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61.
Polychronis Kotoglou Alexandros Kalaitzakis Patra Vezyraki Theodore Tzavaras Lampros K. Michalis Francoise Dantzer Jae U. Jung Charalampos Angelidis 《Cell stress & chaperones》2009,14(4):391-406
For many years, there has been uncertainty concerning the reason for Hsp70 translocation to the nucleus and nucleolus. Herein,
we propose that Hsp70 translocates to the nucleus and nucleoli in order to participate in pathways related to the protection
of the nucleoplasmic DNA or ribosomal DNA from single-strand breaks. The absence of Hsp70 in HeLa cells, via Hsp70 gene silencing
(knockdown), indicated the essential role of Hsp70 in DNA integrity. Therefore, HeLa Hsp70 depleted cells were very sensitive
in heat treatment and their DNA breaks were multiple compared to that of control HeLa cells. The molecular mechanism with
which Hsp70 performs its role at the level of nucleus and nucleolus during stress was examined. Hsp70 co-localizes with PARP1
in the nucleus/nucleoli as was observed in confocal studies and binds to the BCRT domain of PARP1 as was revealed with protein–protein
interaction assays. It was also found that Hsp70 binds simultaneously to XRCC1 and PARP-1, indicating that Hsp70 function
takes place at the level of DNA repair and possibly at the base excision repair system. Making a hypothetical model, we have
suggested that Hsp70 is the molecule that binds and interrelates with PARP1 creating the repair proteins simultaneously, such
as XRCC1, at the single-strand DNA breaks. Our data partially clarify a previously unrecognized cellular response to heat
stress. Finally, we can speculate that Hsp70 plays a role in the quality and integrity of DNA.
Outlining prior scientific knowledge on the subject and novel information: The role of Hsp70 translocation to the nucleus
and nucleolus during heat stress has been nearly unknown. It has been proposed that this biological phenomenon is correlated
to Hsp70-chaperoning activity. Furthermore, some previous observations in yeast have revealed that Rad9 complexes—Rad9 being
the prototype DNA-damage checkpoint gene—contain Ssa1 and or Ssa2 chaperone proteins, both reconstituting the functions of
the corresponding Hsp70 in mammalian cells. Here, we propose that Hsp70 translocates to the nuclei/nucleoli during heat stress,
binds to PARP-1 and/or XRCC1, and protects HeLa cells from increased single-strand DNA breaks. 相似文献
62.
Ashish K. Patra 《Journal of molecular biology》2009,389(4):759-2444
The modulation of the folding mechanism of the small protein single-chain monellin (MNEI) by the Escherichia coli chaperone GroEL has been studied. In the absence of the chaperone, the folding of monellin occurs via three parallel routes. When folding is initiated in the presence of a saturating concentration of GroEL, only 50-60% of monellin molecules fold completely. The remaining 40-50% of the monellin molecules remain bound to the GroEL and are released only upon addition of ATP. It is shown that the basic folding mechanism of monellin is not altered by the presence of GroEL, but that it occurs via only one of the three available routes when folding is initiated in the presence of saturating concentrations of GroEL. Two pathways become nonoperational because GroEL binds very tightly to early intermediates that populate these pathways in a manner that makes the GroEL-bound intermediates incompetent to fold. This accounts for the monellin molecules that remain GroEL-bound at the end of the folding reaction. The third pathway remains operational because the GroEL-bound early intermediate on this pathway is folding-competent, suggesting that this early intermediate binds to GroEL in a manner that is different from that of the binding of the early intermediates on the other two pathways. It appears, therefore, that the same protein can bind GroEL in more than one way. The modulation of the folding energy landscape of monellin by GroEL occurs because GroEL binds folding intermediates on parallel folding pathways, in different ways, and with different affinities. Moreover, when GroEL is added to refolding monellin at different times after commencement of refolding, the unfolding of two late kinetic intermediates on two of the three folding pathways can be observed. It appears that the unfolding of late folding intermediates is enabled by a thermodynamic coupling mechanism, wherein GroEL binds more tightly to an early intermediate than to a late intermediate on a folding pathway, with preferential binding energy being larger than the stability of the late intermediate. Hence, it is shown that GroEL can inadvertently and passively cause, through its ability to bind different folding intermediates differentially, the unfolding of late productive intermediates on folding pathways, and that its unfolding action is not restricted solely to misfolded or kinetically trapped intermediates. 相似文献
63.
