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1.
Wang SH Shih YL Ko WC Wei YH Shih CM 《Cellular and molecular life sciences : CMLS》2008,65(22):3640-3652
The cytotoxicity of cadmium (Cd) induced autophagy and apoptosis in MES-13 cells was determined by flow cytometry. Autophagy
was also assessed by formation of autophagosomes and processing of LC3. Pharmacological inhibition of autophagy resulted in
increased of cell viability, suggesting autophagy plays a role in cell death in Cd-treated mesangial cells. Cd also induced
a rapid elevation in cytosolic calcium ([Ca2+]i ), and modulation of [Ca2+]i via treatment with IP
3R inhibitor or knockdown of calcineurin resulted in a change in the proportion of cell death, suggesting that the release
of calcium from the ER plays a crucial role in Cd-induced cell death. Inhibition of Cd-induced ERK activation by PD 98059
suppressed Cd-induced autophagy, and BAPTA-AM eliminated activation of ERK. BAPTA-AM also inhibited Cd-induced mitochondrial
depolarization and activation of caspases. These findings demonstrated that Cd induces both autophagy and apoptosis through
elevation of [Ca2+]i, followed by Ca2+-ERK and Ca2+-mitochondria-caspase signaling pathways.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 05 July 2008; received after revision 25 August 2008; accepted 17 September 2008 相似文献
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Berger W Steiner E Grusch M Elbling L Micksche M 《Cellular and molecular life sciences : CMLS》2009,66(1):43-61
The unique and evolutionary highly conserved major vault protein (MVP) is the main component of ubiquitous, large cellular
ribonucleoparticles termed vaults. The 100 kDa MVP represents more than 70% of the vault mass which contains two additional
proteins, the vault poly (ADP-ribose) polymerase (vPARP) and the telomerase-associated protein 1 (TEP1), as well as several
short untranslated RNAs (vRNA). Vaults are almost ubiquitously expressed and, besides chemotherapy resistance, have been implicated
in the regulation of several cellular processes including transport mechanisms, signal transmissions and immune responses.
Despite a growing amount of data from diverse species and systems, the definition of precise vault functions is still highly
complex and challenging. Here we review the current knowledge on MVP and vaults with focus on regulatory functions in intracellular
signal transduction and immune defence.
Received 27 June 2008; received after revision 25 July 2008; accepted 30 July 2008 相似文献
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Hsu SP Ho PY Juan SH Liang YC Lee WS 《Cellular and molecular life sciences : CMLS》2008,65(23):3839-3850
Previous studies have shown that progesterone inhibits endothelial cell proliferation through a nuclear receptor-mediated
mechanism. Here, we further demonstrate that progesterone at physiologic levels (5 – 500 nM) dose- and time-dependently inhibited
DNA synthesis of cultured human umbilical vein endothelial cells (HUVEC). The mRNA and protein levels of p21, p27, and p53
in HUVEC were increased by progesterone. The formation of CDK2-p21 and CDK2-p27 were increased and the CDK2 activity was decreased
in the progesterone-treated HUVEC. The progesterone-inhibited [3H]thymidine incorporation was completely blocked when the
expressions of p21 and p27 were knocked-down together. Transfection of HUVEC with dominant negative p53 cDNA prevented the
progesterone-induced increases in p21 and p27 promoter activity and protein level, decreases in thymidine incorporation, and
capillary-like tube formation. Matrigel angiogenesis assay in mice demonstrated the antiangiogenic effect of progesterone
in vivo. These findings demonstrate for the first time that progesterone inhibited endothelial cell proliferation through a p53-dependent
pathway.
Received 28 July 2008; received after revision 25 September 2008; accepted 26 September 2008 相似文献
6.
