共查询到20条相似文献,搜索用时 31 毫秒
1.
Zhang ZG Lambert CA Servotte S Chometon G Eckes B Krieg T Lapière CM Nusgens BV Aumailley M 《Cellular and molecular life sciences : CMLS》2006,63(1):82-91
The GTP-binding proteins RhoA, Cdc42 and Rac1 regulate the organization and turnover of the cytoskeleton and cell-matrix adhesions,
structures bridging cells to their support, and translating forces, external or generated within the cell. To investigate
the specific requirements of Rho GTPases for biomechanical activities of clonal cell populations, we compared side-by-side
stable lines of human fibroblasts expressing constitutively active (CA) RhoA, Cdc42 or Rac1. There was no marked effect of
any CA GTPase on cell adhesion to different extracellular matrix proteins. Cell spreading was CA Rho GTPase specific and independent
of the extracellular matrix proteins allowing adhesion. Mechanical properties were dramatically restricted by CA RhoA on bi-
and in tri-dimensional surroundings, were boosted by CA Rac1 on bi-dimensional surroundings only, and were not or marginally
affected by CA Cdc42. In conclusion, the action of Rho GTPases appears to depend on the task cells are performing.
Received 12 September 2005; received after revision 5 October 2005; accepted 1 November 2005 相似文献
2.
Aflaki E Balenga NA Luschnig-Schratl P Wolinski H Povoden S Chandak PG Bogner-Strauss JG Eder S Konya V Kohlwein SD Heinemann A Kratky D 《Cellular and molecular life sciences : CMLS》2011,68(23):3933-3947
Infiltration of monocytes and macrophages into the site of inflammation is critical in the progression of inflammatory diseases such as atherosclerosis. Cell migration is dependent on the continuous organization of the actin cytoskeleton, which is regulated by members of the small Rho GTPase family (RhoA, Cdc42, Rac) that are also important for the regulation of signal transduction pathways. We have recently reported on reduced plaque formation in an atherosclerotic mouse model transplanted with bone marrow from adipose triglyceride lipase-deficient (Atgl-/-) mice. Here we provide evidence that defective lipolysis in macrophages lacking ATGL, the major enzyme responsible for triacylglycerol hydrolysis, favors an anti-inflammatory M2-like macrophage phenotype. Our data implicate an as yet unrecognized principle that insufficient lipolysis influences macrophage polarization and actin polymerization, resulting in impaired macrophage migration. Sustained phosphorylation of focal adhesion kinase [due to inactivation of its phosphatase by elevated levels of reactive oxygen species (ROS)] results in defective Cdc42, Rac1 and RhoA activation and in increased and sustained activation of Rac2. Inhibition of ROS production restores the migratory capacity of Atgl-/- macrophages. Since monocyte and macrophage migration are a prerequisite for infiltrating the arterial wall, our results provide a molecular link between lipolysis and the development of atherosclerosis. 相似文献
3.
S. P. Yun M. Y. Lee J. M. Ryu H. J. Han 《Cellular and molecular life sciences : CMLS》2009,66(9):1603-1616
Identifying the small molecules that permit precise regulation of embryonic stem (ES) cell proliferation should further support
our understanding of the underlying molecular mechanisms of self renewal. In the present study, we showed that PGE2 increased [3H]-thymidine incorporation in a time and dose dependent manner. In addition, PGE2 increased the expression of cell cycle regulatory proteins, the percentage of cells in S phase and the total number of cells.
PGE2 obviously increased E-type prostaglandin (EP) receptor 1 mRNA expression level compare to 2, 3, 4 subtypes. EP1 antagonist
also blocked PGE2-induced cell cycle regulatory protein expression and thymidine incorporation. PGE2 caused phosphorylation of protine kinase C, Src, epidermal growth factor (EGF) receptor, phosphatidylinositol 3-kinase (PI3K)/Akt
phosphorylation, and p44/42 mitogen-activated protein kinase (MAPK), which were blocked by each inhibitors. In conclusion,
PGE2-stimulated proliferation is mediated by MAPK via EP1 receptor-dependent PKC and EGF receptor-dependent PI3K/Akt signaling
pathways in mouse ES cells.
