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Replication of<i>Vibrio cholerae</i>classical CTX phage
Kim, Eun Jin,Yu, Hyun Jin,Lee, Je Hee,Kim, Jae-Ouk,Han, Seung Hyun,Yun, Cheol-Heui,Chun, Jongsik,Nair, G. Balakrish,Kim, Dong Wook Proceedings of the National Academy of Sciences 2017 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.114 No.9
Graciet, E.,Hu, R.-G.,Piatkov, K.,Rhee, J. H.,Schwarz, E. M.,Varshavsky, A. Proceedings of the National Academy of Sciences 2006 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.103 No.9
<P>The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. Primary destabilizing N-terminal residues (Nd(p)) are recognized directly by the targeting machinery. The recognition of secondary destabilizing N-terminal residues (Nd(s)) is preceded by conjugation of an Nd(p) residue to Nd(s) of a polypeptide substrate. In eukaryotes, ATE1-encoded arginyl-transferases (R(D,E,C*)-transferases) conjugate Arg (R), an Nd(p) residue, to Nd(s) residues Asp (D), Glu (E), or oxidized Cys residue (C*). Ubiquitin ligases recognize the N-terminal Arg of a substrate and target the (ubiquitylated) substrate to the proteasome. In prokaryotes such as Escherichia coli, Nd(p) residues Leu (L) or Phe (F) are conjugated, by the aat-encoded Leu/Phe-transferase (L/F(K,R)-transferase), to N-terminal Arg or Lys, which are Nd(s) in prokaryotes but Nd(p) in eukaryotes. In prokaryotes, substrates bearing the Nd(p) residues Leu, Phe, Trp, or Tyr are degraded by the proteasome-like ClpAP protease. Despite enzymological similarities between eukaryotic R(D,E,C*)-transferases and prokaryotic L/F(K,R)-transferases, there is no significant sequelogy (sequence similarity) between them. We identified an aminoacyl-transferase, termed Bpt, in the human pathogen Vibrio vulnificus. Although it is a sequelog of eukaryotic R(D,E,C*)-transferases, this prokaryotic transferase exhibits a 'hybrid' specificity, conjugating Nd(p) Leu to Nd(s) Asp or Glu. Another aminoacyl-transferase, termed ATEL1, of the eukaryotic pathogen Plasmodium falciparum, is a sequelog of prokaryotic L/F(K,R)-transferases (Aat), but has the specificity of eukaryotic R(D,E,C*)-transferases (ATE1). Phylogenetic analysis suggests that the substrate specificity of R-transferases arose by two distinct routes during the evolution of eukaryotes.</P>
Cho, N.-H.,Kim, H.-R.,Lee, J.-H.,Kim, S.-Y.,Kim, J.,Cha, S.,Kim, S.-Y.,Darby, A. C.,Fuxelius, H.-H.,Yin, J.,Kim, J. H.,Kim, J.,Lee, S. J.,Koh, Y.-S.,Jang, W.-J.,Park, K.-H.,Andersson, S. G. E.,Choi, M Proceedings of the National Academy of Sciences 2007 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.104 No.19
Kim, M.-Y.,Jeong, B. C.,Lee, J. H.,Kee, H. J.,Kook, H.,Kim, N. S.,Kim, Y. H.,Kim, J.-K.,Ahn, K. Y.,Kim, K. K. Proceedings of the National Academy of Sciences 2006 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.103 No.35
<P>The transcription of neuron-specific genes must be repressed in nonneuronal cells. REST/NRSF is a transcription factor that restricts the expression of many neuronal genes through interaction with the neuron-restrictive silencer element at the promoter level. PAHX-AP1 is a neuronal gene that is developmentally up-regulated in the adult mouse brain but that has no functional NRSE motif in its 5' upstream sequence. Here, we report that the transcription factor AP4 and the corepressor geminin form a functional complex in which SMRT and histone deacetylase 3 are recruited. The functional complex represses PAHX-AP1 expression in nonneuronal cells and participates in regulating the developmental expression of PAHX-AP1 in the brain. This complex also serves as a transcriptional repressor of DYRK1A, a candidate gene for Down's syndrome. Furthermore, compared with that in normal fetal brain, the expression of AP4 and geminin is reduced in Down's syndrome fetal brain at 20 weeks of gestation age, at which time premature overexpression of dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) is observed. Our findings indicate that AP4 and geminin act as a previously undescribed repressor complex distinct from REST/NRSF to negatively regulate the expression of target genes in nonneuronal cells and suggest that the AP4-geminin complex may contribute to suppressing the precocious expression of target genes in fetal brain.</P>
Chae, W.-J.,Henegariu, O.,Lee, S.-K.,Bothwell, A. L. M. Proceedings of the National Academy of Sciences 2006 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.103 No.25
