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Results for “Signaling pathways”

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PubMed2002

p38 Mitogen-activated protein kinase-, calcium-calmodulin-dependent protein kinase-, and calcineurin-mediated signaling pathways transcriptionally regulate myogenin expression.

In this report, we identify myogenin as an important transcriptional target under the control of three intracellular signaling pathways, namely, the p38 mitogen-activated protein kinase- (MAPK), calcium-calmodulin-dependent protein kinase- (CaMK), and calcineurin-mediated pathways, during skeletal muscle differentiation. Three cis-elements (i.e., the E box, myocyte enhancer factor [MEF] 2, and MEF3 sites) in the proximal myogenin promoter in response to these three pathways are defined. MyoD, MEF2s, and Six proteins, the trans-activators bound to these cis-elements, are shown to be activated by these signaling pathways. Our data support a model in which all three signaling pathways act in parallel but nonredundantly to control myogenin expression. Inhibition of any one pathway will result in abolished or reduced myogenin expression and subsequent phenotypic differentiation. In addition, we demonstrate that CaMK and calcineurin fail to activate MEF2s in Rhabdomyosarcoma-derived RD cells. For CaMK, we show its activation in response to differentiation signals and its effect on the cytoplasmic translocation of histone deacetylases 5 are not compromised in RD cells, suggesting histone deacetylases 5 cytoplasmic translocation is necessary but not sufficient, and additional signal is required in conjunction with CaMK to activate MEF2 proteins.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2001

An alternative signaling pathway based on nitryl chloride during intercellular induction of apoptosis.

Transforming growth factor (TGF)-beta pretreated nontransformed fibroblasts induce apoptosis selectively in transformed fibroblasts. This potential control step during oncogenesis has been termed intercellular induction of apoptosis. Selectivity and efficiency of intercellular induction of apoptosis depend on transformed target cell-derived superoxide anions that drive two intercellular signaling pathways--the HOCl/hydroxyl radical and the nitric oxide (NO)/peroxynitrite pathway. Other natural antitumor systems like macrophages or cells of the granulocyte lineage seem to utilize the same signaling chemistry. Our data demonstrate the existence of an alternative signaling pathway in these systems. This pathway depends on the presence of nitrite and is still effective when the two conventional signaling pathways are blocked by superoxide dismutase (SOD). Nitrite-dependent apoptosis induction is neither blocked by SOD nor by the hydroxyl radical scavenger terephthalate, but it is inhibited by the peroxidase inhibitor aminobenzoyl hydrazide and by the hypochlorous acid (HOCl) scavenger taurine. Therefore, nitrite, that is nontoxic for our cells, seems to interact with HOCl to form the apoptosis inducer nitryl chloride. Nitryl chloride-mediated apoptosis induction might be relevant for apoptosis induction in tumor cells that release SOD and thus escape the two classical signaling pathways.

Animals↗

PubMed2005

The Drosophila type II receptor, Wishful thinking, binds BMP and myoglianin to activate multiple TGFbeta family signaling pathways.

Wishful thinking (Wit) is a Drosophila transforming growth factor-beta (TGFbeta) superfamily type II receptor most related to the mammalian bone morphogenetic protein (BMP) type II receptor, BMPRII. To better understand its function, we undertook a biochemical approach to establish the ligand binding repertoire and downstream signaling pathway. We observed that BMP4 and BMP7, bound to receptor complexes comprised of Wit and the type I receptor thickveins and saxophone to activate a BMP-like signaling pathway. Further we demonstrated that both myoglianin and its most closely related mammalian ligand, myostatin, interacted with a Wit and Baboon (Babo) type II-type I receptor complex to activate TGFbeta/activin-like signaling pathways. These results thereby demonstrate that Wit binds multiple ligands to activate both BMP and TGFbeta-like signaling pathways. Given that myoglianin is expressed in muscle and glial-derived cells, these results also suggest that Wit may mediate myoglianin-dependent signals in the nervous system.

Activin Receptors↗

PubMed2002

Bone morphogenetic proteins, extracellular matrix, and mitogen-activated protein kinase signaling pathways are required for osteoblast-specific gene expression and differentiation in MC3T3-E1 cells.