Received 30 January 2009; received after revision 03 March 2009; accepted 10 March 2009 相似文献
4.
Sylvia E. Le Dévédec Kuan Yan Hans de Bont Veerander Ghotra Hoa Truong Erik H. Danen Fons Verbeek Bob van de Water 《Cellular and molecular life sciences : CMLS》2010,67(19):3219-3240
Cell migration is essential in a number of processes, including wound healing, angiogenesis and cancer metastasis. Especially,
invasion of cancer cells in the surrounding tissue is a crucial step that requires increased cell motility. Cell migration
is a well-orchestrated process that involves the continuous formation and disassembly of matrix adhesions. Those structural
anchor points interact with the extra-cellular matrix and also participate in adhesion-dependent signalling. Although these
processes are essential for cancer metastasis, little is known about the molecular mechanisms that regulate adhesion dynamics
during tumour cell migration. In this review, we provide an overview of recent advanced imaging strategies together with quantitative
image analysis that can be implemented to understand the dynamics of matrix adhesions and its molecular components in relation
to tumour cell migration. This dynamic cell imaging together with multiparametric image analysis will help in understanding
the molecular mechanisms that define cancer cell migration. 相似文献
5.
The rapid migration of intestinal epithelial cells (IEC) is important for the healing of mucosal wounds. We have previously
shown that polyamine depletion inhibits migration of IEC-6 cells. Akt activation and its downstream target GSK-3β have been
implicated in the regulation of migration. Here we investigated the significance of elevated phosphatidylinositol 3-kinase
(PI3K)/Akt signaling on migration of polyamine-depleted cells. Polyamine-depleted cells had high Akt (Ser473) and GSK-3β (Ser9)
phosphorylation. Pretreatment with 20 μM LY294002 (PI3K inhibitor) for 30 min inhibited phosphorylation of Akt, increased
migration by activating Rac1 in polyamine-depleted IEC-6 cells, and restored the actin structure similar to that in cells
grown in control medium. Treatment of cells with a GSK-3β inhibitor (AR-A014418) altered the actin cytoskeleton and inhibited
migration, mimicking the effects of polyamine depletion. Thus, our results indicate that sustained activation of Akt in response
to polyamine depletion inhibits migration through GSK-3β and Rac1.
Received 25 August 2006; received after revision 3 October 2006; accepted 16 October 2006 相似文献
6.
Physical forces can activate colon cancer cell adhesion, critical for metastasis. Paxillin is phosphorylated by FAK and required
for pressure-stimulated adhesion. However, whether paxillin acts as an inert scaffolding protein or whether paxillin phosphorylation
is required is unknown. Transfection with paxillin point-phosphorylation mutants demonstrated that phosphorylation at tyrosines
31 and 118 together is necessary for pressure-stimulated adhesion. We further evaluated potential paxillin partners. Reducing
the adaptor protein Crk or the focal adhesion protein p130Cas blocked pressure-stimulated adhesion. Furthermore, Crk and p130Cas both displayed increased co-immunoprecipitation with paxillin in response to increased pressure, except in cells transfected
with a Y31Y118 paxillin mutant. Inhibiting the small GTPase Rac1 also abolished pressure-stimulated adhesion, and reducing
paxillin by siRNA blocked Rac1 phosphorylation by pressure. Thus, paxillin phosphorylation at tyrosines 31 and 118 together
is necessary for pressure-induced adhesion. Paxillin, Crk and Cas form a trimeric complex that activates Rac1 and mediates
this effect.
Received 21 January 2008; received after revision 4 March 2008; accepted 19 March 2008 相似文献
7.
