Journal of Biological Chemistry

doi: 10.1016/s0021-9258(18)49641-xpmid: N/A

doi: 10.1074/jbc.p110.124230pmid: N/A

♦ See referenced article, J. Biol. Chem. 2010, 285, 19833–19841

doi: 10.1016/s0021-9258(18)49642-1pmid: N/A

Kresge, Nicole;Simoni, Robert D.;Hill, Robert L.

doi: 10.1074/jbc.o110.000231pmid: N/A

<p>Transition State Analogue Inhibitors of Purine Nucleoside Phosphorylase from <i>Plasmodium falciparum</i></p><p>(Kicska, G. A., Tyler, P. C., Evans, G. B., Furneaux, R. H., Kim, K., and Schramm, V. L. (2002) <i>J. Biol. Chem.</i> 277, 3219–3225)</p><p>Purine-less Death in <i>Plasmodium falciparum</i> Induced by Immucillin-H, a Transition State Analogue of Purine Nucleoside Phosphorylase</p><p>(Kicska, G. A., Tyler, P. C., Evans, G. B., Furneaux, R. H., Schramm, V. L., and Kim, K. (2002) <i>J. Biol. Chem.</i> 277, 3226–3231)</p><p>Achieving the Ultimate Physiological Goal in Transition State Analogue Inhibitors for Purine Nucleoside Phosphorylase</p><p>(Lewandowicz, A., Tyler, P. C., Evans, G. B., Furneaux, R. H., and Schramm, V. L. (2003) <i>J. Biol. Chem.</i> 278, 31465–31468)</p>

Hill, Bradford G.;Dranka, Brian P.;Bailey, Shannon M.;Lancaster, Jack R.;Darley-Usmar, Victor M.

doi: 10.1074/jbc.r110.101618pmid: 20410298

<p>Nitric oxide (NO) regulates biological processes through signaling mechanisms that exploit its unique biochemical properties as a free radical. For the last several decades, the key aspects of the chemical properties of NO relevant to biological systems have been defined, but it has been a challenge to assign these to specific cellular processes. Nevertheless, it is now clear that the high affinity of NO for transition metal centers, particularly iron, and the rapid reaction of NO with oxygen-derived free radicals can explain many of its biological and pathological properties. Emerging studies also highlight a growing importance of the secondary metabolites of NO-dependent reactions in the post-translational modification of key metabolic and signaling proteins. In this minireview, we emphasize the current understanding of the biochemistry of NO and place it in a biological context.</p>

Li, Li;Kim, Eunjung;Yuan, Haixin;Inoki, Ken;Goraksha-Hicks, Pankuri;Schiesher, Rachel L.;Neufeld, Thomas P.;Guan, Kun-Liang

doi: 10.1074/jbc.c110.102483pmid: 20457610

<p>The mammalian target of rapamycin (mTOR) is a key cell growth regulator, which forms two distinct functional complexes (mTORC1 and mTORC2). mTORC1, which is directly inhibited by rapamycin, promotes cell growth by stimulating protein synthesis and inhibiting autophagy. mTORC1 is regulated by a wide range of extra- and intracellular signals, including growth factors, nutrients, and energy levels. Precise regulation of mTORC1 is important for normal cellular physiology and development, and dysregulation of mTORC1 contributes to hypertrophy and tumorigenesis. In this study, we screened <i>Drosophila</i> small GTPases for their function in TORC1 regulation and found that TORC1 activity is regulated by members of the Rab and Arf family GTPases, which are key regulators of intracellular vesicle trafficking. In mammalian cells, uncontrolled activation of Rab5 and Arf1 strongly inhibit mTORC1 activity. Interestingly, the effect of Rab5 and Arf1 on mTORC1 is specific to amino acid stimulation, whereas glucose-induced mTORC1 activation is not blocked by Rab5 or Arf1. Similarly, active Rab5 selectively inhibits mTORC1 activation by Rag GTPases, which are involved in amino acid signaling, but does not inhibit the effect of Rheb, which directly binds and activates mTORC1. Our data demonstrate a key role of Rab and Arf family small GTPases and intracellular trafficking in mTORC1 activation, particularly in response to amino acids.</p>

Shao, Chunli;Lawrence, Michael C.;Cobb, Melanie H.