Sugar moieties serve as specificity markers in a wide variety of biochemical functions, and periplasmic glucose/galactose-binding proteins (GGBPs) serve as the primary receptors for transport and chemotaxis. Recently, complete genome sequencing projects have revealed many open reading frames for such receptors. On the basis of the homology search with the known x-ray structures (PDB ID: 3GBP/1GCA) of a periplasmic receptor protein from Salmonella typhimurium, we selected four putative proteins with amino acid identities between 30 and 48% for the prediction of three-dimensional (3D) structures of the proteins as well as their complexes with glucose and galactose. We could successfully identify the key residues involved in coordination with calcium ion spanning over two loop structures. We calculated the ligand-binding affinities and hydrogen bonding patterns of the modeled structures and compared with those of the x-ray structures. The calculation of free energies of binding of the modeled structures to glucose and galactose in the presence of water suggested that two of four putative proteins can form complexes with dissociation constants in the micromolar range (1-10 microM). Electrostatic potentials on the surfaces near the sugar and calcium-binding sites of the modeled structures were predominately negative as found in case of the x-ray structure. Taken together, our results suggest that the products of two newly discovered genes would serve as receptors for the transport of glucose and galactose. 相似文献
64.
Jones Boby Harihar Prasad Gupta Mustapha Hussain Jan Sanjay Kumar Singh Manas Kumar Patra 《Animal biotechnology》2017,28(3):163-167
Emerging evidence shows that some of the pro-inflammatory cytokines are elevated not only in the endometrium but also in the follicular fluid of cows with endometritis. Developing a cervico-vaginal mucus (CVM) based test has the potential for becoming a pen-side test because of the ease of sample collection. The present study describes the results of two different experiments. The first experiment was conducted to investigate the influence of endometritis on the proinflammatory cytokines of follicular fluid based on the reproductive tracts of buffalo collected at a slaughter house Buffalo genitalia were categorized into purulent endometritis (PE), cytological endometritis (CE), and non-endometritis (NE) based on the white-side test and endometrial cytology, respectively (n?=?14/group). Each group was subdivided into follicular and mid-luteal stage (n?=?7/stage) and the follicular fluid was collected from the largest follicle. Second experiment was done to study the difference in the levels of proinflammatory cytokines in the CVM of repeat breeders with subclinical endometritis presented to the clinic. CVM was collected from the repeaters (n?=?10) and non-repeaters (n?=?10) through aseptic trans-vaginal aspiration. The pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, and TNFα were quantitated through bovine specific ELISA kits. Significantly higher concentrations of pro-inflammatory cytokines (IL-1β, IL-8, IL-6, and TNFα) along with low intra-follicular estradiol in buffaloes of PE and CE groups suggest that endometritis impedes the follicular steroidogenesis. Significantly higher concentration of IL-1β and TNF-α in the CVM of repeaters indicate their potential as a pen-side diagnostic test for CE. 相似文献
65.
Subhadip Hajra Abhishek Basu Somnath Singha Roy Arup Ranjan Patra Sudin Bhattacharya 《Free radical research》2017,51(9-10):812-827
The most crucial complication related to doxorubicin (DOX) therapy is nonspecific cytotoxic effect on healthy normal cells. The clinical use of this broad-spectrum chemotherapeutic agent is restricted due to development of severe form of cardiotoxicity, myelosuppression, and genotoxicity which interfere with therapeutic schedule, compromise treatment outcome and may lead to secondary malignancy. 3,3′-diindolylmethane (DIM) is a naturally occurring plant alkaloid formed by the hydrolysis of indolylmethyl glucosinolate (glucobrassicin). Therefore, the present study was undertaken to investigate the protective role of DIM against DOX-induced toxicity in mice. DOX was administered (5?mg/kg b.w., i.p.) and DIM was administered (25?mg/kg b.w., p.o.) in concomitant and 15 days pretreatment schedule. Results showed that DIM significantly attenuated DOX-induced oxidative stress in the cardiac tissues by reducing the levels of free radicals and lipid peroxidation, and by enhancing the level of glutathione (reduced) and the activity of antioxidant enzymes. The chemoprotective potential of DIM was confirmed by histopathological evaluation of heart and bone marrow niche. Moreover, DIM considerably mitigated DOX-induced clastogenicity, DNA damage, apoptosis, and myeloid hyperplasia in bone marrow niche. In addition, oral administration of DIM significantly (p?.05) stimulated the Nrf2-mediated activation of antioxidant response element (ARE) pathway and promoted expression of ARE-driven cytoprotective proteins, HO-1, NQO1, and glutathione-S-transferase (GST). In connection with that, DIM significantly attenuated DOX-induced apoptosis by upregulation of Bcl-2 expression and downregulation of Bax and caspase-3 expression. Thus, this study suggests that DIM has promising chemoprotective efficacy against DOX-induced toxicity and indicates its future use as an adjuvant in chemotherapy. 相似文献
66.
