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Karen S. Browning - One of the best experts on this subject based on the ideXlab platform.
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A viral sequence in the 3′‐untranslated region mimics a 5′ cap in facilitating translation of uncapped mRNA
The EMBO journal, 1997Co-Authors: Shanping Wang, Karen S. Browning, W. Allen MillerAbstract:For recognition by the translational machinery, most eukaryotic cellular mRNAs have a 5' cap structure [e.g. m7G(5')ppp(5')N]. We describe a translation enhancer sequence (3'TE) located in the 3'-untranslated region (UTR) of the genome of the PAV barley yellow dwarf virus (BYDV-PAV) which stimulates translation from uncapped mRNA by 30- to 100-fold in vitro and in vivo to a level equal to that of efficient capped mRNAs. A four base duplication within the 3'TE destroyed the stimulatory activity. Efficient translation was recovered by addition of a 5' cap to this mRNA. Translation of both uncapped mRNA containing the 3'TE in cis and capped mRNA lacking any BYDV-PAV sequence was inhibited specifically by added 3'TE RNA in trans. This inhibition was reversed by adding Initiation Factor 4F (eIF4F), suggesting that the 3'TE, like the 5' cap, mediates eIF4F-dependent translation Initiation. The BYDV-PAV 5'UTR was necessary for the 3'TE to function, except when the 3'TE itself was moved to the 5'UTR. Thus, the 3'TE is sufficient for recruiting the translation Factors and ribosomes, while the viral 5'UTR may serve only for the long distance 3'-5' communication. Models are proposed to explain this novel mechanism of cap-independent translation Initiation facilitated by the 3'UTR.
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Mutational Analysis of the Functional Domains of the Large Subunit of the Isozyme Form of Wheat Initiation Factor eIF4F
The Journal of biological chemistry, 1996Co-Authors: Anneke M. Metz, Karen S. BrowningAbstract:Abstract The isozyme form of plant eukaryotic Initiation Factor 4F (eIF(iso)4F) contains two subunits: p28, a cap-binding protein, and p86. To identify the functional domains of p86, truncations of the p86 cDNA were made, and the protein was expressed in Escherichia coli and purified. The deletion mutants were tested for the ability to bind the p28 subunit by two methods. In addition, these deletion mutants were evaluated in vitro by the ability to catalyze eIF4A and RNA-dependent ATP hydrolysis and to support polypeptide synthesis. The loss of the ability to bind p28 occurs within the first 90 amino acids of the N terminus and abrogates the ability of p86 to participate in translation Initiation and bind to eIF4A, but does not affect ATP hydrolysis. Up to 299 amino acid residues from the C terminus of p86 must be deleted before an effect is observed on the ATP hydrolysis activity. Thus, the p28 binding and ATP hydrolysis activities appear to lie on two separate domains and are functionally uncoupled. In addition, at least a portion of the eIF4A binding domain appears to be in close proximity to the p28 binding domain and is also uncoupled from the ATP hydrolysis activity.
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Function of the p86 subunit of eukaryotic Initiation Factor (iso)4F as a microtubule-associated protein in plant cells
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Carol L. Bokros, Karen S. Browning, A. Van Heerden, Jeffrey D. Hugdahl, Hyong-ha Kim, Virginia R. Hanesworth, Louis C. MorejohnAbstract:Abstract The isozyme form of eukaryotic Initiation Factor 4F [eIF-(iso)4F] from wheat germ is composed of a p28 subunit that binds the 7-methylguanine cap of mRNA and a p86 subunit having unknown function. The p86 subunit was found to have limited sequence similarity to a kinesin-like protein encoded by the katA gene of Arabidopsis thaliana. Native wheat germ eIF-(iso)4F and bacterially expressed p86 subunit and p86-p28 complex bound to taxol-stabilized maize microtubules (MTs) in vitro. Binding saturation occurred at 1 mol of p86 per 5-6 mol of polymerized tubulin dimer, demonstrating a substoichiometric interaction of p86 with MTs. No evidence was found for a direct interaction of the p28 subunit with MTs. Unlike kinesin, cosedimentation of eIF-(iso)4F with MTs was neither reduced by MgATP nor enhanced by adenosine 5'-[gamma-imido]triphosphate. Both p86 subunit and p86-p28 complex induced the bundling of MTs in vitro. The p86 subunit was immunolocalized to the cytosol in root maize cells and existed in three forms: fine particles, coarse particles, and linear patches. Many coarse particles and linear patches were colocalized or closely associated with cortical MT bundles in interphase cells. The results indicate that the p86 subunit of eIF-(iso)4F is a MT-associated protein that may simultaneously link the translational machinery to the cytoskeleton and regulate MT disposition in plant cells.