doi: 10.1074/jbc.m109.087486pmid: 20424162

<p>Apoptosis contributes to immune-mediated pancreatic β cell destruction in type I diabetes. Exposure of β cells to interleukin-1β (IL-1β) causes endoplasmic reticulum stress and activates proapoptotic networks. Here, we show that nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways regulate the expression of CCAAT/enhancer-binding protein homologous protein (CHOP), which mediates endoplasmic reticulum stress-induced apoptosis. Both CHOP mRNA and protein increase in β cells treated with IL-1β. In addition, prolonged exposure to high glucose further increases IL-1β-triggered CHOP expression. IL-1β also causes increased expression of C/EBP-β and a reduction of MafA, NFATc2, and Pdx-1 expression in β cells. Inhibition of the NF-κB and MAPK signaling pathways differentially attenuates CHOP expression. Knocking down CHOP by RNA interference protects β cells from IL-1β-induced apoptosis. These studies provide direct mechanistic links between cytokine-induced signaling pathways and CHOP-mediated apoptosis of β cells.</p>

Hong, Cynthia;Duit, Sarah;Jalonen, Pilvi;Out, Ruud;Scheer, Lilith;Sorrentino, Vincenzo;Boyadjian, Rima;Rodenburg, Kees W.;Foley, Edan;Korhonen, Laura;Lindholm, Dan;Nimpf, Johannes;van Berkel, Theo J.C.;Tontonoz, Peter;Zelcer, Noam

doi: 10.1074/jbc.m110.123729pmid:

Bergström, Rosita;Savary, Katia;Morén, Anita;Guibert, Sylvain;Heldin, Carl-Henrik;Ohlsson, Rolf;Moustakas, Aristidis

doi: 10.1074/jbc.m109.088385pmid: 20427289

<p>Whether signal transduction pathways regulate epigenetic states in response to environmental cues remains poorly understood. We demonstrate here that Smad3, signaling downstream of transforming growth factor β, interacts with the zinc finger domain of CCCTC-binding factor (CTCF), a nuclear protein known to act as "the master weaver of the genome." This interaction occurs via the Mad homology 1 domain of Smad3. Although Smad2 and Smad4 fail to interact, an alternatively spliced form of Smad2 lacking exon 3 interacts with CTCF. CTCF does not perturb well established transforming growth factor β gene responses. However, Smads and CTCF co-localize to the <i>H19</i> imprinting control region (ICR), which emerges as an insulator in <i>cis</i> and regulator of transcription and replication in <i>trans</i> via direct CTCF binding to the ICR. Smad recruitment to the ICR requires intact CTCF binding to this locus. Smad2/3 binding to the ICR requires Smad4, which potentially provides stability to the complex. Because the CTCF-Smad complex is not essential for the chromatin insulator function of the <i>H19</i> ICR, we propose that it can play a role in chromatin cross-talk organized by the <i>H19</i> ICR.</p>

直登, Naoto Watanabe 渡邊;穏香, Shizuka Takagi 高木;綾, Aya Tominaga 富永;泰輔, Taisuke Tomita 富田;威, Takeshi Iwatsubo 岩坪

doi: 10.1074/jbc.m110.101287pmid: 20418378

<p>γ-Secretase is a multimeric membrane protein complex composed of presenilin (PS), nicastrin, Aph-1, and Pen-2, which mediates intramembrane proteolysis of a range of type I transmembrane proteins. We previously analyzed the functional roles of the N-terminal transmembrane domains (TMDs) 1–6 of PS1 in the assembly and proteolytic activity of the γ-secretase using a series of TMD-swap PS1 mutants. Here we applied the TMD-swap method to all the TMDs of PS1 for the structure-function analysis of the proteolytic mechanism of γ-secretase. We found that TMD2- or -6-swapped mutant PS1 failed to bind the helical peptide-based, substrate-mimic γ-secretase inhibitor. Cross-linking experiments revealed that both TMD2 and TMD6 of PS1 locate in proximity to the TMD9, the latter being implicated in the initial substrate binding. Taken together, our data suggest that TMD2 and the luminal side of TMD6 are involved in the formation of the initial substrate-binding site of the γ-secretase complex.</p>