News Article | May 4, 2017
MORGANTOWN, W.Va. and KALAMAZOO, Mich., May 4, 2017 /PRNewswire/ -- Protea Biosciences Group, Inc. (OTCQB: PRGB) ("Protea") and Proteos, Inc. ("Proteos") announced today that they have entered into a joint co-marketing agreement. This mutual partnership allows Protea to combine Proteos' p...
Graf M.,National University of Singapore |
Graf M.,Proteos, Inc. |
Qi-Wen E.-R.T.,National University of Singapore |
Sarusie M.V.,National University of Singapore |
And 2 more authors.
Molecular Endocrinology | Year: 2015
Dmrt transcription factors control sex determination or sex-specific differentiation across all invertebrate and vertebrate species, in which they have been studied so far. In addition to important functions in the reproductive system, also nongonadal roles have been assigned to several dmrt family members. One example is dmrt5, which was shown to guide neurogenesis in the forebrain of some vertebrates including fish. Here we show that in zebrafish, dmrt5 is also expressed adjacent to the pituitary anlage and later in the anterior pars distalis in which it organizes differentiation of endocrine cells. We find that pituitary induction, cell survival, proliferation, and early lineage specification in the pituitary is independent of dmrt5. Instead, dmrt5 is required for terminal differentiation of corticotropes and gonadotropes. Gene knockdown and mutant analysis revealed that dmrt5 promotes corticotrope differentiation via tbx19 expression, whereas it prevents gonadotrope differentiation in the anterior pars distalis. In dmrt5 morphants and mutants, reduced corticotrope numbers may result in irregular positioning and reduced maintenance of lactotropes. In conclusion, our study establishes a novel function for dmrt5 for cell differentiation in the anterior pituitary. Intriguingly, its effect on gonadotrope numbers defines a first nongonadal role for a dmrt family member that appears crucial for the activity of the reproductive system. © 2015 by the Endocrine Society.
Teo H.,Proteos, Inc. |
Ghosh S.,University of Arizona |
Luesch H.,University of Florida |
Luesch H.,Genomics Institute of the Novartis Research Foundation |
And 16 more authors.
Nature Cell Biology | Year: 2010
We describe a genome-wide gain-of-function screen for regulators of NF-κB, and identify Rap1 (Trf2IP), as an essential modulator of NF-κB-mediated pathways. NF-κB is induced by ectopic expression of Rap1, whereas its activity is inhibited by Rap1 depletion. In addition to localizing on telomeres, mammalian Rap1 forms a complex with IKKs (IκB kinases), and is crucial for the ability of IKKs to be recruited to, and phosphorylate, the p65 subunit of NF-κB to make it transcriptionally competent. Rap1-mutant mice display defective NF-κB activation and are resistant to endotoxic shock. Furthermore, levels of Rap1 are positively regulated by NF-κB, and human breast cancers with NF-κB hyperactivity show elevated levels of cytoplasmic Rap1. Similar to inhibiting NF-κB, knockdown of Rap1 sensitizes breast cancer cells to apoptosis. These results identify the first cytoplasmic role of Rap1 and provide a mechanism through which it regulates an important signalling cascade in mammals, independent of its ability to regulate telomere function. © 2010 Macmillan Publishers Limited. All rights reserved.
Ghosh A.,Proteos, Inc. |
Saginc G.,Genome Institute of Singapore |
Leow S.C.,Proteos, Inc. |
Khattar E.,Proteos, Inc. |
And 12 more authors.