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Expression in Escherichia coli of the two subunits of the isozyme form of wheat germ protein synthesis Initiation Factor 4F. Purification of the subunits and formation of an enzymatically active complex.
The Journal of biological chemistry, 1994Co-Authors: A. Van Heerden, Karen S. BrowningAbstract:Abstract The subunits (p28 and p86) of the isoenzyme form of eukaryotic Initiation Factor 4F (eIF-(iso)4F) from wheat were expressed separately in Escherichia coli. The subunits were purified by affinity chromatography (p28) and ion-exchange chromatography (p86). The purified subunits alone did not support polypeptide synthesis in an eIF-(iso)4F and eIF-4F-deficient translation system from wheat germ. However, when the two subunits were mixed together, activity equal to that of the native form of eIF-(iso)4F was obtained. These results show that subunits expressed separately are able to associate and form an enzymatically active complex.
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The 5' and 3' untranslated regions of satellite tobacco necrosis virus RNA affect translational efficiency and dependence on a 5' cap structure.
The Journal of biological chemistry, 1993Co-Authors: Richard T. Timmer, Anneke M. Metz, Joanne M. Ravel, Lisa A. Benkowski, David Schodin, Sandra R. Lax, Karen S. BrowningAbstract:Abstract Satellite tobacco necrosis virus RNA (STNV RNA) is a naturally uncapped viral RNA that contains 1239 nucleotides: 29 in the 5' untranslated region (UTR), 591 in the coding region and 619 in the 3' UTR. Mutations were made in the 5' and 3' UTRs, and the effects of these mutations on translational efficiency and cap independence were measured in an in vitro translation system from wheat germ. Removal of the first 12 nucleotides or 10 changes in the nucleotide sequence of the 5' UTR reduced translational efficiency approximately 3-fold; capping of these 5' mutant mRNAs restored their translational efficiencies. Truncation of the 3' UTR to nucleotide 627 or 700, or deletion of nucleotides 627-737, reduced translational efficiency more than 20-fold; capping of these 3' mutant mRNAs restored their translational efficiencies. These modifications in the 3' UTR increased the concentration of Initiation Factor 4F required for translation. Chimeric mRNAs were constructed which contained the coding region of rabbit alpha-globin mRNA and either the 5' UTR, 3' UTR, or both the 5' and 3' UTRs of STNV RNA. Both the 5' and 3' UTRs of STNV RNA were necessary to obtain cap-independent translation. These findings indicate that interaction between 5' UTR and the region between nucleotides 627 and 737 in the 3' UTR are required for cap-independent translation.
Nahum Sonenberg - One of the best experts on this subject based on the ideXlab platform.
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Eukaryotic Initiation Factor 4F-sidestepping resistance mechanisms arising from expression heterogeneity.