S. M. Houten M. Chegary H. te Brinke W. J. Wijnen J. F. C. Glatz J. J. F. P. Luiken F. A. Wijburg R. J. A. Wanders 《Cellular and molecular life sciences : CMLS》2009,66(7):1283-1294
Organs are flexible as to which substrates they will use to maintain energy homeostasis. Under well-fed conditions, glucose
is a preferred substrate for oxidation. During fasting, fatty acid oxidation will become a more important energy source. Glucose
oxidation is decreased by fatty acids, a process in which the pyruvate dehydrogenase complex (PDH) and its regulator pyruvate
dehydrogenase kinase 4 (PDK4) play important roles. It is currently unknown how energy status influences PDH activity. We
show that AMP-activated protein kinase (AMPK) activation by hypoxia and AICAR treatment combined with fatty acid administration
synergistically induce PDK4 expression. We provide evidence that AMPK activation modulates ligand-dependent activation of
peroxisome proliferator-activated receptor. Finally, we show that this synergistic induction of PDK4 decreases cellular glucose
oxidation. In conclusion, AMPK and fatty acids play a direct role in fuel selection in response to cellular energy status
in order to spare glucose.
S. M. Houten, M. Chegary: These two authors contributed equally to this work.
Received 11 July 2008; received after revision 26 January 2009; accepted 02 February 2009 相似文献
7.
Structural biology of the purine biosynthetic pathway 总被引:1,自引:0,他引:1
Purine biosynthesis requires ten enzymatic transformations to generate inosine monophosphate. PurF, PurD, PurL, PurM, PurC,
and PurB are common to all pathways, while PurN or PurT, PurK/PurE-I or PurE-II, PurH or PurP, and PurJ or PurO catalyze the
same steps in different organisms. X-ray crystal structures are available for all 15 purine biosynthetic enzymes, including
7 ATP-dependent enzymes, 2 amidotransferases and 2 tetrahydrofolate-dependent enzymes. Here we summarize the structures of
the purine biosynthetic enzymes, discuss similarities and differences, and present arguments for pathway evolution. Four of
the ATP-dependent enzymes belong to the ATP-grasp superfamily and 2 to the PurM superfamily. The amidotransferases are unrelated,
with one utilizing an N-terminal nucleophileglutaminase and the other utilizing a triad glutaminase. Likewise the tetrahydrofolate-dependent
enzymes are unrelated. Ancestral proteins may have included a broad specificity enzyme instead of PurD, PurT, PurK, PurC,
and PurP, and a separate enzyme instead of PurM and PurL.
Received 26 May 2008; received after revision 30 June 2008; accepted 9 July 2008 相似文献
8.
Interaction of galectin-1 with caveolae induces mouse embryonic stem cell proliferation through the Src, ERas, Akt and mTOR signaling pathways 总被引:1,自引:0,他引:1
M. Y. Lee S. H. Lee J. H. Park H. J. Han 《Cellular and molecular life sciences : CMLS》2009,66(8):1467-1478
Galectins have the potential to provide a promising alternative for unveiling the complexity of embryonic stem (ES) cell self-renewal,
although the mechanism by which galectins maintain ES cell self-renewal has yet to be identified. Galectin-1 increased [3H]-thymidine incorporation as well as cyclin expression and decreased p27kip1 expression. Src and caveolin-1 phosphorylation was increased by galectin-1, and phospho-caveolin-1 was inhibited by PP2.
In addition, inhibition of caveolin-1 by small interfering RNA and methyl-β-cyclodextrin (Mβ-CD) decreased galectin-1-induced
cyclin expression and [3H]-thymidine incorporation. Galectin-1 caused Akt and mTOR phosphorylation, which is involved in cyclin expression. Galectin-1-induced
phospho-Akt and -mTOR was inhibited by PP2, ERas siRNA, caveolin-1 siRNA and Mβ-CD. Furthermore, mTOR phosphorylation was
decreased by LY294002 and Akt inhibitor. Galectin-1-induced increase in cyclin expression and decrease in p27kip1 was blocked by Akt inhibitor and rapamycin. In conclusion, galectin-1 increased DNA synthesis in mouse ES cells via Src,
caveolin-1 Akt, and mTOR signaling pathways.
Received 30 October 2008; received after revision 18 February 2009; accepted 24 February 2009 相似文献
9.
Junger WG 《Cellular and molecular life sciences : CMLS》2008,65(16):2528-2540
Chemotaxis allows polymorphonuclear neutrophils (PMN) to rapidly reach infected and inflamed sites. However, excessive influx of PMN damages host tissues. Better knowledge of the mechanisms that control PMN chemotaxis may lead to improved treatments of inflammatory diseases. Recent findings suggest that ATP and adenosine are involved in PMN chemotaxis. Therefore, these purinergic signaling processes may be suitable targets for novel therapeutic approaches to ameliorate host tissue damage. 相似文献
10.