<P>Regulatory T cells that express the Foxp3 transcription factor play important roles in preventing autoimmune diseases. Although several studies have demonstrated that the lack of the forkhead DNA-binding domain of Foxp3 caused severe autoimmune disease in scurfy mutant mice, the other functional domains of Foxp3 are less well characterized. Here, we show that the deletion of glutamic acid (DeltaE250) in the leucine-zipper domain of Foxp3 causes a loss of hyporesponsiveness when compared with wild-type Foxp3 upon antigenic stimulation. CD4 T cells that ectopically express the glutamic acid mutant show significant losses of suppressor activity both in vitro and in vivo. We also demonstrate that regulation of both Th1- and Th2-type cytokine secretion in CD4 T cells that express wild-type Foxp3 is significantly altered by the deletion of glutamic acid. Defects are also observed in the expression of adhesion molecules, such as l-selectin (CD62L) and CD103, suggesting an important role of glutamic acid in the migratory behavior of regulatory T cells. Finally, this mutation reduces transcriptional repressor activity and impairs the homodimerization of Foxp3. Taken together, our results provide insight into the mechanism that controls autoimmune diseases via the deletion of this single glutamic acid residue in the leucine-zipper domain of Foxp3.</P>
Hormonal activity of AIMP1/p43 for glucose homeostasis
Park, S. G.,Kang, Y. S.,Kim, J. Y.,Lee, C. S.,Ko, Y. G.,Lee, W. J.,Lee, K.-U.,Yeom, Y. I.,Kim, S. Proceedings of the National Academy of Sciences 2006 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.103 No.40
<P>AIMP1/p43 is known as a cytokine working in the control of angiogenesis, inflammation, and wound healing. Here we report its enrichment in pancreatic alpha cells and glucagon-like hormonal activity. AIMP1 is secreted from the pancreas upon glucose starvation. Exogenous infusion of AIMP1 increased plasma levels of glucose, glucagon, and fatty acid, and AIMP1-deficient mice showed reduced plasma glucose levels compared with the wild-type mice under fasting conditions. Thus, AIMP1 plays a glucagon-like role in glucose homeostasis.</P>
Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo
Farokhzad, O. C.,Cheng, J.,Teply, B. A.,Sherifi, I.,Jon, S.,Kantoff, P. W.,Richie, J. P.,Langer, R. Proceedings of the National Academy of Sciences 2006 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.103 No.16
<P>Targeted uptake of therapeutic nanoparticles in a cell-, tissue-, or disease-specific manner represents a potentially powerful technology. Using prostate cancer as a model, we report docetaxel (Dtxl)-encapsulated nanoparticles formulated with biocompatible and biodegradable poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2'-fluoropyrimidine RNA aptamers that recognize the extracellular domain of the prostate-specific membrane antigen (PSMA), a well characterized antigen expressed on the surface of prostate cancer cells. These Dtxl-encapsulated nanoparticle-aptamer bioconjugates (Dtxl-NP-Apt) bind to the PSMA protein expressed on the surface of LNCaP prostate epithelial cells and get taken up by these cells resulting in significantly enhanced in vitro cellular toxicity as compared with nontargeted nanoparticles that lack the PSMA aptamer (Dtxl-NP) (P < 0.0004). The Dtxl-NP-Apt bioconjugates also exhibit remarkable efficacy and reduced toxicity as measured by mean body weight loss (BWL) in vivo [body weight loss of 7.7 +/- 4% vs. 18 +/- 5% for Dtxl-NP-Apt vs. Dtxl-NP at nadir, respectively (mean +/- SD); n = 7]. After a single intratumoral injection of Dtxl-NP-Apt bioconjugates, complete tumor reduction was observed in five of seven LNCaP xenograft nude mice (initial tumor volume of approximately 300 mm3), and 100% of these animals survived our 109-day study. In contrast, two of seven mice in the Dtxl-NP group had complete tumor reduction with 109-day survivability of only 57%. Dtxl alone had a survivability of only 14%. Saline and nanoparticles without drug were similarly nonefficacious. This report demonstrates the potential utility of nanoparticle-aptamer bioconjugates for a therapeutic application.</P>
Kodack, D. P.,Chung, E.,Yamashita, H.,Incio, J.,Duyverman, A. M. M. J.,Song, Y.,Farrar, C. T.,Huang, Y.,Ager, E.,Kamoun, W.,Goel, S.,Snuderl, M.,Lussiez, A.,Hiddingh, L.,Mahmood, S.,Tannous, B. A.,Eic Proceedings of the National Academy of Sciences 2012 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.109 No.45