Current opinion in genetics & development, 2017Co-Authors: Jennifer Chu, Santiago Ramón Y Cajal, Nahum Sonenberg, Jerry PelletierAbstract:There is enormous diversity in the genetic makeup and gene expression profiles between and within tumors. This heterogeneity leads to phenotypic variation and is a major mechanism of resistance to molecular targeted therapies. Here we describe a conceptual framework for targeting eukaryotic Initiation Factor (eIF) 4F in cancer-an essential complex that drives and promotes multiple Cancer Hallmarks. The unique nature of eIF4F and its druggability bypasses several of the heterogeneity issues that plague molecular targeted drugs developed for cancer therapy.
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targeting the eif4F translation Initiation complex a critical nexus for cancer development
Cancer Research, 2015Co-Authors: Jerry Pelletier, Jeremy R Graff, Davide Ruggero, Nahum SonenbergAbstract:Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic Initiation Factor 4F (eIF4F), the key regulator of the mRNA–ribosome recruitment phase of translation Initiation. In many cellular and preclinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes, such as cell growth and proliferation, enhanced cell survival and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion, and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g., Ras, PI3K/AKT/TOR, and MYC), eIF4F serves as a direct link between important steps in cancer development and translation Initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation Initiation as antineoplastic agents. Cancer Res; 75(2); 250–63. ©2014 AACR.
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Repair of isoaspartate formation modulates the interaction of deamidated 4E-BP2 with mTORC1 in brain.
The Journal of biological chemistry, 2010Co-Authors: Michael Bidinosti, Yvan Martineau, Filipp Frank, Nahum SonenbergAbstract:In eukaryotes, a rate-limiting step of translation Initiation is recognition of the mRNA 5′ m7GpppN cap structure by the eukaryotic Initiation Factor 4F (eIF4F), a heterotrimeric complex consisting of the cap-binding protein, eIF4E, along with eIF4G, and eIF4A. The eIF4E-binding proteins (4E-BPs) repress translation by disrupting eIF4F formation, thereby preventing ribosome recruitment to the mRNA. Of the three 4E-BPs, 4E-BP2 is the predominant paralog expressed in the mammalian brain and plays an important role in synaptic plasticity and learning and memory. 4E-BP2 undergoes asparagine deamidation, solely in the brain, during early postnatal development. Deamidation spontaneously converts asparagines into a mixture of aspartates or isoaspartates, the latter of which may be destabilizing to proteins. The enzyme protein l-isoaspartyl methyltransferase (PIMT) prevents isoaspartate accumulation by catalyzing the conversion of isoaspartates to aspartates. PIMT exhibits high activity in the brain, relative to other tissues. We report here that 4E-BP2 is a substrate for PIMT. In vitro deamidated 4E-BP2 accrues isoapartyl residues and is methylated by recombinant PIMT. Using an antibody that recognizes 4E-BP2, which harbors isoaspartates at the deamidation sites, Asn99 and Asn102, we demonstrate that 4E-BP2 in PIMT−/− brain lysates contains isoaspartate residues. Further, we show that 4E-BP2 containing isoaspartates lacks the augmented association with raptor that is a feature of deamidated 4E-BP2.
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Requirement of RNA Binding of Mammalian Eukaryotic Translation Initiation Factor 4GI (eIF4GI) for Efficient Interaction of eIF4E with the mRNA Cap
Molecular and cellular biology, 2008Co-Authors: Akiko Yanagiya, Yuri V Svitkin, Shoichiro Shibata, Satoshi Mikami, Hiroaki Imataka, Nahum SonenbergAbstract:Eukaryotic mRNAs possess a 5′-terminal cap structure (cap), m7GpppN, which facilitates ribosome binding. The cap is bound by eukaryotic translation Initiation Factor 4F (eIF4F), which is composed of eIF4E, eIF4G, and eIF4A. eIF4E is the cap-binding subunit, eIF4A is an RNA helicase, and eIF4G is a scaffolding protein that bridges between the mRNA and ribosome. eIF4G contains an RNA-binding domain, which was suggested to stimulate eIF4E interaction with the cap in mammals. In Saccharomyces cerevisiae, however, such an effect was not observed. Here, we used recombinant proteins to reconstitute the cap binding of the mammalian eIF4E-eIF4GI complex to investigate the importance of the RNA-binding region of eIF4GI for cap interaction with eIF4E. We demonstrate that chemical cross-linking of eIF4E to the cap structure is dramatically enhanced by eIF4GI fragments possessing RNA-binding activity. Furthermore, the fusion of RNA recognition motif 1 (RRM1) of the La autoantigen to the N terminus of eIF4GI confers enhanced association between the cap structure and eIF4E. These results demonstrate that eIF4GI serves to anchor eIF4E to the mRNA and enhance its interaction with the cap structure.