G. M. C. Janssen P. Schwertman T. A. T. Wanga R. S. Jahangir Tafrechi P. J. A. van den Broek A. K. Raap 《Cellular and molecular life sciences : CMLS》2009,66(4):721-730
Cytoplasmic translation is under sophisticated control but how cells adapt its rate to constitutive loss of mitochondrial
oxidative phosphorylation is unknown. Here we show that translation is repressed in cells with the pathogenic A3243G mtDNA
mutation or in mtDNA-less ρ0 cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor
eIF-2α constitutively. Under conditions of exponential cell growth and mammalian target of rapamycin (mTOR) activation, eEF-2
becomes transiently phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, especially high in mutant
cells. Independent of AMPK and mTOR, eIF-2α is constitutively phosphorylated in mutant cells, likely a signature of endoplasmic
reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. While the AMPK/eEF-2K/eEF-2 pathway appears
to function in adaptation to physiological fluctuations in ATP levels in the mutant cells, the ER stress signified by constitutive
protein synthesis inhibition through eIF-2α-mediated repression of translation initiation may have pathobiochemical consequences.
Received 29 October 2008; received after revision 11 December 2008; accepted 16 December 2008 相似文献
11.
Protein kinase C (PKC) is an important signaling molecule in the heart, but its targets remain unclear. Using a PKC substrate
antibody, we detected a 40-kDa phosphorylated cardiac protein that was subsequently identified by tandem mass spectroscopy
as muscle creatine kinase (M-CK) with phosphorylation at serine 128. The forward reaction using ATP to generate phosphocreatine
was reduced, while the reverse reaction using phosphocreatine to generate ATP was increased following dephosphorylation of
immunoprecipitated M-CK with protein phosphatase 2A (PP2A) or PP2C. Despite higher PKC levels in diabetic hearts, decreased
phosphorylation of M-CK was more prominent than the reduction in its expression. Changes in CK activity in diabetic hearts
were similar to those found following dephosphorylation of M-CK from control hearts. The decrease in phosphorylation may act
as a compensatory mechanism to maintain CK activity at an appropriate level for cytosolic ATP regeneration in the diabetic
heart.
Received 15 September 2008; received after revision 30 September 2008; accepted 13 October 2008 相似文献
12.
Cho SJ Huh JE Song J Rhee DK Pyo S 《Cellular and molecular life sciences : CMLS》2008,65(20):3290-3303
Ikaros is known as a critical regulator of lymphocyte development. We examined the regulatory role of Ikaros in LPS/IFN-gamma-induced inducible nitric oxide synthase (iNOS) expression by macrophages. Our results showed that IK6 (Ikaros dominant negative isoform) induction increases the iNOS expression. Ikaros DNA binding activity on the iNOS promoter was decreased, and a mutation of the Ikaros-binding site on the iNOS promoter resulted in an increase in LPS/IFN-gamma-induced iNOS expression. LPS/IFN-gamma increased the histone (H3) acetylation on the Ikaros DNA binding site. These results suggest that Ikaros acts as a negative regulator on iNOS expression. Treatment with a casein kinase 2 (CK2) inhibitor reversed LPS/IFN-gamma-induced decrease in Ikaros DNA binding activity. Moreover, overexpression of kinase-inactive CK2 decreased iNOS expression and a significant amount of CK2alpha1 translocated into the nucleus in LPS/IFN-gamma-treated cells. Overall, these data indicate that LPS/IFN-gamma decreases the Ikaros DNA binding activity via the CK2 pathway, resulting in an increase of iNOS expression. 相似文献
13.
S. K. Grant 《Cellular and molecular life sciences : CMLS》2009,66(7):1163-1177
Protein kinase inhibitors represent an important and still emerging class of targeted therapeutic agents. Drug discovery and
development strategies have explored numerous approaches to target the inhibition of protein kinase signaling. This review
will highlight some of the strategies that have led to the successful clinical development of therapeutic protein kinase inhibitors,
particularly as anticancer drugs. Some notable advances have been made in the development of novel protein and oligonucleotide-based
biologics that target growth factor or receptor tyrosine kinases. Also, advances have been made in the rational design of
small-molecule inhibitors that target unique kinase conformational forms and binding sites, and have specific kinase selectivity
profiles. A review will also be given of some of the potential clinical toxicities and adverse side-effects associated with
these kinase-targeted drugs. Therapeutic protein kinase inhibitors have been highly beneficial to cancer patients and offer
the promise of future therapies for other diseases as well.