One monomeric neutral Cu(II) complex [(pmtpm)CuCl2] (1) is reported by Lindoy and Livingstone [8]. Two new complexes namely, μ-Cl bridged binuclear Cu(II) complex [{(pmtpm)Cu(Cl)}2 μ-Cl](ClO4) (2) and a bis μ-Cl bridged binuclear Cu(II) complex [{(pmtpm)Cu}2(μ-Cl)2](ClO4)2 (3) derived from a tridentate Schiff base ligand, 2-pyridyl-N-(2′-methylthiophenyl)methyleneimine (pmtpm) were synthesized and characterized by various spectroscopic methods and by X-ray crystallography. (N2S)CuCl2 chromophore(s) of distorted square pyramidal coordination geometries around Cu(II) ion(s) have been observed for all the complexes 1-3. The equatorial sites of the square plane comprise two N and a thioether S donor atoms of the pmtpm ligand as well as one Cl− ion (terminal in 1 and 2, and bridging in 3) while the remaining axial site is occupied by a terminal Cl− ion (for 1) or a bridging Cl− ion (for 2 and 3). The equatorial Cu-Cl distances are much shorter [1: 2.2511(4) Å, 2: 2.2307(12) Å, 3: 2.2513(12) Å] than the axial Cu-Cl distances [1: 2.4394(4) Å, 2: 2.5597(9) Å, 3: 2.7037(12) Å]. The correlation of an axial Cu-Cl bond elongation with a lower g|| value in the solid state EPR spectrum and a blue shifted ligand field transition in the solid and solution phase absorption spectrum has been observed. 相似文献
67.
Patra D DeLassus E Hayashi S Sandell LJ 《The Journal of biological chemistry》2011,286(33):29227-29240
Site-1 protease (S1P) is a proprotein convertase with essential functions in lipid homeostasis and unfolded protein response pathways. We previously studied a mouse model of cartilage-specific knock-out of S1P in chondroprogenitor cells. These mice exhibited a defective cartilage matrix devoid of type II collagen protein (Col II) and displayed chondrodysplasia with no endochondral bone formation even though the molecular program for endochondral bone development appeared intact. To gain insights into S1P function, we generated and studied a mouse model in which S1P is ablated in postnatal chondrocytes. Postnatal ablation of S1P results in chondrodysplasia. However, unlike early embryonic ablations, the growth plates of these mice exhibit a lack of Ihh, PTHrP-R, and Col10 expression indicating a loss of chondrocyte hypertrophic differentiation and thus disruption of the molecular program required for endochondral bone development. S1P ablation results in rapid growth plate disruption due to intracellular Col II entrapment concomitant with loss of chondrocyte hypertrophy suggesting that these two processes are related. Entrapment of Col II in the chondrocytes of the prospective secondary ossification center precludes its development. Trabecular bone formation is dramatically diminished in the primary spongiosa and is eventually lost. The primary growth plate is eradicated by apoptosis but is gradually replaced by a fully functional new growth plate from progenitor stem cells capable of supporting new bone growth. Our study thus demonstrates that S1P has fundamental roles in the preservation of postnatal growth plate through chondrocyte differentiation and Col II deposition and functions to couple growth plate maturation to trabecular bone development in growing mice. 相似文献
68.
Zhao H Patra A Yeh CC Tanaka Y Oh BR Dahiya R 《Biochemical and biophysical research communications》2002,292(2):482-491
We hypothesize that various growth factors and their receptors gene and protein are modulated in dorsal and ventral lobes of aging prostate. To test this hypothesis, TGFbeta1, TGFbeta2 TGFbeta3, TGFbetaR-I, TGFbetaR-II, TGFalpha, EGF, EGFR, KGF and KGFR gene and protein expression were analyzed in dorsal and ventral lobes of aging rat prostates (1, 3, 6, 9, 12, 18, 24, and 28/30 months). KGF gene expression was very weak or absent in 1, 3, and 6 month old rat dorsal and ventral lobes of prostate whereas it re-expressed in 9, 12, 18, 24 and 30 month old rat prostate. All growth factors and their receptors expect KGF and EGFR were mainly localized in epithelium of ventral and dorsal lobes of aging rat prostates. EGF, TGFalpha, TGFbeta1, and TGFbetaR-I protein expression was lacking in stroma of dorsal and ventral lobes of 1, 3, 6, 9, 12/18 months old rat prostates. However, EGF, TGFbeta1 and TGFbetaR-I proteins re-expressed in stroma of 24 and 28 months old rat prostates. KGF protein expression was lacking in epithelium of dorsal and ventral lobes of all aging rat prostates. This is the first report to demonstrate differential gene and protein expression of growth factors in dorsal and ventral lobes is associated with aging rat prostate, suggesting their role in pathogenesis of prostatic diseases with aging. 相似文献
69.
70.