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eukaryotic translation Initiation Factor 4e availability controls the switch between cap dependent and internal ribosomal entry site mediated translation
Molecular and Cellular Biology, 2005Co-Authors: Yuri V Svitkin, Anne-claude Gingras, Barbara Herdy, Mauro Costamattioli, Brian Raught, Nahum SonenbergAbstract:Translation of m7G-capped cellular mRNAs is initiated by recruitment of ribosomes to the 5′ end of mRNAs via eukaryotic translation Initiation Factor 4F (eIF4F), a heterotrimeric complex comprised of a cap-binding subunit (eIF4E) and an RNA helicase (eIF4A) bridged by a scaffolding molecule (eIF4G). Internal translation Initiation bypasses the requirement for the cap and eIF4E and occurs on viral and cellular mRNAs containing internal ribosomal entry sites (IRESs). Here we demonstrate that eIF4E availability plays a critical role in the switch from cap-dependent to IRES-mediated translation in picornavirus-infected cells. When both capped and IRES-containing mRNAs are present (as in intact cells or in vitro translation extracts), a decrease in the amount of eIF4E associated with the eIF4F complex elicits a striking increase in IRES-mediated viral mRNA translation. This effect is not observed in translation extracts depleted of capped mRNAs, indicating that capped mRNAs compete with IRES-containing mRNAs for translation. These data explain numerous reported observations where viral mRNAs are preferentially translated during infection.
Wei Xing - One of the best experts on this subject based on the ideXlab platform.
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acemannan accelerates cell proliferation and skin wound healing through akt mtor signaling pathway
Journal of Dermatological Science, 2015Co-Authors: Wei Xing, Cun-hua Zou, Jiao Song, Chen-hui Dong, Peisong Yuan, Yong Xiao, Wei Guo, Ming Zhu, Hong HuangAbstract:Abstract Background Acemannan is a bioactive polysaccharides promoting tissue repair. However, the roles of acemannan in skin wound healing and the underlying molecular mechanisms are largely unclear. Objective The goal of this study is to investigate the positive role of acemannan in cutaneous wound healing and its mechanism. Methods Mouse skin wound model and skin primary fibroblasts were used to demonstrate the positive effect of acemannan on cutaneous wound healing. The expressions of cell proliferation nuclear antigen ki-67, cyclin D1 and activity of AKT/mTOR signaling were analyzed in acemannan-treated fibroblasts and mice. Rapamycin and AKT inhibitor VIII were used to determine the key role of AKT/mTOR signaling in acemannan-promoting cutaneous wound healing. Results We found that acemannan significantly accelerated skin wound closure and cell proliferation. Acemannan promoted the expression of cyclin D1 in cultured fibroblasts, which was mediated by AKT/mTOR signal pathway leading to enhanced activity of the eukaryotic translation Initiation Factor-4F (eIF4F) and increased translation of cyclin D1. In contrast, pharmaceutical blockade of AKT/mTOR signaling by mTOR inhibitor rapamycin or AKT inhibitor VIII abolished acemannan-induced cyclin D1 translation and cell proliferation. In vivo studies confirmed that the activation of AKT/mTOR by acemannan played a key role in wound healing, which could be reversed by rapamycin. Conclusion Acemannan promoted skin wound healing partly through activating AKT/mTOR-mediated protein translation mechanism, which may represent an alternative therapy approach for cutaneous wound.