Received 02 September 2008; received after revision 13 October 2008; accepted 15 October 2008 相似文献
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Gene expression in spermiogenesis 总被引:10,自引:0,他引:10
Germ cells convey parental genes to the next generation, and only germ cells perform meiosis, which is a mechanism that preserves the parental genes. The fusion of the products of germ cell meiosis, the haploid sperm and egg, creates the next generation. Sperm are the haploid germ cells that contribute genes to the egg. In preparation for this, the haploid round spermatids produced by meiosis undergo drastic morphological changes to become sperm. During this process of spermiogenesis, the nuclear form of the haploid germ cell takes shape, the mitochondria are rearranged in a specific manner, the flagellum develops and the acrosome forms. Spermatogenesis is supported by precise and orderly regulation of gene expression during the changes in chromatin structure, when protamine replaces histone. In this report, we summarize the molecular mechanisms involved in spermiogenesis.Received 2 September 2004; received after revision 7 October 2004; accepted 7 October 2004 相似文献
17.
C. Akgul 《Cellular and molecular life sciences : CMLS》2009,66(8):1326-1336
Resistance to apoptosis is a common challenge in human malignancies contributing to both progress of cancer and resistance
to conventional therapeutics. Abnormalities in a variety of cell intrinsic and extrinsic molecular mechanisms cooperatively
promote tumor formation. Therapeutic approaches that specifically target components of these molecular mechanisms are getting
widespread attention. Mcl-1 is a highly expressed pro-survival protein in human malignancies and its cellular expression is
tightly regulated via multiple mechanisms. Mcl-1 differs from other members of the Bcl-2 family in having a very short half-life. So inhibition
of its expression and/or neutralization of its anti-apoptotic function will rapidly make Mcl-1-dependent cells more susceptible
to apoptosis and provide an opportunity to combat several types of cancers. This review summarizes the current knowledge on
the regulation of Mcl-1 expression and discusses the alternative approaches targeting Mcl-1 in human cancer cells whose survivals
mainly depend on Mcl-1.
Received 6 October 2008; received after revision 21 October 2008; accepted 10 November 2008 相似文献
18.
Bile acids and bile alcohols in the form of their conjugates are amphipathic end products of cholesterol metabolism with multiple physiological functions. The great variety of bile acids and bile alcohols that are present in vertebrates are tabulated. Bile salts have an enterohepatic circulation resulting from efficient vectorial transport of bile salts through the hepatocyte and the ileal enterocyte; such transport leads to the accumulation of a pool of bile salts that cycles between the liver and intestine. Bile salt anions promote lipid absorption, enhance tryptic cleavage of dietary proteins, and have antimicrobial effects. Bile salts are signaling molecules, activating nuclear receptors in the hepatocyte and ileal enterocyte, as well as an increasing number of G-protein coupled receptors. Bile acids are used therapeutically to correct deficiency states, to decrease the cholesterol saturation of bile, or to decrease the cytotoxicity of retained bile acids in cholestatic liver disease. 相似文献
19.
Zolkiewska A 《Cellular and molecular life sciences : CMLS》2008,65(13):2056-2068
ADAM metalloproteases play important roles in development and disease. One of the key functions of ADAMs is the proteolytic processing of Notch receptors and their ligands. ADAM-mediated cleavage of Notch represents the first step in regulated intramembrane proteolysis of the receptor, leading to activation of the Notch pathway. Recent reports indicate that the transmembrane Notch ligands also undergo ADAM-mediated processing in cultured cells and in vivo. The proteolytic processing of Notch ligands modulates the strength and duration of Notch signals, leads to generation of soluble intracellular domains of the ligands, and may support a bi-directional signaling between cells. 相似文献
20.
Multi-layered regulation of intestinal antimicrobial defense 总被引:1,自引:0,他引:1
Mukherjee S Vaishnava S Hooper LV 《Cellular and molecular life sciences : CMLS》2008,65(19):3019-3027