Modulation of mRNA stability as a novel therapeutic approach

Eberhardt, W.; Doller, Anke; Akool, El-Sayed; Pfeilschifter, Josef

doi:10.1016/j.pharmthera.2007.01.002

Cited by 156 publications

(135 citation statements)

References 204 publications

Supporting

Mentioning

131

Contrasting

Unclassified

Order By: Relevance

“…In view of the contradictory effects of rapamycin on MMP-9 mRNA levels and MMP-9 promoter activity, we postulated that the negative effects on MMP-9 by rapamycin may result from additional posttranscriptional events. Notably, we previously could demonstrate that several copies of destabilizing AU-rich elements (AREs) present in the 3´-UTR of rat MMP-9 gene are critically involved in the posttranscriptional regulation of MMP-9 [15,30,31].…”

Section: Discussionmentioning

confidence: 99%

Differential modulation of the cytokine-induced MMP-9/TIMP-1 protease–antiprotease system by the mTOR inhibitor rapamycin

Osman

Akool

Doller

et al. 2011

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

The mTOR-inhibitor rapamycin is a potent drug used in many immunosuppressive and antiinflammatory therapeutic regimes. In renal transplantation despite its benefical roles rapamycin in some cases can promote renal fibrosis in the kidney but the underlying mechanisms are unknown. In this study, we tested for possible modulatory effects of rapamycin on the cytokine-triggered matrix metalloproteinase 9 (MMP-9)/ tissue inhibitor of metalloproteinase (TIMP)-1 protease-antiprotease system which is critically involved in renal inflammation and fibrosis. Treatment of rat mesangial cells (MC) with rapamycin dosedependently reduced the interleukin 1 (IL-1-triggered increase in gelatinolytic levels as demonstrated by zymography. The reduction in the extracellular MMP-9 content by rapamycin coincided with an attenuation in cytokine-induced steady-state MMP-9 mRNA levels. Conversely, rapamycin caused a dose-dependent increase in cytokine-evoked TIMP-1 expression in a Smad binding element (SBE) -dependent manner. Surprisingly, the attenuation of MMP-9 mRNA levels by rapamycin is accompanied by a potentiation of IL-1-induced MMP-9 promoter activity in which the stimulatory effects by rapamycin are mainly attributed to a proximal AP-1 binding site. Furthermore, the rapamycin-dependent potentiation of MMP-9 expression is accompanied by an amplification of cytokine-triggered activities of nuclear factor B (NF-B) and activator protein 1 (AP-1) transcription factors. Importantly, rapamycin-triggered increase in MMP-9 promoter activity is fully impaired when we used a MMP-9 reporter construct which is under the additional control of the 3´untranslated region (3´-UTR) of MMP-9. Collectively, these data imply that rapamycin inhibits the cytokineinduced MMP-9 mainly through posttranscriptional events and thereby exerts profibrotic activities.

show abstract

Section: Discussionmentioning

confidence: 99%

Differential modulation of the cytokine-induced MMP-9/TIMP-1 protease–antiprotease system by the mTOR inhibitor rapamycin

Osman

Akool

Doller

et al. 2011

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In particular, such mechanisms involve MAP kinases, AMP-activated kinases, PKC, or PI3-kinase. 26 The question which of them is triggered by PMPs in tumor cells requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Platelet‐derived microparticles promote invasiveness of prostate cancer cells via upregulation of MMP‐2 production

