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1.
Wood-grown cultures of Daldinia concentrica oxidized a permethylated beta-(14)C-labeled synthetic lignin to (14)CO(2) and also cleaved a permethylated alpha-(13)C-labeled synthetic lignin to give C(alpha)-C(beta) cleavage products that were detected by (13)C nuclear magnetic resonance spectrometry. Therefore, this ascomycete resembles white-rot basidiomycetes in attacking the recalcitrant nonphenolic structures that predominate in lignin. 相似文献
2.
Mitochondrial outer membrane permeabilization and the release of intermembrane space proteins, such as cytochrome c, are early events during intrinsic (mitochondria-mediated) apoptotic signaling. Although this process is generally accepted to require the activation of Bak or Bax, the underlying mechanism responsible for their activation during true intrinsic apoptosis is not well understood. In the current study, we investigated the molecular requirements necessary for Bak activation using distinct clones of Bax-deficient Jurkat T-lymphocytes in which the intrinsic pathway had been inhibited. Cells stably overexpressing Bcl-2/Bcl-x(L) or stably depleted of Apaf-1 were equally resistant to apoptosis induced by the DNA-damaging anticancer drug etoposide as determined by phosphatidylserine externalization and caspase activation. Strikingly, characterization of mitochondrial apoptotic events in all three drug-resistant cell lines revealed that, without exception, resistance to apoptosis was associated with an absence of Bak activation, cytochrome c release, and mitochondrial membrane depolarization. Furthermore, we found that etoposide-induced apoptosis and mitochondrial events were inhibited in cells stably overexpressing either full-length X-linked inhibitor of apoptosis protein (XIAP) or the BIR1/BIR2 domains of XIAP. Combined, our findings suggest that caspase-mediated positive amplification of initial mitochondrial changes can determine the threshold for irreversible activation of the intrinsic apoptotic pathway. 相似文献
3.
S V Shirshev N N Kevorkov N I Shary? 《Biulleten' eksperimental'no? biologii i meditsiny》1987,104(9):337-340
The influence of chorionic gonadotropin (CG) on the interaction of spleen T- and B-cells has been studied in adoptive transfer system. It has been established that CG increases the primary immune response in non-ovariectomized mice. This effect reversely depended on the hormone concentration and was independent of prostaglandins (PG). In the experiments on ovariectomized mice the influence of CG was opposite and the immune response was decreased. This action was completely abolished by Voltren-induced blockade of UG-synthetase. In spleen cell culture of female mice CG suppresses the synthesis of interleukin-2 (IL-2). It is suggested that CG may have an independent immunosuppressive action, the mechanism of which consists of disturbed cell-to-cell communications on the level of short-acting mediators of the immunity--PG and IL-2. 相似文献
4.
P. A. Shary L. S. Sharaya L. V. Sidyakina S. V. Saksonov 《Contemporary Problems of Ecology》2017,10(5):464-475
The perpendicularity of sunlight incidence on the land surface, called slope insolation, is calculated as the nonlinear function of steepness and exposure. This variable better describes the light and thermal regimes of slopes. We demonstrate that grass-cover insolation can be estimated based on the slope insolation and tree-crown closure. It is found for a terrain at the southern boundary of the forest steppe that species richness and green mass of grasses are closely related to topography and grass-cover insolation (R 2 = 0.77 and R 2 = 0.83, respectively), and crown closure is closely related to topography and slope insolation from the south (R 2 = 0.85). A critical level of crown closure (15%) is determined, so that the limiting factor for grasses is soil moisture below and light above this level. It is shown that grass-cover insolation close to its average value (400 W/m2) differentiates phytocenotic and soil characteristics into areas of increased and diminished values. 相似文献
5.
The effect of radiation on the production of interleukin 2 by activated lymphocytes was shown to be a function of time interval between irradiation and mitogen stimulation of cells. The most intensive production of interleukin 2 was noted in cells exposed 24 h following the effect of the mitogen. The enhancing effect of in vivo irradiation was less pronounced. 相似文献
6.
