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Jacques E Dumont

Publications and source records attributed to Jacques E Dumont.

At least 19 recordsLinked to original sources
PubMed2006

Differential utilization of cyclin D1 and cyclin D3 in the distinct mitogenic stimulations by growth factors and TSH of human thyrocytes in primary culture.

Two distinct mitogenic modes coexist in thyroid epithelial cells. TSH via cAMP induces proliferation and differentiation expression, whereas growth factors including epidermal growth factor (EGF) induce proliferation and dedifferentiation. Divergent models of TSH/cAMP-dependent mitogenesis have emerged from different thyroid cell culture systems. In the FRTL-5 rat cell line, cAMP cross-signals with transduction pathways of growth factors to induce cyclin D1 and p21(cip1) and down-regulate p27(kip1). By contrast, in canine primary cultures, mitogenic pathways of cAMP and growth factors are fully distinct. cAMP does not induce D-type cyclins and p21, it up-regulates p27, and it stimulates the formation and activity of cyclin D3-cyclin-dependent kinase (CDK) 4 complexes. In primary cultures of normal human thyrocytes, EGF + serum increased cyclin D1 and p21 accumulation, and it stimulated the assembly and activity of cyclin D1-CDK4-p21 complexes. By contrast, TSH repressed or did not induce cyclin D1 and p21, and it rather up-regulated p27. TSH did not increase cyclin D1-CDK4 activity, but it stimulated the activating phosphorylation of CDK4 and the pRb-kinase activity of preexisting cyclin D3-CDK4 complexes. As recently demonstrated in dog thyrocytes and other systems, cyclin D1 and cyclin D3 differently oriented the site specificity of CDK4 pRb-kinase activity, which might differently impact some pRb functions. Cyclin D1 or cyclin D3 are thus differentially used in the distinct mitogenic stimulations by growth factors or TSH, and potentially in hyperproliferative diseases generated by the overactivation of their respective signaling pathways. At variance with dog thyroid primary cultures, rat thyroid cell lines might not be valid models of TSH-dependent mitogenesis of human thyrocytes.

Animals↗
PubMed2006

G1/S Cyclins interact with regulatory subunit of PKA via A-kinase anchoring protein, AKAP95.

The mechanisms by which cyclins promote mammalian cell cycle progression have been a topic of intense investigation over the last decade. We previously described an interaction between D-type cyclins and A-kinase anchoring protein, AKAP95. Here, we demonstrate that AKAP95 can also bind cyclin E1. Association between AKAP95 and cyclins is displaced by CDKs. We show that these G(1)/S cyclins can interact with RII subunit of PKAalpha through AKAP95. The presence of alternate complexes cyclin-CDK and cyclin D/E-AKAP95-PKA.RIIalpha suggest different roles of G(1)/S cyclins and a wider biological importance of these interactions in cells.

A Kinase Anchor Proteins↗
PubMed2006

Distinct specificities of pRb phosphorylation by CDK4 activated by cyclin D1 or cyclin D3: differential involvement in the distinct mitogenic modes of thyroid epithelial cells.

Two distinct mitogenic modes coexist in the physiologically relevant model of primary cultures of dog thyroid epithelial cells. The differentiation-associated mitogenic stimulation by TSH and cAMP specifically requires the assembly and activation of cyclin D3-cyclin-dependent kinase (CDK)4 associated to p27(kip1), while the dedifferentiating proliferation induced by growth factors is associated with induction of cyclin D1. Here, we suggest that the related CDK "inhibitors" p21(cip1) and p27 are differentially utilized as positive CDK4 regulators in these mitogenic stimulations. p21 was induced by EGF + serum, but repressed by TSH, which, as previously shown, upregulates p27. In response to EGF + serum, p21 supported the nuclear localization, phosphorylation and pRb-kinase activity of CDK4. Unexpectedly, partly different site-specificities of pRb-kinase activity, leading to similar differences in the phosphorylation pattern of pRb in intact cells, were associated with cyclin D3-CDK4 bound to p27 in TSH-stimulated cells, or with CDK4 bound to p21 in growth factor-stimulated cells. These differences were ascribed to the predominant association of the latter complex to cyclin D1. Indeed, in different cell types and species, cyclin D1 varied from cyclin D3 by more efficiently driving the phosphorylation of pRb at sites (Ser807/811 and Thr826) required for its electrophoretic mobility shift. Therefore, different D-type cyclins could differently impact some pRb functions, which should be considered not only in the understanding of the relationships between cell cycle and differentiation expression in the distinct mitogenic modes of thyroid cells, but also in various development or differentiation models associated with dramatic switches in the expression of individual D-type cyclins.