Dashevsky

Varon

Brill

2009

Intl Journal of Cancer

124

View full text Add to dashboard Cite

Prostate cancer commonly affects men in the Western world. A major factor of the life-threatening course of this disease is the high rate of metastasis, predominantly to bones. Circulating tumor cells encounter platelets and may activate them, resulting in a production of microparticles (MPs). MPs are small platelet fragments expressing membrane receptors as well as cytoplasmic constituents. Here, we report that prostate cancer cells, Clone-1 (Cl-1), preincubated with platelet-derived MPs (PMPs), demonstrate increased invasion through a gelatin-coated (a denatured form of collagen) membrane of the Boyden chamber system. This effect was accompanied by an increased secretion of metalloproteinase-2 (MMP-2) as demonstrated by a gelatin zymography. Application of MMP-2/9 inhibitor reversed the PMP-induced tumor cell invasion. PMPs were shown to adhere to Cl-1 cells, but direct contact between them may not be mandatory for MMP secretion because PMP lysate induced MMP-2 production by Cl-1 cells to the same extent as did intact PMPs. PMP-induced MMP-2 secretion was inhibited by neutralization of either PKC or total intracellular tyrosine phosphorylation, but was not affected by blocking major intraplatelet cytokines. Actinomycin D (a transcription inhibitor) did not modify this effect, whereas cycloheximide (an inhibitor of protein translation) abolished the MMP-2 release. MMP-2 secretion was accompanied by a rapid and transient increase in MMP-2 mRNA level after a 2-hr coincubation of prostate cancer cells with PMPs. Thus, PMPs promote tumor invasiveness, at least in part by stimulation of MMP-2 production. ' 2008 Wiley-Liss, Inc.Key words: platelet-derived microparticles; prostate cancer; MMP-2 Platelet involvement in dissemination of tumor metastasis was first experimentally demonstrated several decades ago. 1 Potential mechanisms of the platelet effect on metastatic dissemination include PAR receptors, platelet-derived lysophosphatidic acid and others. 2,3 Platelets were previously shown to directly mediate tumor cell adhesion to the vascular wall thus facilitating their future egress into tissues. 4 However, functional platelet depletion several weeks after tumor inoculation also results in reduction of metastasis, 3 an effect that cannot be explained by decreased tumor cell survival or extravasation. In addition, platelets may serve as a source of numerous proangiogenic cytokines that support growth of new capillaries in the vicinity of metastasis. 5 Angiogenesis is a prerequisite for tumor growth. 6 The ability of platelets as a cellular system to induce angiogenesis in spite of numerous antiangiogenic compounds in their alpha-granules has recently been demonstrated. 7,8 Matrix metalloproteinases (MMPs) belong to a family of zinccontaining enzymes that are tightly involved in the angiogenic process as well as in tumor cell extravasation and metastasis. 9 Among this group of endopeptidases, MMP-2 and MMP-9 are considered most important for metastatic spread. Both enzymes cleave collagen that constitutes a major co...

show abstract

“…Recent studies demonstrated that MMP-9 regulation is not limited by transcriptional level. In addition to transcriptional events, MMP-9 gene expression is regulated by posttranscriptional events, such as those controlling mRNA turnover and translation [32][33][34][35]. However, detailed molecular mechanisms regulating MMP-9 expression via 3′-UTR needs to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase 9 expression: new regulatory elements

Surgucheva

Chidambaram

Willoughby

et al. 2010

j ocul biol dis inform

View full text Add to dashboard Cite

Retinal ganglion cells apoptosis is linked to matrix metalloproteinase 9 (MMP-9) controlled changes of extracellular matrix. Abnormal expression of MMP-9 is associated with glaucomatous alterations. Thus, the knowledge of MMP-9 regulation is important for the understanding the pathogenesis of glaucoma. Here, we investigated the role of 3′-untranslated regions (3′-UTR) and microRNAs in MMP-9 regulation. We used in vitro mutagenesis and Luc reporter system to identify regulatory elements in the 3′-UTR of MMP-9. microRNAs were analyzed by qRT-PCR, and their role was investigated with inhibitors and mimics. We identified targets for miRNAs in 3′-UTR of MMP-9 involved in the regulation of MMP-9 expression. We then isolated miRNAs from the optic nerve A7 astrocytes and 293 T cells and confirmed the role of mi340 in the regulation using specific inhibitors and mimics. The results obtained show a new miRNA-mediated mechanism of MMP-9 expression regulation.

show abstract

Modulation of mRNA stability as a novel therapeutic approach

Cited by 156 publications

References 204 publications

Differential modulation of the cytokine-induced MMP-9/TIMP-1 protease–antiprotease system by the mTOR inhibitor rapamycin

Differential modulation of the cytokine-induced MMP-9/TIMP-1 protease–antiprotease system by the mTOR inhibitor rapamycin

Platelet‐derived microparticles promote invasiveness of prostate cancer cells via upregulation of MMP‐2 production

Matrix metalloproteinase 9 expression: new regulatory elements

Contact Info

Product

Resources

About