Osteoblasts secrete a complex extracellular matrix (ECM) containing collagenous and noncollagenous proteins, bone morphogenetic proteins (BMPs), and growth factors. Osteoblast-specific gene expression requires ascorbic acid (AA)-dependent assembly of a collagenous ECM. Matrix responsiveness requires an alpha2beta1 integrin-collagen interaction and mitogen-activated protein kinase (MAPK) activity, which phosphorylates and activates the osteoblast-specific transcription factor Cbfa1. This study examines interactions between this integrin/MAPK-mediated pathway and signals initiated by BMPs contained in the osteoblast matrix. MC3T3-E1 cells were shown to constitutively express BMP-2, BMP-4, and BMP-7. Noggin, a specific BMP inhibitor, reversibly blocked AA-induced gene expression, indicating that BMP production by MC3T3-E1 cells was necessary for differentiation. The ability of exogenously added BMP-2, BMP-4, or BMP-7 to stimulate osteocalcin (OCN) and bone sialoprotein (BSP) mRNAs or OCN promoter activity was synergistically increased in cells that were actively synthesizing an ECM (i.e., were grown in the presence of AA). A minimum of 4 days of ECM accumulation was required for this synergistic response to be observed. Neither BMP-7, AA, nor a combination of these two treatments had major effects on Cbfa1 messenger RNA (mRNA) or protein levels, as would be expected if regulation was mainly at the posttranscriptional level. U0126, a specific inhibitor of MAPK/extracellular signal-regulated kinase (MEK), blocked AA- or BMP-7/AA-dependent gene expression in a time- and dose-dependent manner that was closely correlated with inhibition of extracellular signal-regulated kinase (ERK) phosphorylation. This work establishes that autocrine BMP production as well as integrin-mediated cell-collagen interactions are both required for osteoblast differentiation, and both these pathways require MAP kinase activity.

3T3 Cells↗

PubMed1998

Cross-talk between signaling pathways in murine embryonic palate cells: effect of TGF beta and cAMP on EGF-induced DNA synthesis.

Signaling pathways utilized by EGF, cAMP, and TGF beta have been demonstrated to play critical roles in normal palate development. Stimulation of these pathways has been shown in palate cells and numerous other systems to affect cell growth. Because proper regulation of cell growth is critical to palate development, we speculate that fine regulation of palatal cell growth may be accomplished through crosstalk between these signaling pathways. We therefore set out to determine the effects of cAMP and TGF beta on EGF-induced cell proliferation in murine embryonic palate cells. We found that both TGF beta and cAMP inhibited the proliferative response of cells to treatment with EGF, whereas H89, a serine/ threonine protein kinase inhibitor with selectivity towards cAMP-dependent protein kinase, increased the cells' proliferative response to EGF. Genestein, a selective inhibitor of tyrosine kinases, at high doses abrogated the cells' proliferative response to EGF, confirming that EGF's ability to induce cell proliferation is critically dependent upon tyrosine kinase activity. Lower doses of genestein, however, actually enhanced cellular response to EGF. The data suggest that both the TGF beta- and cAMP-mediated signaling pathways may be involved in modulation of the effects of EGF on palate cell growth in vivo.

Animals↗

PubMed2004

Neuronal death/survival signaling pathways in cerebral ischemia.

Cumulative evidence suggests that apoptosis plays a pivotal role in cell death in vitro after hypoxia. Apoptotic cell death pathways have also been implicated in ischemic cerebral injury in in vivo ischemia models. Experimental ischemia and reperfusion models, such as transient focal/global ischemia in rodents, have been thoroughly studied and the numerous reports suggest the involvement of cell survival/death signaling pathways in the pathogenesis of apoptotic cell death in ischemic lesions. In these models, reoxygenation during reperfusion provides a substrate for numerous enzymatic oxidation reactions. Oxygen radicals damage cellular lipids, proteins and nucleic acids, and initiate cell signaling pathways after cerebral ischemia. Genetic manipulation of intrinsic antioxidants and factors in the signaling pathways has provided substantial understanding of the mechanisms involved in cell death/survival signaling pathways and the role of oxygen radicals in ischemic cerebral injury. Future studies of these pathways may provide novel therapeutic strategies in clinical stroke.

Animals↗

PubMed2001

The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway.

