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101.
Mechanism of HIV-1 viral protein R-induced apoptosis 总被引:5,自引:0,他引:5
Muthumani K Choo AY Hwang DS Chattergoon MA Dayes NN Zhang D Lee MD Duvvuri U Weiner DB 《Biochemical and biophysical research communications》2003,304(3):583-592
The paradigm of HIV-1 infection includes the diminution of CD4(+) T cells, loss of immune function, and eventual progression to AIDS. However, the mechanisms that drive host T cell depletion remain elusive. One HIV protein thought to participate in this destructive cascade is the Vpr gene product. Accordingly, we review the biology of the HIV-1 viral protein R (Vpr) an apoptogenic HIV-1 accessory protein that is packaged into the virus particle. In this review we focus specifically on Vpr's ability to induce host cell apoptosis. Recent evidence suggests that Vpr implements a unique mechanism to drive host cell apoptosis, by directly depolarizing the mitochondria membrane potential. Vpr's attack on the mitochondria results in release of cytochrome c resulting in activation of the caspase 9 pathway culminating in the activation of caspase 3 and the downstream events of apoptosis. Vpr may interact with the adenine nucleotide translocator (ANT) to prompt this cascade. The role of Vpr-induced apoptosis in HIV pathogenesis is considered. 相似文献
102.
Tang L Li MH Cao P Wang F Chang WR Bach S Reinhardt J Ferandin Y Galons H Wan Y Gray N Meijer L Jiang T Liang DC 《The Journal of biological chemistry》2005,280(35):31220-31229
Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs. 相似文献
103.
Boya P González-Polo RA Casares N Perfettini JL Dessen P Larochette N Métivier D Meley D Souquere S Yoshimori T Pierron G Codogno P Kroemer G 《Molecular and cellular biology》2005,25(3):1025-1040
Mammalian cells were observed to die under conditions in which nutrients were depleted and, simultaneously, macroautophagy was inhibited either genetically (by a small interfering RNA targeting Atg5, Atg6/Beclin 1-1, Atg10, or Atg12) or pharmacologically (by 3-methyladenine, hydroxychloroquine, bafilomycin A1, or monensin). Cell death occurred through apoptosis (type 1 cell death), since it was reduced by stabilization of mitochondrial membranes (with Bcl-2 or vMIA, a cytomegalovirus-derived gene) or by caspase inhibition. Under conditions in which the fusion between lysosomes and autophagosomes was inhibited, the formation of autophagic vacuoles was enhanced at a preapoptotic stage, as indicated by accumulation of LC3-II protein, ultrastructural studies, and an increase in the acidic vacuolar compartment. Cells exhibiting a morphology reminiscent of (autophagic) type 2 cell death, however, recovered, and only cells with a disrupted mitochondrial transmembrane potential were beyond the point of no return and inexorably died even under optimal culture conditions. All together, these data indicate that autophagy may be cytoprotective, at least under conditions of nutrient depletion, and point to an important cross talk between type 1 and type 2 cell death pathways. 相似文献
104.
Ye H Cande C Stephanou NC Jiang S Gurbuxani S Larochette N Daugas E Garrido C Kroemer G Wu H 《Nature structural biology》2002,9(9):680-684
The execution of apoptosis or programmed cell death comprises both caspase-dependent and caspase-independent processes. Apoptosis inducing factor (AIF) was identified as a major player in caspase-independent cell death. It induces chromatin condensation and initial DNA cleavage via an unknown molecular mechanism. Here we report the crystal structure of human AIF at 1.8 A resolution. The structure reveals the presence of a strong positive electrostatic potential at the AIF surface, although the calculated isoelectric point for the entire protein is neutral. We show that recombinant AIF interacts with DNA in a sequence-independent manner. In addition, in cells treated with an apoptotic stimulus, endogenous AIF becomes co-localized with DNA at an early stage of nuclear morphological changes. Structure-based mutagenesis shows that DNA-binding defective mutants of AIF fail to induce cell death while retaining nuclear translocation. The potential DNA-binding site identified from mutagenesis also coincides with computational docking of a DNA duplex. These observations suggest that AIF-induced nuclear apoptosis requires a direct interaction with DNA. 相似文献
105.