Zhang Y Yu G Wang Y Xiang Y Gao Q Jiang P Zhang J Lee W Zhang Y 《Cellular and molecular life sciences : CMLS》2011,68(22):3771-3780
Trefoil factors (TFFs) promote epithelial cell migration to reseal superficial wounds after mucosal injury, but their receptors
and the molecular mechanisms underlying this process are poorly understood. In this study, we showed that frog TFF2 activates
protease-activated receptor (PAR) 1 to induce human platelet aggregation. Based on this result, we further tested the involvement
of PARs in human TFF2 (hTFF2)-promoted mucosal healing. hTFF2-stimulated migration of epithelial HT-29 cells was largely inhibited
by PAR4 depletion with small interfering RNAs but not by PAR1 or PAR2 depletion. The PAR4-negative epithelial cell lines AGS
and LoVo were highly responsive to hTFF2 as assessed by phosphorylation of ERK1/2 and cell migration upon PAR4 expression.
Our findings suggest that hTFF2 promotes cell migration via PAR4. These findings will be helpful in further investigations
into the functions and molecular mechanisms of TFFs and PARs in physiology and disease. 相似文献
8.
Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment 总被引:12,自引:0,他引:12
The fatality of cancer predominantly results from the dissemination of primary tumor cells to distant sites and the subsequent
formation of metastases. During tumor progression, some of the primary tumor cells as well as the tumor microenvironment undergo
characteristic molecular changes, which are essential for the metastatic dissemination of tumor cells. In this review, we
will discuss recent insights into pro-metastatic events occurring in tumor cells themselves and in the tumor stroma. Tumor
cell-intrinsic alterations include the loss of cell polarity and alterations in cell-cell and cell-matrix adhesion as well
as deregulated receptor kinase signaling, which together support detachment, migration and invasion of tumor cells. On the
other hand, the tumor stroma, including endothelial cells, fibroblasts and cells of the immune system, is engaged in an active
molecular crosstalk within the tumor microenvironment. Subsequent activation of blood vessel and lymph vessel angiogenesis
together with inflammatory and immune-suppressive responses further promotes cancer cell migration and invasion, as well as
initiation of the metastatic process.
Received 4 July 2005; received after revision 3 November 2005; accepted 14 November 2005 相似文献
9.
Antiepileptic drugs and the developing brain 总被引:3,自引:0,他引:3
Kaindl AM Asimiadou S Manthey D Hagen MV Turski L Ikonomidou C 《Cellular and molecular life sciences : CMLS》2006,63(4):399-413
Epilepsy is the most common neurological disorder in young humans. Antiepileptic drugs (AEDs) which are used to treat seizures
in infants, children and pregnant women can cause cognitive impairment, microcephaly and birth defects. Ion channels, neurotransmitters
and second messenger systems constitute molecular targets of AEDs. The same targets regulate brain processes essential both
for propagation of seizures and for learning, memory and emotional behavior. Thus, AEDs can influence brain function and brain
development in undesired ways. Here we review mechanisms of action of AEDs, examine clinical evidence for their adverse effects
in the developing human brain, and present studies on cognitive and behavioral effects in animal models. Furthermore, we discuss
mechanisms responsible for adverse effects of AEDs in the developing mammalian brain, including interference with cell proliferation
and migration, axonal arborization, synaptogenesis, synaptic plasticity and physiological apoptotic cell death.
Received 3 August 2005; received after revision 13 October 2005; accepted 1 November 2005 相似文献
10.
The parvins 总被引:5,自引:0,他引:5
The parvins are a family of proteins involved in linking integrins and associated proteins with intracellular pathways that
regulate actin cytoskeletal dynamics and cell survival. Both α-parvin (PARVA) and β-parvin (PARVB) localize to focal adhesions
and function in cell adhesion, spreading, motility and survival through interactions with partners, such as integrin-linked
kinase (ILK), paxillin, α-actinin and testicular kinase 1. A complex of PARVA with ILK and the LIM protein PINCH-1 is critical
for cell survival in a variety of cells, including certain cancer cells, kidney podocytes and cardiac myocytes. While PARVA
inhibits the activities of Rac1 and testicular kinase 1 and cell spreading, PARVB binds αPIX and α-actinin, and can promote
cell spreading. In contrast to PARVA, PARVB inhibits ILK activity and reverses some of its oncogenic effects in cancer cells.
This review focuses on the structure and function of the parvins and some possible roles in human diseases.
Received 5 August 2005; received after revision 5 September 2005; accepted 22 September 2005 相似文献
11.
