fbln3 Pelvic organ prolapse is a common pelvic floor disorder with substantial financial, social, and psychological implications.1-3 More than 11% of women will ultimately require surgical correction of prolapse or incontinence in their lifetimes. 4 Despite the prevalence of prolapse, the true pathophysiology of the disease is not well understood although epidemiological studies indicate that aging and vaginal parity are major risk factors.

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Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice

Cited by 149 publications

References 43 publications

EFEMP1 Expression Promotes In vivo Tumor Growth in Human Pancreatic Adenocarcinoma

EFEMP1 Expression Promotes In vivo Tumor Growth in Human Pancreatic Adenocarcinoma

Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase

Failure of Pelvic Organ Support in Mice Deficient In Fibulin-3

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