Animals↗
PubMed2006

Regulated activating Thr172 phosphorylation of cyclin-dependent kinase 4(CDK4): its relationship with cyclins and CDK "inhibitors".

Cyclin-dependent kinase 4 (CDK4) is a master integrator of mitogenic and antimitogenic extracellular signals. It is also crucial for many oncogenic transformation processes. Various molecular features of CDK4 activation remain poorly known or debated, including the regulation of its association with D-type cyclins, its activating Thr172 phosphorylation, and the roles of Cip/Kip CDK "inhibitors" in these processes. Thr172 phosphorylation of CDK4 was reinvestigated using two-dimensional gel electrophoresis in various experimental systems, including human fibroblasts, canine thyroid epithelial cells stimulated by thyrotropin, and transfected mammalian and insect cells. Thr172 phosphorylation of CDK4 depended on prior D-type cyclin binding, but Thr172 phosphorylation was also found in p16-bound CDK4. Opposite effects of p27 on cyclin D3-CDK4 activity observed in different systems depended on its stoichiometry in this complex. Thr172-phosphorylated CDK4 was enriched in complexes containing p21 or p27, even at inhibitory levels of p27 that precluded CDK4 activity. Deletion of the p27 nuclear localization signal sequence relocalized cyclin D3-CDK4 in the cytoplasm but did not affect CDK4 phosphorylation. Within cyclin D3 complexes, T-loop phosphorylation of CDK4, but not of CDK6, was directly regulated, identifying it as a determining target for cell cycle control by extracellular factors. Collectively, these unexpected observations indicate that CDK4-activating kinase(s) should be reconsidered.

Animals↗
PubMed2005

Thyrotropin stimulates the generation of inositol 1,4,5-trisphosphate in human thyroid cells.

CONTEXT: Dual activation by TSH of the phospholipase C and cAMP cascades has been reported in human thyroid cells. In contrast, Singh et al. reported convincing data in FRTL-5 thyrocytes arguing against such an effect in this model. Their data in FRTL-5 cells indicated no increase in inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] in response to TSH. Therefore, the authors questioned results previously obtained on human cells by cruder methodology. OBJECTIVE: We investigated the formation of inositol phosphates by HPLC techniques in human thyroid slices to separate the inositol phosphate isomers. RESULTS: Ins(1,4,5)P3, inositol 1,3,4-trisphosphate, and inositol 1,3,4,5-tetrakisphosphate were increased after TSH stimulation. The effect of TSH in human thyroid cells was reproduced by recombinant TSH and prevented by antibodies blocking the TSH receptor. Thyroid-stimulating antibodies at concentrations eliciting a cAMP response equivalent to TSH failed to stimulate inositol phosphate generation. CONCLUSIONS: TSH, but not thyroid-stimulating antibodies, activates both cAMP and the phospholipase C cascade in human thyroid as now demonstrated by an increase in Ins(1,4,5)P3 and its inositol phosphate metabolites. Therefore, this effect cannot be extrapolated to the FRTL-5 cell line. The apparent discrepancy may be due to a difference between species (human vs. rat) or to the loss of the fresh tissue properties in a cell line. The dual effect of TSH in human cells, through cAMP on secretion of thyroid hormones and through the diacylglycerol, Ins(1,4,5)P3 Ca2+ pathway on thyroid hormone synthesis, implies the possible separation of these effects in thyroid disease.

Animals↗
PubMed2005

Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis.