Ernst S Zobiack N Boecker K Gerke V Rescher U 《Cellular and molecular life sciences : CMLS》2004,61(13):1684-1692
The formyl peptide-like receptor FPRL1 is a member of the chemoattractant subfamily of G protein- coupled receptors involved in regulating leukocyte migration in inflammation. To elucidate mechanisms underlying the internalization of ligand-bound FPRL1 and possible receptor recycling, we characterized the endocytic itinerary of FPRL1. We show that agonist-triggered internalization from the plasma membrane into intracellular compartments is prevented by perturbation of clathrin-mediated endocytosis, such as expression of the dominant-negative clathrin Hub mutant, siRNA-mediated depletion of cellular clathrin and expression of a dominant-negative mutant of the large GTPase dynamin. Internalized FPRL1 co-localized with endocytosed transferrin and the small GTPases Rab4 and Rab11 in vesicular structures most resembling recycling endosomes. Recycling of FPRL1 was significantly reduced by pretreatment with PI3-kinase inhibitors. Thus, ligand-bound FPRL1 undergoes primarily clathrin-mediated and dynamin-dependent endocytosis and the receptor recycles via a rapid PI3-kinase-sensitive route as well as pathways involving perinuclear recycling endosomes.Received 19 March 2004; received after revision 26 April 2004; accepted 12 May 2004 相似文献
12.
Caron L Prot M Rouleau M Rolando M Bost F Binétruy B 《Cellular and molecular life sciences : CMLS》2005,62(14):1605-1612
Control of mammalian gene promoters by the bacterial LacI repressor provides reversible regulation and dose-response levels of derepressed expression by the lactose analog isopropyl thiogalactose (IPTG). Here, we show that insertion of LacI-binding sites in the ubiquitous β-actin promoter confers a strong and dose-dependent IPTG-regulatable expression of transiently transfected reporter genes in mouse embryonic stem (ES) cells expressing LacI. We established ES cell lines stably expressing reporter genes under inducible control and found a five- to tenfold IPTG induction of transgene expression. The kinetics of induction is rapid and stable, and can be rapidly reversed after IPTG removal. Importantly, this regulatable expression was maintained throughout the differentiation process of ES cells, and observed in individual differentiated cardiomyocyte-like cells and neuronal-like cells. This reversible system is the first to function from undifferentiated to individual welldifferentiated ES cells, providing a very useful tool to understand molecular mechanisms underlying ES cell self-renewal, commitment and differentiation.Received 17 March 2005; received after revision 19 April 2005; accepted 25 April 2005 相似文献
13.
Antiproliferative effect of β-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase 总被引:3,自引:0,他引:3
Li X Wang G Zhao J Ding H Cunningham C Chen F Flynn DC Reed E Li QQ 《Cellular and molecular life sciences : CMLS》2005,62(7-8):894-904
Elemene is a natural antitumor plant drug. However, the effect of elemene on cell growth in ovarian cancer is unknown. In this study, we show that -elemene inhibited the proliferation of cisplatin-resistant human ovarian cancer cells and their parental cells, but had only a marginal effect in human ovary cells, indicating differential inhibitory effects on cell growth between ovarian cancer cells and normal ovary cells. We also demonstrated for the first time that -elemene markedly enhanced cisplatin-induced growth inhibition in resistant cells compared to sensitive cells. In addition, cell cycle analysis revealed a synergistic effect of -elemene and cisplatin on the induction of cell cycle G2-M arrest in our resistant ovarian carcinoma cells. Furthermore, we showed that treatment of these cells with both drugs downregulated cyclin B1 and Cdc2 expression, but elevated the levels of p53, p21waf1/cip1, p27kip1 and Gadd45. Finally, the combination of -elemene and cisplatin was found to increase the phosphorylation of Cdc2 and Cdc25C, which leads to a reduction in Cdc2-cyclin B1 activity. These novel findings suggest that -elemene sensitizes chemoresistant ovarian carcinoma cells to cisplatin-induced growth suppression partly through modulating the cell cycle G2 checkpoint and inducing cell cycle G2-M arrest, which lead to blockade of cell cycle progression.Received 19 January 2005; accepted 5 February 2005 相似文献
14.