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Acemannan accelerates cell proliferation and skin wound healing through AKT/mTOR signaling pathway
Journal of Dermatological Science, 2015Co-Authors: Wei Xing, Cun-hua Zou, Jiao Song, Wei Guo, Ming Zhu, Chen-hui DongAbstract:Abstract Background Acemannan is a bioactive polysaccharides promoting tissue repair. However, the roles of acemannan in skin wound healing and the underlying molecular mechanisms are largely unclear. Objective The goal of this study is to investigate the positive role of acemannan in cutaneous wound healing and its mechanism. Methods Mouse skin wound model and skin primary fibroblasts were used to demonstrate the positive effect of acemannan on cutaneous wound healing. The expressions of cell proliferation nuclear antigen ki-67, cyclin D1 and activity of AKT/mTOR signaling were analyzed in acemannan-treated fibroblasts and mice. Rapamycin and AKT inhibitor VIII were used to determine the key role of AKT/mTOR signaling in acemannan-promoting cutaneous wound healing. Results We found that acemannan significantly accelerated skin wound closure and cell proliferation. Acemannan promoted the expression of cyclin D1 in cultured fibroblasts, which was mediated by AKT/mTOR signal pathway leading to enhanced activity of the eukaryotic translation Initiation Factor-4F (eIF4F) and increased translation of cyclin D1. In contrast, pharmaceutical blockade of AKT/mTOR signaling by mTOR inhibitor rapamycin or AKT inhibitor VIII abolished acemannan-induced cyclin D1 translation and cell proliferation. In vivo studies confirmed that the activation of AKT/mTOR by acemannan played a key role in wound healing, which could be reversed by rapamycin. Conclusion Acemannan promoted skin wound healing partly through activating AKT/mTOR-mediated protein translation mechanism, which may represent an alternative therapy approach for cutaneous wound.
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SUMO-2 Promotes mRNA Translation by Enhancing Interaction between eIF4E and eIF4G
PloS one, 2014Co-Authors: Li-zhao Chen, Wei Xing, Hong Huang, Wei-wei Guo, Zhi-ya Sun, An-xiong Luo, Huaping LiangAbstract:Small ubiquitin-like modifier (SUMO) proteins regulate many important eukaryotic cellular processes through reversible covalent conjugation to target proteins. In addition to its many well-known biological consequences, like subcellular translocation of protein, subnuclear structure formation, and modulation of transcriptional activity, we show here that SUMO-2 also plays a role in mRNA translation. SUMO-2 promoted formation of the active eukaryotic Initiation Factor 4F (eIF4F) complex by enhancing interaction between Eukaryotic Initiation Factor 4E (eIF4E) and Eukaryotic Initiation Factor 4G (eIF4G), and induced translation of a subset of proteins, such as cyclinD1 and c-myc, which essential for cell proliferation and apoptosis. As expected, overexpression of SUMO-2 can partially cancel out the disrupting effect of 4EGI-1, a small molecule inhibitor of eIF4E/eIF4G interaction, on formation of the eIF4F complex, translation of the cap-dependent protein, cell proliferation and apoptosis. On the other hand, SUMO-2 knockdown via shRNA partially impaired cap-dependent translation and cell proliferation and promoted apoptosis. These results collectively suggest that SUMO-2 conjugation plays a crucial regulatory role in protein synthesis. Thus, this report might contribute to the basic understanding of mammalian protein translation and sheds some new light on the role of SUMO in this process.
Jerry Pelletier - One of the best experts on this subject based on the ideXlab platform.
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Eukaryotic Initiation Factor 4F-sidestepping resistance mechanisms arising from expression heterogeneity.