The cAMP signaling pathway regulates growth of many cell types, including somatotrophs, thyrocytes, melanocytes, ovarian follicular granulosa cells, adrenocortical cells, and keratinocytes. Mutations of partners from the cAMP signaling cascade are involved in tumor formation. Thyroid-stimulating hormone (TSH) receptor and Gsalpha activating mutations have been detected in thyroid autonomous adenomas, Gsalpha mutations in growth hormone-secreting pituitary adenomas, and PKAR1A mutations in Carney complex, a multiple neoplasia syndrome. To gain more insight into the role of cAMP signaling in tumor formation, human primary cultures of thyrocytes were treated for different times (1.5, 3, 16, 24, and 48 h) with TSH to characterize modulations in gene expression using cDNA microarrays. This kinetic study showed a clear difference in expression, early (1.5 and 3 h) and late (16-48 h) after the onset of TSH stimulation. This result suggests a progressive sequential process leading to a change of cell program. The gene expression profile of the long-term stimulated cultures resembled the autonomous adenomas, but not papillary carcinomas. The molecular phenotype of the adenomas thus confirms the role of long-term stimulation of the TSH-cAMP cascade in the pathology. TSH induced a striking up-regulation of different negative feedback modulators of the cAMP cascade, presumably insuring the one-shot effect of the stimulus. Some were down- or nonregulated in adenomas, suggesting a loss of negative feedback control in the tumors. These results suggest that in tumorigenesis, activation of proliferation pathways may be complemented by suppression of multiple corresponding negative feedbacks, i.e., specific tumor suppressors.

Adenoma↗
PubMed2005

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology.

The purpose of this study was to use the microarray technology to define expression profiles characteristic of thyroid autonomous adenomas and relate these findings to physiological mechanisms. Experiments were performed on a series of separated adenomas and their normal counterparts on Micromax cDNA microarrays covering 2400 genes (analysis I), and on a pool of adenomatous tissues and their corresponding normal counterparts using microarrays of 18,000 spots (analysis II). Results for genes present on the two arrays corroborated and several gene regulations previously determined by Northern blotting or microarrays in similar lesions were confirmed. Five overexpressed and 24 underexpressed genes were also confirmed by real-time RT-PCR in some of the samples used for microarray analysis, and in additional tumor specimens. Our results show: (1) a change in the cell populations of the tumor, with a marked decrease in lymphocytes and blood cells and an increase in endothelial cells. The latter increase would correspond to the establishment of a close relation between thyrocytes and endothelial cells and is related to increased N-cadherin expression. It explains the increased blood flow in the tumor; (2) a homogeneity of tumor samples correlating with their common physiopathological mechanism: the constitutive activation of the thyrotropin (TSH)/cAMP cascade; (3) a low proportion of regulated genes consistent with the concept of a minimal deviation tumor; (4) a higher expression of genes coding for specific functional proteins, consistent with the functional hyperactivity of the tumors; (5) an increase of phosphodiesterase gene expression which explains the relatively low cyclic AMP levels measured in these tumors; (6) an overexpression of antiapoptotic genes and underexpression of proapoptotic genes compatible with their low apoptosis rate; (7) an overexpression of N-cadherin and downregulation of caveolins, which casts doubt about the use of these expressions as markers for malignancy.

Adenoma↗
PubMed2005

Differential involvement of the actin cytoskeleton in differentiation and mitogenesis of thyroid cells: inactivation of Rho proteins contributes to cyclic adenosine monophosphate-dependent gene expression but prevents mitogenesis.

In thyroid epithelial cells, TSH via cAMP induces a rounding up of the cells associated with actin stress fiber disruption, expression of differentiation genes and cell cycle progression. Here we have evaluated the role of small G proteins of the Rho family and their impact on the actin cytoskeleton in these different processes in primary cultures of canine thyrocytes. TSH and forskolin, but not growth factors, rapidly inactivated RhoA, Rac1, and Cdc42, as assayed by detection of GTP-bound forms. Using toxins that inactivate Rho proteins (toxin B, C3 exoenzyme) or activate them [cytotoxic necrotizing factor 1 (CNF1)], in comparison with disruption of the actin cytoskeleton by dihydrocytochalasin B (DCB) or latrunculin, two unexpected conclusions were reached: 1) inactivation of Rho proteins by cAMP, by disorganizing actin microfilaments and inducing cell retraction, could be necessary and sufficient to mediate at least part of the cAMP-dependent induction of thyroglobulin and thyroid oxidases, but only partly necessary for the induction of Na(+)/I(-) symporter and thyroperoxidase; 2) as indicated by the effect of their inhibition by toxin B and C3, some residual activity of Rho proteins could be required for the induction by cAMP-dependent or -independent mitogenic cascades of DNA synthesis and retinoblastoma protein (pRb) phosphorylation, through mechanisms targeting the activity, but not the stimulated assembly, of cyclin D3-cyclin-dependent kinase 4 complexes. However, at variance with current concepts mostly derived from fibroblast models, DNA synthesis induction and cyclin D3-cyclin-dependent kinase 4 activation were resistant to actin depolymerization by dihydrocytochalasin B in canine thyrocytes, which provides a first such example in a normal adherent cell.