Nature Cell Biology | Year: 2012
Although elongation of telomeres is thought to be the prime function of reactivated telomerase in cancers, this activity alone does not account for all of the properties that telomerase reactivation attributes to human cancer cells. Here, we uncover a link between telomerase and NF-B, a master regulator of inflammation. We observe that while blocking NF-B signalling can inhibit effects of telomerase overexpression on processes relevant to transformation, increasing NF-B activity can functionally substitute for reduced telomerase activity. Telomerase directly regulates NF-B-dependent gene expression by binding to the NF-B p65 subunit and recruitment to a subset of NF-B promoters such as those of IL-6 and TNF-α, cytokines that are critical for inflammation and cancer progression. As NF-B can transcriptionally upregulate telomerase levels, our findings suggest that a feed-forward regulation between them could be the key mechanistic basis for the coexistence of chronic inflammation and sustained telomerase activity in human cancers. © 2012 Macmillan Publishers Limited. All rights reserved.
Ho S.B.,University of California at San Diego |
Ho S.B.,VA San Diego Healthcare System |
Luu Y.,University of California at San Diego |
Luu Y.,VA San Diego Healthcare System |
And 7 more authors.
Biochimica et Biophysica Acta - General Subjects | Year: 2010
Background: The membrane-bound mucins, MUC17 (human) and Muc3 (mouse), are highly expressed on the apical surface of intestinal epithelia and have cytoprotective properties. Their extracellular regions contain two EGF-like Cys-. rich domains (CRD1 and CRD2) connected by an intervening linker segment with SEA module (L), and may function to stimulate intestinal cell restitution. The purpose of this study was to determine the effect of size, recombinant host source, and external tags on mucin CRD1-L-CRD2 protein activity. Methods: Four recombinant Muc3-CRD proteins and three MUC17-CRD proteins were generated using Escherichia coli or baculovirus-insect cell systems and tested in colonic cell cultures for activity related to cell migration and apoptosis. Results: N-terminal glutathione-S-transferase (GST) or C-terminal His8 tags had no effect on either the cell migration or anti-apoptosis activity of Muc3-CRD1-L-CRD2. His-tagged Muc3-CRD1-L-CRD2 proteins with truncated linker regions, or the linker region alone, did not demonstrate biologic activity. The human recombinant MUC17-CRD1-L-CRD2-His8 was shown to have anti-apoptotic and pro-migratory activity, but did not stimulate cell proliferation. This protein showed similar in vitro biologic activity, whether produced in E. coli or a baculovirus-insect cell system. Conclusions: Recombinant mucin proteins containing a bivalent display of Cys-rich domains accelerate colon cell migration and inhibit apoptosis, require a full-length intervening Linker-SEA segment for optimal biologic activity, and are functional when synthesized in either E. coli and insect cell systems. General Significance: These results indicate that an Escherichia coli-derived full-length His8-tagged human MUC17 CRD1-L-CRD2 recombinant protein is a biologically active candidate for further development as a therapeutic agent. © 2010.
Luu Y.,University of California at San Diego |
Junker W.,University of Nebraska Medical Center |
Rachagani S.,University of Nebraska Medical Center |
Das S.,University of Nebraska Medical Center |
And 4 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2010
The membrane-bound mucins, MUC17 (human) and Muc3 (mouse), are highly expressed on the apical surface of intestinal epithelia and are thought to be cytoprotective. The extracellular regions of these mucins contain EGF-like Cys-rich segments (CRD1 and CRD2) connected by an intervening linker domain (L). The purpose of this study was to determine the functional activity of human MUC17 membrane-bound mucin. Methods: Endogenous MUC17 was inhibited in LS174T colon cells by stable transfection of a small hairpin RNA targeting MUC17 (LSsi cells). The effect of recombinant MUC17-CRD1-L-CRD2 protein on migration, apoptosis, and experimental colitis was determined. Results: Reduced MUC17 expression in LSsi cells was associated with visibly reduced cell aggregation, reduced cell-cell adherence, and reduced cell migration, but no change in tumorigenicity. LSsi cells also demonstrated a 3.7-fold increase in apoptosis rates compared with control cells following treatment with etoposide. Exposure of colonic cell lines to exogenous recombinant MUC17-CRD1-L-CRD2 protein significantly increased cell migration and inhibited apoptosis. As a marker of biologic activity, MUC17-CRD1-L-CRD2 proteins stimulate ERK phosphorylation in colonic cell lines; and inhibition of ERK phosphorylation reduced the anti-apoptosis and migratory effect of MUC17-CRD1-L-CRD2. Finally, mice treated with MUC17-CRD1-L-CRD2 protein given per rectum demonstrated accelerated healing in acetic acid and dextran sodium sulfate induced colitis in vivo. These data indicate that both native MUC17 and the exogenous recombinant cysteine-rich domain of MUC17 play a role in diverse cellular mechanisms related to cell restitution, and suggest a potential role for MUC17-CRD1-L-CRD2 recombinant protein in the treatment of mucosal inflammatory diseases. © 2010.