Kinases represent one of the most important target classes of current drug discovery efforts. However, because the vast majority of potential small-molecule therapeutics is directed toward the highly conserved ATP-binding cleft, kinase inhibitors often exhibit significant unintended off-target effects. A recent report describes a chemical proteomics methodology that enables the simultaneous in vivo quantification of the on- and off-binding targets of kinase inhibitors across hundreds of nucleotide-dependent enzymes. 相似文献
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107.
Tamara Hirsch Didier Decaudin Santos A. Susin Philippe Marchetti Nathanael Larochette Michèle Resche-Rigon Guido Kroemer 《Experimental cell research》1998,241(2):426
One critical step of the apoptotic process is the opening of the mitochondrial permeability transition (PT) pore leading to the disruption of mitochondrial membrane integrity and to the dissipation of the inner transmembrane proton gradient (ΔΨm). The mitochondrial PT pore is a polyprotein structure which is inhibited by the apoptosis-inhibitory oncoprotein Bcl-2 and which is closely associated with the mitochondrial benzodiazepine receptor (mBzR). Here we show that PK11195, a prototypic ligand of the 18-kDa mBzR, facilitates the induction of ΔΨmdisruption and subsequent apoptosis by a number of different agents,including agonists of the glucocorticoid receptor,chemotherapeutic agents (etoposide, doxorubicin),gamma irradiation, and the proapoptotic second messenger ceramide. Whereas PK11195 itself has no cytotoxic effect, it enhances apoptosis induction by these agents. This effect is not observed for benzodiazepine diazepam, whose binding site in the mBzR differs from PK11195. PK11195 partially reverses Bcl-2 mediated inhibition of apoptosis in two different cell lines. Thus, transfection-enforced Bcl-2 overexpression confers protection against glucocorticoids and chemotherapeutic agents, and this protection is largely reversed by the addition of PK11195. This effect is observed at the level of ΔΨmdissipation as well as at the level of nuclear apoptosis. To gain insights into the site of action of PK11195, we performed experiments on isolated organelles. PK11195 reverses the Bcl-2-mediated mitochondrial retention of apoptogenic factors which cause isolated nuclei to undergo apoptosis in a cell-free system. Mitochondria from control cells, but not mitochondria from Bcl-2-overexpressing cells, readily release such apoptogenic factors in response to atractyloside, a ligand of the adenine nucleotide translocator. However, control and Bcl-2-overexpressing mitochondria respond equally well to a combination of atractyloside and PK11195. Altogether, these findings indicate that PK11195 abolishes apoptosis inhibition by Bcl-2 via a direct effect on mitochondria. Moreover, they suggest a novel strategy for enhancing the susceptibility of cells to apoptosis induction and, concomitantly, for reversing Bcl-2-mediated cytoprotection. 相似文献
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109.
Mehmet Haluk Morgul Katrin Splith Christoph Leonhardt Nathanael Raschzok Anja Reutzel-Selke Rosa Bianca Schmuck 《Biomarkers》2018,23(1):25-32
Context: Non-invasive markers for diagnosis of acute rejection (AR) following liver transplantation have not been developed, yet.Objective: We analyzed the correlation of plasma microparticle levels (MP) with AR.Materials and Methods: MP (CD4, CD8, CD25, CD31, MHC) of 11?AR patients and 11 controls were analyzed within the first week after transplantation.Results: CD4, CD8 and CD31 positive MP were higher in the AR, whereas overall MP count, CD25 and MHCI positive MP proportions did not differ between both groups.Discussion and Conclusion: MP dynamics within the first period of transplantation could help to clarify on-going mechanisms of immunomodulation. 相似文献
110.
Mariscal Carlos Barahona Ana Aubert-Kato Nathanael Aydinoglu Arsev Umur Bartlett Stuart Cárdenas María Luz Chandru Kuhan Cleland Carol Cocanougher Benjamin T. Comfort Nathaniel Cornish-Bowden Athel Deacon Terrence Froese Tom Giovannelli Donato Hernlund John Hut Piet Kimura Jun Maurel Marie-Christine Merino Nancy Moreno Alvaro Nakagawa Mayuko Peretó Juli Virgo Nathaniel Witkowski Olaf James Cleaves H. 《Origins of life and evolution of the biosphere》2019,49(3):111-145
Origins of Life and Evolution of Biospheres - In this review, we describe some of the central philosophical issues facing origins-of-life research and provide a targeted history of the developments... 相似文献