Actins↗
PubMed2005

Phosphatidylinositol 3,4,5-trisphosphate modulation in SHIP2-deficient mouse embryonic fibroblasts.

SHIP2, the ubiquitous SH2 domain containing inositol 5-phosphatase, includes a series of protein interacting domains and has the ability to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)]in vitro. The present study, which was undertaken to evaluate the impact of SHIP2 on PtdIns(3,4,5)P(3) levels, was performed in a mouse embryonic fibroblast (MEF) model using SHIP2 deficient (-/-) MEF cells derived from knockout mice. PtdIns(3,4,5)P(3) was upregulated in serum stimulated -/- MEF cells as compared to +/+ MEF cells. Although the absence of SHIP2 had no effect on basal PtdIns(3,4,5)P(3) levels, we show here that this lipid was significantly upregulated in SHIP2 -/- cells but only after short-term (i.e. 5-10 min) incubation with serum. The difference in PtdIns(3,4,5)P(3) levels in heterozygous fibroblast cells was intermediate between the +/+ and the -/- cells. In our model, insulin-like growth factor-1 stimulation did not show this upregulation. Serum stimulated phosphoinositide 3-kinase (PI 3-kinase) activity appeared to be comparable between +/+ and -/- cells. Moreover, protein kinase B, but not mitogen activated protein kinase activity, was also potentiated in SHIP2 deficient cells stimulated by serum. The upregulation of protein kinase B activity in serum stimulated cells was totally reversed in the presence of the PI 3-kinase inhibitor LY-294002, in both +/+ and -/- cells. Altogether, these data establish a link between SHIP2 and the acute control of PtdIns(3,4,5)P(3) levels in intact cells.

Animals↗
PubMed2005

Normal thyroid structure and function in rhophilin 2-deficient mice.

Rhophilin 2 is a Rho GTPase binding protein initially isolated by differential screening of a chronically thyrotropin (TSH)-stimulated dog thyroid cDNA library. In thyroid cell culture, expression of rhophilin 2 mRNA and protein is enhanced following TSH stimulation of the cyclic AMP (cAMP) transduction cascade. Yeast two-hybrid screening and coimmunoprecipitation have revealed that the GTP-bound form of RhoB and components of the cytoskeleton are protein partners of rhophilin 2. These results led us to suggest that rhophilin 2 could play an important role downstream of RhoB in the control of endocytosis during the thyroid secretory process which follows stimulation of the TSH/cAMP pathway. To validate this hypothesis, we generated rhophilin 2-deficient mice and analyzed their thyroid structure and function. Mice lacking rhophilin 2 develop normally, have normal life spans, and are fertile. They have no visible goiter and no obvious clinical signs of hyper- or hypothyroidism. The morphology of thyroid cells and follicles in these mice were normal, as were the different biological tests performed to investigate thyroid function. Our results indicate that rhophilin 2 does not play an essential role in thyroid physiology.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Identification of a novel partner of duox: EFP1, a thioredoxin-related protein.

H(2)O(2) is a crucial substrate of thyroproxidase (TPO) to iodinate thyroglobulin and synthesize thyroid hormones in thyroid. ThOX proteins (thyroid oxidase) also called Duox are believed to be responsible for H(2)O(2) generation. Duoxs expressed in transfected cells do not generate an active system, nor permit their membrane localization suggesting that other proteins are required to fulfill these functions. In this study, we demonstrate interactions of Duoxs with TPO and with p22(phox) without any effect on Duox activity. By yeast two-hybrid method using EF-hand fragment of dog Duox1 as the bait we have isolated EFP1 (EF-hand binding protein 1), one partner of Duoxs that belongs to the thioredoxin-related protein family. EFP1 shares moderate similarities with other members of thioredoxin-related proteins, but the characteristic active site and the folding structures are well conserved. EFP1 can be co-immunoprecipitated with Duoxs in transfected COS cells as well as in primary cultured human thyrocytes. It interacts also with TPO but not thyroglobulin. Immunofluorescence studies show that EFP1 and Duox proteins are co-localized inside the transfected cells, suggesting that EFP1 is not sufficient to induce either the expression of Duox at the plasma membrane or to permit H(2)O(2) production. EFP1 and Duox mRNA share similar distribution in nine different tissues. These results suggest that EFP1 could be one of the partners in the assembly of the multiprotein complex constituting the thyroid H(2)O(2) generating system but is certainly not sufficient to permit H(2)O(2) generation.

