Identification of an initiator-like element essential for the expression of the tissue inhibitor of metalloproteinases-4 (Timp-4) gene

Young, David A.; Phillips, Blaine; Lundy, Caroline J.; Nuttall, Robert K.; Hogan, Aileen; Schultz, Gilbert A.; Leco, Kevin J.; Clark, Ian M.; Edwards, Dylan R.

doi:10.1042/bj3640089

Cited by 64 publications

(64 citation statements)

References 47 publications

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“…are transcription factors activated by the Ras-ERK signaling pathway (41). These findings imply the involvement of the Ras-ERK signaling pathway in transcriptional control of Timp4.…”

Section: Discussionmentioning

confidence: 65%

DA-Raf–dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation

Watanabe-Takano

Takano

Sakamoto

et al. 2014

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

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Alveolar formation is coupled to the spatiotemporally regulated differentiation of alveolar myofibroblasts (AMYFs), which contribute to the morphological changes of interalveolar walls. Although the Ras-ERK signaling pathway is one of the key regulators for alveolar formation in developing lungs, the intrinsic molecular and cellular mechanisms underlying its role remain largely unknown. By analyzing the Ras-ERK signaling pathway during postnatal development of lungs, we have identified a critical role of DA-Raf1 (DA-Raf)-a dominant-negative antagonist for the Ras-ERK signaling pathway-in alveolar formation. DA-Raf-deficient mice displayed alveolar dysgenesis as a result of the blockade of AMYF differentiation. DA-Raf is predominantly expressed in type 2 alveolar epithelial cells (AEC2s) in developing lungs, and DA-Rafdependent MEK1/2 inhibition in AEC2s suppresses expression of tissue inhibitor of matalloprotienase 4 (TIMP4), which prevents a subsequent proteolytic cascade matrix metalloproteinase (MMP)14-MMP2. Furthermore, MMP14-MMP2 proteolytic cascade regulates AMYF differentiation and alveolar formation. Therefore, DA-Raf-dependent inhibition of the Ras-ERK signaling pathway in AEC2s is required for alveolar formation via triggering MMP2 activation followed by AMYF differentiation. These findings reveal a pivotal role of the Ras-ERK signaling pathway in the dynamic regulation of alveolar development.

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“…are transcription factors activated by the Ras-ERK signaling pathway (41). These findings imply the involvement of the Ras-ERK signaling pathway in transcriptional control of Timp4.…”

Section: Discussionmentioning

confidence: 65%

DA-Raf–dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation

Watanabe-Takano

Takano

Sakamoto

et al. 2014

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

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“…TIMP-2 expression increases throughout development and is maintained at high levels into adulthood (Fager and Jaworski, 2000;Young et al, 2002). In vivo, TIMP-2 expression is restricted to postmitotic neurons in divergent regions of the nervous system (Fager and Jaworski, 2000); thus, it likely regulates the acquisition of a neuronal phenotype.…”

Section: Introductionmentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinase-2 Promotes Neuronal Differentiation by Acting as an Anti-Mitogenic Signal

Pérez-Martı́nez

Jaworski²

2005

J. Neurosci.

109

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“…Taqman reactions were carried out in 96-well plates by use of 0.5% cDNA, 12.5 L of 2X Taqman universal polymerase chain reaction (PCR) master mix, 100 mol/L probe, and 200 mol/L of each primer and water to a final volume of 25 L. 18S rRNA was used as an endogenous control. Primer sequences for murine TIMPs were as described 15 : for ANF, forward primer: 5Ј-GGAGGAGAAGATGCCGGTAGA-3Ј; reverse primer: 5Ј-GCT-TCCTCAGTCTGCTCACTCA-3Ј; probe: 5Ј-FAM-TGAGGTCAT-GCCCCCGCAGG-TAMRA-3Ј; and for ␤-MHC, forward primer: 5Ј-GTGCCAAGGGCCTGAATGAG-3Ј; reverse primer: 5Ј-GCAAAGGCTCCAGGTCTGA-3Ј; probe: 5Ј-FAM-ATCTTGTG-CTACCCAGCTCTAA-TAMRA-3Ј).…”

Section: Confocal Microscopy Of Matrix Structurementioning

confidence: 99%

“…12 Quantitative Taqman Real-Time PCR Quantification of expression of TIMPs, and the markers of hypertrophy, atrial natriuretic factor (ANF) and ␤-myosin heavy chain (␤-MHC) was performed by use of the Applied Biosystems ABI prism 7700 sequence detection system (Taqman). 15 Briefly, 1 g of total RNA extracted from hearts was reverse-transcribed by use of random hexamers. Taqman reactions were carried out in 96-well plates by use of 0.5% cDNA, 12.5 L of 2X Taqman universal polymerase chain reaction (PCR) master mix, 100 mol/L probe, and 200 mol/L of each primer and water to a final volume of 25 L. 18S rRNA was used as an endogenous control.…”

Section: Confocal Microscopy Of Matrix Structurementioning

confidence: 99%

TIMP-3 Deficiency Leads to Dilated Cardiomyopathy

et al. 2004

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Background-Despite the mounting clinical burden of heart failure, the biomolecules that control myocardial tissue remodeling are poorly understood. TIMP-3 is an endogenous inhibitor of matrix metalloproteinases (MMPs) that has been found to be deficient in failing human myocardium. We hypothesized that TIMP-3 expression prevents maladaptive tissue remodeling in the heart, and accordingly, its deficiency in mice would alone be sufficient to trigger progressive cardiac remodeling and dysfunction similar to human heart failure. Methods and Results-Mice with a targeted timp-3 deficiency were evaluated with aging and compared with age-matched wild-type littermates. Loss of timp-3 function triggered spontaneous LV dilatation, cardiomyocyte hypertrophy, and contractile dysfunction at 21 months of age consistent with human dilated cardiomyopathy. Its absence also resulted in interstitial matrix disruption with elevated MMP-9 activity, and activation of the proinflammatory tumor necrosis factor-␣ cytokine system, molecular hallmarks of human myocardial remodeling. Conclusions-TIMP-3 deficiency disrupts matrix homeostasis and the balance of inflammatory mediators, eliciting the transition to cardiac dilation and dysfunction. Therapeutic restoration of myocardial TIMP-3 may provide a novel approach to limit cardiac remodeling and the progression to failure in patients with dilated cardiomyopathy.

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Identification of an initiator-like element essential for the expression of the tissue inhibitor of metalloproteinases-4 (Timp-4) gene

Cited by 64 publications

References 47 publications

DA-Raf–dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation

DA-Raf–dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation

Tissue Inhibitor of Metalloproteinase-2 Promotes Neuronal Differentiation by Acting as an Anti-Mitogenic Signal

TIMP-3 Deficiency Leads to Dilated Cardiomyopathy

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