Shary N. Shelton Mary E. Shawgo John D. Robertson 《The Journal of biological chemistry》2009,284(17):11247-11255
The extent to which the BH3-only protein Bid is important for intrinsic
(mitochondria-mediated) apoptotic cell death induced by genotoxic stress
remains controversial. In the present study, we examine this issue using a
panel of gene-manipulated Bax-deficient Jurkat T-lymphocytes. Cells stably
depleted of Bid were far less sensitive than control-transfected cells to
etoposide-induced apoptosis. In particular, drug-induced Bak activation,
cytochrome c release, loss of mitochondrial membrane potential, and
caspase activation were all decreased in cells lacking Bid. Reconstitution
experiments using recombinant proteins and permeabilized Bid-deficient cells
demonstrated that truncated Bid (tBid), but not full-length Bid, potently
induced Bak activation and the release of cytochrome c. Further,
caspase-8-deficient Jurkat cells efficiently cleaved Bid and were sensitive to
drug-induced apoptosis. By comparison, Apaf-1-deficient cells, as well as
cells overexpressing full-length X-linked inhibitor of apoptosis protein
(XIAP) or the BIR1/BIR2 domains of XIAP, failed to cleave Bid in response to
genotoxic stress. These data suggest that tBid plays an important regulatory
role in the execution of DNA damage-induced cytochrome c release and
apoptosis. However, the fact that cleavage of Bid to tBid is mediated by
executioner caspases suggests that a self-amplifying feed forward loop
involving caspases, Bid, and mitochondria may help determine irreversible
commitment to apoptosis.Apoptosis is an active form of cell death that plays an essential role
during normal embryonic development and in the maintenance of tissue
homeostasis in the adult organism
(1). Consequently,
dysregulation of apoptosis has been implicated as a contributing factor to the
onset of different pathological conditions, including cancer. In addition, it
is now generally accepted that many genotoxic anticancer drugs are effective
against tumor cells for their ability to induce mitochondria-mediated
apoptosis (2). Similarly,
mutations or the altered expression of pro- and anti-apoptotic proteins can
contribute to the development of drug resistance.Execution of apoptosis is mediated by a family of cysteine-dependent
aspartate-specific proteases (caspases). During true mitochondria-mediated
apoptosis, members of the Bcl-2 family of proteins are the primary regulators
of caspase activation for their role in controlling mitochondrial outer
membrane permeabilization
(MOMP)2
(3). The process of MOMP
results in the release of cytochrome c, second mitochondria-derived
activator of caspase (Smac, also known as DIABLO), and Omi (also known as
HtrA2) into the cytosol where they converge to promote the activation of
caspase-9 within the apoptotic protease-activating factor-1 (Apaf-1)
apoptosome complex. The Bcl-2 family contains proteins with opposing
functions, and it is generally thought that the induction of MOMP requires the
activation of either Bak or Bax triggered by a Bcl-2 homology 3 (BH3)-only
protein
(4–6).
Indeed, evidence in the literature indicates that cells lacking either Bak or
Bax exhibit only subtle defects in MOMP, whereas doubly deficient cells are
often found to be highly resistant to mitochondria-mediated apoptosis
(7,
8).At present, there are two models for the activation of Bax or Bak by
BH3-only proteins. One model argues that BH3-only proteins function as either
“sensitizer” (e.g. Bad and Noxa) or
“activator” proteins (e.g. truncated Bid (tBid), Bim, and
perhaps Puma) (9). In this
scenario, a sensitizer protein is needed to displace an activator protein from
a prosurvival protein (e.g. Bcl-2, Bcl-xL, or Mcl-1) to
activate Bak or Bax. The second model argues that BH3-only proteins bind and
inhibit the function of prosurvival Bcl-2 proteins, which normally bind to and
inhibit Bak and Bax (10,
11). Of the seven or so known
BH3-only proteins (6), Bid is
unique in that it requires post-translational modification for activation,
most notably involving caspase-8-mediated cleavage to tBid
(12–14).
Bid normally resides in the cytosol and possibly the nucleus
(15). Upon being cleaved, the
C-terminal fragment (tBid) is myristoylated at its newly exposed N terminus,
translocates to the outer mitochondrial membrane (OMM), and/or activates Bak
or Bax protein (16). Recently,
it was shown that the N-terminal cleavage fragment of Bid is quickly
ubiquitinated for degradation and that this degradation is necessary for the
pro-apoptotic function of tBid
(17). The same study also
concluded that, although full-length Bid is capable of translocating to the
OMM, it is not able to induce MOMP on its own
(17). A well characterized
example of tBid involvement during apoptosis is in the engagement of the
mitochondrial apoptotic pathway in so-called type II cells upon activation of
the extrinsic pathway
(18).Here, we have investigated whether Bid plays a functional role in the
induction of MOMP during apoptosis in response to the genotoxic anticancer
drug etoposide. To that end, we used Bax-deficient Jurkat cells that are
stably depleted of Bid and evaluated the extent to which these cells underwent
drug-induced MOMP. In addition, Jurkat clones in which the intrinsic pathway
had been inhibited due to the stable knockdown of Apaf-1 or the overexpression
of full-length XIAP or the baculoviral IAP repeats 1 and 2 (BIR1/BIR2) of XIAP
were used to gain insight into the molecular requirements necessary for
cleavage of Bid to tBid during drug-induced apoptosis. Strikingly, the data
showed that etoposide-induced apoptosis was decreased in Bid-deficient Jurkat
cells. In particular, cells lacking Bid expression exhibited decreased Bak
activation, cytochrome c release, loss of mitochondrial membrane
potential (ΔΨ), and caspase activation. Further, incubation of
permeabilized Bid-deficient cells with recombinant tBid, but not full-length
Bid, induced Bak dimerization and cytochrome c release.