Amino Acid Sequence↗
PubMed2004

A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95.

Using a yeast interaction screen to search for proteins that interact with cyclin D3 in thyroid gland, we identified the cAMP-dependent AKAP95 (protein kinase A-anchoring protein 95). AKAP95 is a scaffolding protein that primarily co-fractionates with the nuclear matrix, whereas a minor fraction associates with chromatin in interphase cells. In co-transfected Chinese-hamster ovary cells, AKAP95 strongly interacted with the three D-type cyclins, but not with CDK4 (cyclin-dependent kinase 4) or with p27kip1. CDK4 displaced the interaction between cyclin D3 and AKAP95, suggesting that AKAP95 could not be the elusive bridging adaptor between D-type cyclins and CDK4 or play a role in the regulation of cyclin D3-CDK4 activity. Interaction between endogenous AKAP95 and cyclin D3 or cyclin D1 was detected in canine thyrocytes, human fibroblasts and NIH-3T3 cells. As both AKAP95 and cyclins D were recently reported to associate with minichromosome maintenance proteins [Eide, Tasken, Carlson, Williams, Jahnsen, Tasken and Collas (2003) J. Biol. Chem. 278, 26750-26756; Gladden and Diehl (2003) J. Biol. Chem. 278, 9754-9760], we hypothesize that the interaction between AKAP95 and D-type cyclins might serve to facilitate the emerging regulatory role of cyclin D-CDK4 in the formation of the prereplication complex at the DNA replication origins.

A Kinase Anchor Proteins↗
PubMed2003

The cyclin D3-CDK4-p27kip1 holoenzyme in thyroid epithelial cells: activation by TSH, inhibition by TGFbeta, and phosphorylations of its subunits demonstrated by two-dimensional gel electrophoresis.

The cAMP-dependent mitogenic stimulation elicited by thyroid-stimulating hormone (TSH) in primary cultures of canine thyroid epithelial cells is unique as it upregulates the cyclin-dependent kinase (CDK) inhibitor p27kip1 but not D-type cyclins. TSH and cAMP promote the assembly of required cyclin D3-CDK4 complexes and their nuclear import. Here, the nuclear translocation of these complexes strictly correlated in individual cells with the enhanced presence of nuclear p27. p27, like cyclin D3, supported the TSH-stimulated pRb-kinase activity of the CDK4 complex and, as demonstrated using the high-resolution power of the two-dimensional (2D) gel electrophoresis, the phosphorylation of CDK4, presumably by the nuclear CDK-activating kinase. In the presence of TSH, transforming growth factor beta (TGFbeta) did not affect the assembly of cyclin D3-CDK4, but it strongly inhibited the pRb-kinase activity associated with both cyclin D3 and p27, not only by preventing the nuclear import of cyclin D3-CDK4 and its binding to p27, but also by inhibiting CDK4 phosphorylation within residual p27-bound cyclin D3-CDK4 complexes. No alterations of the relative abundance of multiple (un)phosphorylated forms of cyclin D3 and p27 demonstrated by 2D-gel electrophoresis were associated with these processes. This study suggests a crucial positive role of p27 in the TSH-stimulated nuclear import, phosphorylation, and catalytic activity of cyclin D3-bound CDK4. Moreover, it demonstrates a technique to directly assess the in vivo phosphorylation of endogenous CDK4, which might appear as a last regulated step targeted by the antagonistic cell cycle effects of TSH and TGFbeta.

Active Transport, Cell Nucleus↗
PubMed2003

Integration and cross-validation of high-throughput gene expression data: comparing heterogeneous data sets.