Current opinion in genetics & development, 2017Co-Authors: Jennifer Chu, Santiago Ramón Y Cajal, Nahum Sonenberg, Jerry PelletierAbstract:There is enormous diversity in the genetic makeup and gene expression profiles between and within tumors. This heterogeneity leads to phenotypic variation and is a major mechanism of resistance to molecular targeted therapies. Here we describe a conceptual framework for targeting eukaryotic Initiation Factor (eIF) 4F in cancer-an essential complex that drives and promotes multiple Cancer Hallmarks. The unique nature of eIF4F and its druggability bypasses several of the heterogeneity issues that plague molecular targeted drugs developed for cancer therapy.
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Developing anti-neoplastic biotherapeutics against eIF4F
Cellular and Molecular Life Sciences, 2017Co-Authors: Jutta Steinberger, Jennifer Chu, Rayelle Itoua Maïga, Katia Sleiman, Jerry PelletierAbstract:Biotherapeutics have revolutionized modern medicine by providing medicines that would not have been possible with small molecules. With respect to cancer therapies, this represents the current sector of the pharmaceutical industry having the largest therapeutic impact, as exemplified by the development of recombinant antibodies and cell-based therapies. In cancer, one of the most common regulatory alterations is the perturbation of translational control. Among these, changes in eukaryotic Initiation Factor 4F (eIF4F) are associated with tumor Initiation, progression, and drug resistance in a number of settings. This, coupled with the fact that systemic suppression of eIF4F appears well tolerated, indicates that therapeutic agents targeting eIF4F hold much therapeutic potential. Here, we discuss opportunities offered by biologicals for this purpose.
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targeting the eif4F translation Initiation complex a critical nexus for cancer development
Cancer Research, 2015Co-Authors: Jerry Pelletier, Jeremy R Graff, Davide Ruggero, Nahum SonenbergAbstract:Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic Initiation Factor 4F (eIF4F), the key regulator of the mRNA–ribosome recruitment phase of translation Initiation. In many cellular and preclinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes, such as cell growth and proliferation, enhanced cell survival and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion, and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g., Ras, PI3K/AKT/TOR, and MYC), eIF4F serves as a direct link between important steps in cancer development and translation Initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation Initiation as antineoplastic agents. Cancer Res; 75(2); 250–63. ©2014 AACR.
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Eukaryotic Initiation Factor 4F: a vulnerability of tumor cells
Future medicinal chemistry, 2012Co-Authors: Teresa Lee, Jerry PelletierAbstract:Protein synthesis is a complex, tightly regulated process in eukaryotic cells and its deregulation is a hallmark of many cancers. Translational control occurs primarily at the rate-limiting Initiation step, where ribosomal subunits are recruited to template mRNAs through the concerted action of several eukaryotic Initiation Factors (eIFs). One Factor that interacts with both the mRNA and ribosomes, and appears limiting for translation is eIF4F, a complex composed of the cap-binding protein, eIF4E; the scaffold protein, eIF4G; and the ATP-dependent DEAD-box helicase, eIF4A. eIF4E appears to play an important role in tumor Initiation and progression since its overexpression can cooperate with oncogenes to accelerate transformation in cell lines and animal models, and its levels are elevated in many human cancers. This, therefore, represents a vulnerability for transformed cells, and presents an opportunity for therapeutic intervention. In this review, we discuss approaches for targeting eIF4F activity.
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c-Myc and eIF4F Constitute a Feedforward Loop That Regulates Cell Growth: Implications for Anticancer Therapy
Cancer research, 2009Co-Authors: Chen-ju Lin, Abba Malina, Jerry PelletierAbstract:The Myc/Max/Mad family of transcription Factors and the eukaryotic Initiation Factor 4F (4F) complex play fundamental roles in regulating cell growth, proliferation, differentiation, and oncogenic transformation. Recent findings indicate that the role of Myc during cell growth and proliferation is linked to an increase in eIF4F activity in a feedforward relationship, providing a possible molecular mechanism of cell transformation by Myc. Developing therapeutics to inhibit eIF4F and/or Myc could be a potential treatment for a wide range of human cancers. [Cancer Res 2009;69(19):7491–4]
Chen-hui Dong - One of the best experts on this subject based on the ideXlab platform.