15.
Mijatovic S Maksimovic-Ivanic D Radovic J Miljkovic D Kaludjerovic GN Sabo TJ Trajkovic V 《Cellular and molecular life sciences : CMLS》2005,62(11):1275-1282
The present study describes the ability of an anthraquinone derivative aloe emodin (AE) to reduce the cytotoxic activity of the platinum(II)-based anticancer agent cisplatin toward murine L929 fibrosarcoma and C6 glioma cell lines. The protective effect of AE was demonstrated by MTT and crystal violet assays for cell viability, and involved supression of cisplatin-induced apoptosis and necrosis, as assessed by lactate dehydrogenase release and flow cytometric analysis of DNA fragmentation or phosphatidylserine exposure. Cell-based ELISA and Western blot analysis revealed that AE abolished cisplatin-triggered activation of extracellular signal-regulated kinase (ERK) in tumor cells, while activation of c-Jun N-terminal kinase was not significantly altered. A selective blockade of ERK activation with PD98059 mimicked the protective effect of AE treatment in both tumor cell lines. Moreover, AE failed to protect tumor cells against the ERK-independent toxicity of the Pt(IV)-based complex tetrachloro(O,O-dibutyl-ethylenediamine-N,N′-di-3-propanoate)platinum(IV). Taken together, these data indicate that herbal anthraquinone AE can downregulate the anticancer activity of cisplatin by blocking the activation of ERK in tumor cells.Received 30 January 2005; received after revision 21 March 2005; accepted 31 March 2005 相似文献
16.
Genes involved in breast cancer metastasis to bone 总被引:12,自引:0,他引:12
Metastasis to bone occurs frequently in advanced breast cancer and is accompanied by debilitating skeletal complications.
Current treatments are palliative and new therapies that specifically prevent the spread of breast cancer to bone are urgently
required. While our understanding of interactions between breast cancer cells and bone cells has greatly improved, we still
know little about the molecular determinants that regulate specific homing of breast cancer cells to the bone. In this review,
we focus on genes that have been implicated in migration and adhesion of breast cancer cells to bone, as well as genes that
promote tumor cell proliferation in the bone microenvironment. In addition, the review discusses new technologies, including
better animal models, that will further assist with the identification of the molecular determinants of bone metastasis and
will guide the development of new therapies.
Received 25 January 2002; received after revision 27 March 2002; accepted 5 April 2002
RID="*"
ID="*"Corresponding author. 相似文献
17.
“Jnking” atherosclerosis 总被引:1,自引:0,他引:1
Numerous studies in animal models established a key role of the C-jun N-terminal kinase (JNK) family (JNK1, JNK2 and JNK3)
in numerous pathological conditions, including cancer, cardiac hypertrophy and failure, neurodegenerative disorders, diabetes,
arthritis and asthma. A possible function of JNK in atherosclerosis remained uncertain since conclusions have mainly been
based on in vitro studies investigating endothelial cell activation, T-effector cell differentiation and proliferation of
vascular smooth muscle cells, all of which represent crucial cellular processes involved in atherosclerosis. However, recent
experiments demonstrated that macrophage-restricted deletion of JNK2 was sufficient to efficiently reduce atherosclerosis
in mice. Furthermore, it has been shown that JNK2 specifically promotes scavenger receptor A-mediated foam cell formation,
an essential step during early atherogenesis, which occurs when vascular macrophages internalize modified lipoproteins. Thus,
specific inhibition of JNK2 activity may emerge as a novel and promising therapeutic approach to attenuate atheroma formation
in the future. In this review, we discuss JNK-dependent cellular and molecular mechanisms underlying atherosclerosis.
Received 9 June 2005; received after revision 18 July 2005; accepted 18 July 2005 相似文献
18.