Sandin S.,Nanyang Technological University |
Rhodes D.,Proteos, Inc.
Current Opinion in Structural Biology | Year: 2014
The telomerase reverse transcriptase has an essential role in telomere maintenance and in cancer biology. Progress during the last year has revealed the three-dimensional architecture of both human and ciliate telomerase at about 25. Å resolution, obtained using single particle electron microscopy (EM). The structural analysis of the two holoenzyme complexes isolated from cells shows that whilst the ciliate telomerase is monomeric, the human telomerase is dimeric and only functional as a dimer. We critically discuss the approaches taken to assign the location of protein and RNA subunits, as well as fitting the crystal structure of the catalytic protein subunit in the medium resolution EM density maps. Comparison of the two structural interpretations reveals not only a common RNA/reverse transcriptase core, but also significant differences due to different RNA subunit size and protein composition. These differences suggest that the oligomeric state and subunit composition of telomerase in evolutionary distant organism have evolved. © 2014.
Mauro C.,Imperial College London |
Leow S.C.,Imperial College London |
Leow S.C.,Proteos, Inc. |
Anso E.,Northwestern University |
And 10 more authors.
Nature Cell Biology | Year: 2011
Cell proliferation is a metabolically demanding process. It requires active reprogramming of cellular bioenergetic pathways towards glucose metabolism to support anabolic growth. NF-κB/Rel transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis, but whether NF-κB regulates the metabolic reprogramming required for cell division during these processes is unknown. Here, we report that NF-κB organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondrial respiration. NF-κB inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose starvation. The metabolic reorganization that results from NF-κB inhibition overcomes the requirement for tumour suppressor mutation in oncogenic transformation and impairs metabolic adaptation in cancer in vivo. This NF-κB-dependent metabolic pathway involves stimulation of oxidative phosphorylation through upregulation of mitochondrial synthesis of cytochrome c oxidase 2 (SCO2; ref. ). Our findings identify NF-κB as a physiological regulator of mitochondrial respiration and establish a role for NF-κB in metabolic adaptation in normal cells and cancer. © 2011 Macmillan Publishers Limited. All rights reserved.
PubMed | Proteos, Inc.
Type: Journal Article | Journal: Nature cell biology | Year: 2012
Although elongation of telomeres is thought to be the prime function of reactivated telomerase in cancers, this activity alone does not account for all of the properties that telomerase reactivation attributes to human cancer cells. Here, we uncover a link between telomerase and NF-B, a master regulator of inflammation. We observe that while blocking NF-B signalling can inhibit effects of telomerase overexpression on processes relevant to transformation, increasing NF-B activity can functionally substitute for reduced telomerase activity. Telomerase directly regulates NF-B-dependent gene expression by binding to the NF-B p65 subunit and recruitment to a subset of NF-B promoters such as those of IL-6 and TNF-, cytokines that are critical for inflammation and cancer progression. As NF-B can transcriptionally upregulate telomerase levels, our findings suggest that a feed-forward regulation between them could be the key mechanistic basis for the coexistence of chronic inflammation and sustained telomerase activity in human cancers.
Proteos, Inc. | Date: 2016-05-16
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