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acemannan accelerates cell proliferation and skin wound healing through akt mtor signaling pathway
Journal of Dermatological Science, 2015Co-Authors: Wei Xing, Cun-hua Zou, Jiao Song, Chen-hui Dong, Peisong Yuan, Yong Xiao, Wei Guo, Ming Zhu, Hong HuangAbstract:Abstract Background Acemannan is a bioactive polysaccharides promoting tissue repair. However, the roles of acemannan in skin wound healing and the underlying molecular mechanisms are largely unclear. Objective The goal of this study is to investigate the positive role of acemannan in cutaneous wound healing and its mechanism. Methods Mouse skin wound model and skin primary fibroblasts were used to demonstrate the positive effect of acemannan on cutaneous wound healing. The expressions of cell proliferation nuclear antigen ki-67, cyclin D1 and activity of AKT/mTOR signaling were analyzed in acemannan-treated fibroblasts and mice. Rapamycin and AKT inhibitor VIII were used to determine the key role of AKT/mTOR signaling in acemannan-promoting cutaneous wound healing. Results We found that acemannan significantly accelerated skin wound closure and cell proliferation. Acemannan promoted the expression of cyclin D1 in cultured fibroblasts, which was mediated by AKT/mTOR signal pathway leading to enhanced activity of the eukaryotic translation Initiation Factor-4F (eIF4F) and increased translation of cyclin D1. In contrast, pharmaceutical blockade of AKT/mTOR signaling by mTOR inhibitor rapamycin or AKT inhibitor VIII abolished acemannan-induced cyclin D1 translation and cell proliferation. In vivo studies confirmed that the activation of AKT/mTOR by acemannan played a key role in wound healing, which could be reversed by rapamycin. Conclusion Acemannan promoted skin wound healing partly through activating AKT/mTOR-mediated protein translation mechanism, which may represent an alternative therapy approach for cutaneous wound.
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Acemannan accelerates cell proliferation and skin wound healing through AKT/mTOR signaling pathway
Journal of Dermatological Science, 2015Co-Authors: Wei Xing, Cun-hua Zou, Jiao Song, Wei Guo, Ming Zhu, Chen-hui DongAbstract:Abstract Background Acemannan is a bioactive polysaccharides promoting tissue repair. However, the roles of acemannan in skin wound healing and the underlying molecular mechanisms are largely unclear. Objective The goal of this study is to investigate the positive role of acemannan in cutaneous wound healing and its mechanism. Methods Mouse skin wound model and skin primary fibroblasts were used to demonstrate the positive effect of acemannan on cutaneous wound healing. The expressions of cell proliferation nuclear antigen ki-67, cyclin D1 and activity of AKT/mTOR signaling were analyzed in acemannan-treated fibroblasts and mice. Rapamycin and AKT inhibitor VIII were used to determine the key role of AKT/mTOR signaling in acemannan-promoting cutaneous wound healing. Results We found that acemannan significantly accelerated skin wound closure and cell proliferation. Acemannan promoted the expression of cyclin D1 in cultured fibroblasts, which was mediated by AKT/mTOR signal pathway leading to enhanced activity of the eukaryotic translation Initiation Factor-4F (eIF4F) and increased translation of cyclin D1. In contrast, pharmaceutical blockade of AKT/mTOR signaling by mTOR inhibitor rapamycin or AKT inhibitor VIII abolished acemannan-induced cyclin D1 translation and cell proliferation. In vivo studies confirmed that the activation of AKT/mTOR by acemannan played a key role in wound healing, which could be reversed by rapamycin. Conclusion Acemannan promoted skin wound healing partly through activating AKT/mTOR-mediated protein translation mechanism, which may represent an alternative therapy approach for cutaneous wound.