Data analysis--not data production--is becoming the bottleneck in gene expression research. Data integration is necessary to cope with an ever increasing amount of data, to cross-validate noisy data sets, and to gain broad interdisciplinary views of large biological data sets. New Internet resources may help researchers to combine data sets across different gene expression platforms. However, noise and disparities in experimental protocols strongly limit data integration. A detailed review of four selected studies reveals how some of these limitations may be circumvented and illustrates what can be achieved through data integration.

Animals↗
PubMed2003

Cyclic AMP-dependent phosphorylation of cyclin D3-bound CDK4 determines the passage through the cell cycle restriction point in thyroid epithelial cells.

According to current concepts, the cell cycle commitment after restriction (R) point passage requires the sustained stimulation by mitogens of the synthesis of labile d-type cyclins, which associate with cyclin-dependent kinase (CDK) 4/6 to phosphorylate pRb family proteins and sequester the CDK inhibitor p27kip1. In primary cultures of dog thyroid epithelial cells, the cAMP-dependent cell cycle induced by a sustained stimulation by thyrotropin or forskolin differs from growth factor mitogenic pathways, as cAMP does not upregulate d-type cyclins but increases p27 levels. Instead, cAMP induces the assembly of required cyclin D3-CDK4 complexes, which associate with nuclear p27. In this study, the arrest of forskolin stimulation rapidly slowed down the entry of dog thyrocytes into S phase and the phosphorylation of pRb family proteins. The pRb kinase activity, but not the formation, of the cyclin D3-CDK4-p27 complex was strongly reduced. Using two-dimensional gel electrophoresis, a phosphorylated form of CDK4 was separated. It appeared in response to forskolin and was bound to both cyclin D3 and p27, presumably reflecting the activating Thr-172 phosphorylation of CDK4. Upon forskolin withdrawal or after cycloheximide addition, this CDK4 phosphoform unexpectedly persisted in p27 complexes devoid of cyclin D3 but it disappeared from the more labile cyclin D3 complexes. These data demonstrate that the assembly of the cyclin D3-CDK4-p27 holoenzyme and the subsequent phosphorylation and activation of CDK4 depend on distinct cAMP actions. This provides a first example of a crucial regulation of CDK4 phosphorylation by a mitogenic cascade and a novel mechanism of cell cycle control at the R point.

Animals↗
PubMed2003

The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2.

SHIP2 is a phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) 5-phosphatase which contains motifs susceptible to mediate protein-protein interaction. Using yeast two-hybrid, GST-pulldown, and coimmunoprecipitation studies, we isolated the CAP cDNA as a specific partner of SHIP2 proline-rich domain and showed by GST-pulldown experiments that the interaction took place with the SH3C of CAP. The interaction was not modulated in COS-7 cells stimulated by EGF neither in CHO cells overexpressing the insulin receptor in the presence or absence of insulin stimulation. We also showed that SHIP2 was able to coimmunoprecipitate with endogenous c-Cbl protein in the absence of CAP and with the insulin receptor in CHO-IR cell extracts. The presence of SHIP2 in a complex around the insulin receptor could account for the very specific increase in insulin sensitivity of SHIP2 knock-out mice.

Animals↗
PubMed2003

Survival pathways regulating the apoptosis induced by tumour necrosis factor-alpha in primary cultured bovine endothelial cells.

The aim of the present study was to identify biochemical pathways driving the resistance of endothelial cells to apoptosis induced by tumour necrosis factor-alpha (TNF). (1) Although nuclear factor-kappa B (NF-kappaB) was activated by TNF, its inhibition by MG-132 failed to sensitize these cells. (2) The activation of protein kinase C (PKC) by phorbol ester completely abolished the TNF-induced cell death. (3) The phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (Wo) triggered apoptosis and enhanced the TNF-induced cell death. (4) The MEK inhibitor PD98059 did not affect the TNF-induced apoptotic process. (5) The p38 is activated by TNF and its inhibition by SB203580 sensitized the cells to TNF. This is correlated with the inhibition of phosphorylation of heat-shock protein of 27 kDa (HSP27). These results indicate that TNF activates NF-kappaB, which does not drive any anti-apoptotic response, and p38, which plays an anti-apoptotic function probably through HSP27 phosphorylation. Moreover, PKC and PI3K are involved in the control of survival pathways.

Animals↗