Actin polymerization machinery: the finish line of signaling networks, the starting point of cellular movement 总被引:9,自引:0,他引:9
Disanza A Steffen A Hertzog M Frittoli E Rottner K Scita G 《Cellular and molecular life sciences : CMLS》2005,62(9):955-970
Dynamic assembly of actin filaments generates the forces supporting cell motility. Several recent biochemical and genetic studies have revealed a plethora of different actin binding proteins whose coordinated activity regulates the turnover of actin filaments, thus controlling a variety of actin-based processes, including cell migration. Additionally, emerging evidence is highlighting a scenario whereby the same basic set of actin regulatory proteins is also the convergent node of different signaling pathways emanating from extracellular stimuli, like those from receptor tyrosine kinases. Here, we will focus on the molecular mechanisms of how the machinery of actin polymerization functions and is regulated, in a signaling-dependent mode, to generate site-directed actin assembly leading to cell motility.These authors contributed equally to this work.Received 26 October 2004; received after revision 27 December 2004; accepted 6 January 2005 Available online 09 March 2005 相似文献
19.
Phosphatidylinositol 3-kinase (PI3-kinase) activity has been implicated in regulating cell cycle progression at distinct points
in the cell cycle by preventing cell cycle arrest or apoptosis. In this study, the role of PI3-kinase activity during the
entire G1 phase of the ongoing cell cycle was studied in Chinese hamster ovary (CHO) cells synchronized by mitotic shake-off.
We show that inhibition of PI3-kinase activity during and 2 h after mitosis inhibited cell cycle progression into S phase.
In the presence of the PI3-kinase inhibitor wortmannin or LY294002, cells were arrested during early G1 phase, leading to
the expression of the cleaved caspase-3, a central mediator of apoptosis. These results demonstrate that PI3-kinase activity
is required for progression through the M/G1 phase. In the absence of PI3-kinase activity, cells are induced for apoptosis
in this particular phase of the cell cycle.
Received 7 September 2005; received after revision 26 October 2005; accepted 11 November 2005 相似文献
20.
Katia Fettucciari Pamela Ponsini Davide Gioè Lara Macchioni Camilla Palumbo Elisabetta Antonelli Stefano Coaccioli Vincenzo Villanacci Lanfranco Corazzi Pierfrancesco Marconi Gabrio Bassotti 《Cellular and molecular life sciences : CMLS》2017,74(8):1527-1551
Clostridium difficile causes nosocomial/antibiotic-associated diarrhoea and pseudomembranous colitis. The major virulence factors are toxin A and toxin B (TcdB), which inactivate GTPases by monoglucosylation, leading to cytopathic (cytoskeleton alteration, cell rounding) and cytotoxic effects (cell-cycle arrest, apoptosis). C. difficile toxins breaching the intestinal epithelial barrier can act on underlying cells, enterocytes, colonocytes, and enteric neurons, as described in vitro and in vivo, but until now no data have been available on enteric glial cell (EGC) susceptibility. EGCs are crucial for regulating the enteric nervous system, gut homeostasis, the immune and inflammatory responses, and digestive and extradigestive diseases. Therefore, we evaluated the effects of C. difficile TcdB in EGCs. Rat-transformed EGCs were treated with TcdB at 0.1–10 ng/ml for 1.5–48 h, and several parameters were analysed. TcdB induces the following in EGCs: (1) early cell rounding with Rac1 glucosylation; (2) early G2/M cell-cycle arrest by cyclin B1/Cdc2 complex inactivation caused by p27 upregulation, the downregulation of cyclin B1 and Cdc2 phosphorylated at Thr161 and Tyr15; and (3) apoptosis by a caspase-dependent but mitochondria-independent pathway. Most importantly, the stimulation of EGCs with TNF-α plus IFN-γ before, concomitantly or after TcdB treatment strongly increased TcdB-induced apoptosis. Furthermore, EGCs that survived the cytotoxic effect of TcdB did not recover completely and showed not only persistent Rac1 glucosylation, cell-cycle arrest and low apoptosis but also increased production of glial cell-derived neurotrophic factor, suggesting self-rescuing mechanisms. In conclusion, the high susceptibility of EGCs to TcdB in vitro, the increased sensitivity to inflammatory cytokines related to apoptosis and the persistence of altered functions in surviving cells suggest an important in vivo role of EGCs in the pathogenesis of C. difficile infection. 相似文献