Significantly, we also found that cleavage of Bid to tBid occurred strictly
downstream of Apaf-1 by a mechanism that required active executioner
caspases. 相似文献
7.
Mary E. Shawgo Shary N. Shelton John D. Robertson 《The Journal of biological chemistry》2009,284(48):33447-33455
Activation of executioner caspases during receptor-mediated apoptosis in type II cells requires the engagement of the mitochondrial apoptotic pathway. Although it is well established that recruitment of mitochondria in this context involves the cleavage of Bid to truncated Bid (tBid), the precise post-mitochondrial signaling responsible for executioner caspase activation is controversial. Here, we used distinct clones of type II Jurkat T-lymphocytes in which the mitochondrial apoptotic pathway had been inhibited to investigate the molecular requirements necessary for Fas-induced apoptosis. Cells overexpressing either Bcl-2 or Bcl-xL were protected from apoptosis induced by agonistic anti-Fas antibody. By comparison, Apaf-1-deficient Jurkat cells were sensitive to anti-Fas, exhibiting Bid cleavage, Bak activation, the release of cytochrome c and Smac, and activation of executioner caspase-3. Inhibiting downstream caspase activation with the pharmacological inhibitor Z-DEVD-fmk or by expressing the BIR1/BIR2 domains of X-linked inhibitor of apoptosis protein (XIAP) decreased all anti-Fas-induced apoptotic changes. Additionally, pretreatment of Bcl-xL-overexpressing cells with a Smac mimetic sensitized these cells to Fas-induced apoptosis. Combined, our findings strongly suggest that Fas-mediated activation of executioner caspases and induction of apoptosis do not depend on apoptosome-mediated caspase-9 activation in prototypical type II cells. 相似文献
8.
Multiple targeting modules on peroxisomal proteins are not redundant: discrete functions of targeting signals within Pmp47 and Pex8p 总被引:1,自引:0,他引:1 下载免费PDF全文
Wang X McMahon MA Shelton SN Nampaisansuk M Ballard JL Goodman JM 《Molecular biology of the cell》2004,15(4):1702-1710
Several peroxisomal proteins have two nonoverlapping targeting signals. These signals have been termed “redundant” because targeting can still occur with only one signal. We now report that separate targeting motifs within both Pmp47 and Pex8 provide complementary function. Pmp47 is an ATP translocator that contains six transmembrane domains (TMDs). We had previously shown that the TMD2 region (termed TMD2R, consisting of TMD2 and a short adjacent segment of cytosolic loop) was required for targeting to proliferated peroxisomes in Saccharomyces cerevisiae. We now report that the analogous TMD4R, which cannot target to proliferated peroxisomes, targets at least as well, or much better (depending on strain and growth conditions) in cells containing only basal (i.e., nonproliferated) peroxisomes. These data suggest differences in the targeting pathway among peroxisome populations. Pex8p, a peripheral protein facing the matrix, contains a typical carboxy terminal targeting sequence (PTS1) that has been shown to be nonessential for targeting, indicating the existence of a second targeting domain (not yet defined in S. cerevisiae); thus, its function was unknown. We show that targeting to basal peroxisomes, but not to proliferated peroxisomes, is more efficient with the PTS1 than without it. Our results indicate that multiple targeting signals within peroxisomal proteins extend coverage among heterogeneous populations of peroxisomes and increase efficiency of targeting in some metabolic states. 相似文献
9.
Background
Appropriate responses to damaged DNA are indispensible for preserving genome stability and preventing cancer. Tumor viruses often target DNA repair machinery to achieve transformation. The Human T-cell leukemia virus type I (HTLV-I) is the only known transforming human retrovirus and the etiological agent of Adult T-cell Leukemia (ATLL). Although HTLV-I-transformed leukemic cells have numerous genetic lesions, the precise role of the viral tax gene in this process is not fully understood.Results
Our results show a novel function of HTLV-I oncoprotein Tax as an inducer of genomic DNA double strand breaks (DDSB) during DNA replication. We also found that Tax acts as a potent inhibitor of homologous recombination (HR) DNA repair through the activation of the NF-kB pathway. These results were confirmed using HTLV-I molecular clones expressing Tax at physiological levels in a natural context. We further found that HTLV-I- and Tax-transformed cells are not more susceptible to DNA damaging agents and repair DNA lesions at a rate similar to that of normal cells. Finally, we demonstrated that during S phase, Tax-associated DDSB are preferentially repaired using the error-prone non-homologous end joining (NHEJ) pathway.Conclusions
This study provides new insights in Tax effects on DNA repair and genome instability. Although it may not be self sufficient, the creation of DNA breaks and subsequent abnormal use of the non-conservative NHEJ DNA repair during the S phase in HTLV-I-infected Tax-expressing cells may cooperate with other factors to increase genetic and genome instability and favor transformation. 相似文献10.