We have identified a gene encoding a novel protein that is transcriptionally regulated by the Notch signaling pathway in mammals. This gene, named Nrarp (for Notch-regulated ankyrin-repeat protein), encodes a 114 amino acid protein that has a unique amino-terminus and a carboxy-terminal domain containing two ankyrin-repeat motifs. A Xenopus homolog of the Nrarp gene was previously identified in a large-scale in situ hybridization screen of randomly isolated cDNA clones. We demonstrate that in T-cell and myoblast cell lines expression of the Nrarp gene is induced by the intracellular domain of the Notch1 protein, and that this induction is mediated by a CBF1/Su(H)/Lag-1 (CSL)-dependent pathway. During mouse embryogenesis, the Nrarp gene is expressed in several tissues in which cellular differentiation is regulated by the Notch signaling pathway. Expression of the Nrarp gene is downregulated in Notch1 null mutant mouse embryos, indicating that expression of the Nrarp gene is regulated by the Notch pathway in vivo. Thus, Nrarp transcript levels are regulated by the level of Notch1 signaling in both cultured cell lines and mouse embryos. During somitogenesis, the Nrarp gene is expressed in a pattern that suggests that Nrarp expression may play a role in the formation of somites, and Nrarp expression in the paraxial mesoderm is altered in several Notch pathway mutants that exhibit defects in somite formation. These observations demonstrate that the Nrarp gene is an evolutionarily conserved transcriptional target of the Notch signaling pathway.

Alleles↗

PubMed2002

[Rescue of auditory hair cells from ototoxicity by CEP-11 004, an inhibitor of the JNK signaling pathway].

The hair cells (HCs) are the most vulnerable elements in the cochlea and damage to them is the most common cause of sensorineural hearing loss (SNHL). Understanding the intracellular events that lead to the death of HCs is a key to developing protective strategies. Recently, it has been shown that the c-Jun-N-terminal kinase (JNK) pathway is activated in HCs in response to aminoglycosides and CEP-1347, an inhibitor of the JNK signaling pathway protected HCs from ototoxicity. We have studied another inhibitor (CEP-11 004) of this signaling pathway in its ability to protect HCs from aminoglycoside ototoxicity in vitro. Organ of Corti explants from p5 rat basal turns were maintained in tissue culture and treated with CEP-11 004 for 12 hours. They were then treated with CEP-11 004 plus gentamicin for 72 hours. Significantly less HC death was observed compared to gentamicin alone. CEP-11 004 alone had no effect on HCs. We conclude that the JNK signaling pathway plays a role in aminoglycoside ototoxicity signaling.

Animals↗

PubMed2004

Multiple signaling pathways and a selector protein sequentially regulate Drosophila wing development.

Drosophila wing development is a useful model to study organogenesis, which requires the input of selector genes that specify the identity of various morphogenetic fields (Weatherbee, S. D. and Carroll, S. B. (1999) Cell 97, 283-286) and cell signaling molecules. In order to understand how the integration of multiple signaling pathways and selector proteins can be achieved during wing development, we studied the regulatory network that controls the expression of Serrate (Ser), a ligand for the Notch (N) signaling pathway, which is essential for the development of the Drosophila wing, as well as vertebrate limbs. Here, we show that a 794 bp cis-regulatory element located in the 3' region of the Ser gene can recapitulate the dynamic patterns of endogenous Ser expression during wing development. Using this enhancer element, we demonstrate that Apterous (Ap, a selector protein), and the Notch and Wingless (Wg) signaling pathways, can sequentially control wing development through direct regulation of Ser expression in early, mid and late third instar stages, respectively. In addition, we show that later Ser expression in the presumptive vein cells is controlled by the Egfr pathway. Thus, a cis-regulatory element is sequentially regulated by multiple signaling pathways and a selector protein during Drosophila wing development. Such a mechanism is possibly conserved in the appendage outgrowth of other arthropods and vertebrates.

Animals↗

PubMed2002

Bayesian network approach to cell signaling pathway modeling.

The modeling of cellular signaling pathways is an emerging field. Sachs et al. illustrate the application of Bayesian networks to an example cellular pathway involving the activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) in response to fibronectin binding to an integrin. They describe how to use the analysis to select from among proposed models, formulate hypotheses regarding component interactions, and uncover potential dynamic changes in the interactions between these components. Although the data sets currently available for this example problem are too small to definitively point to a particular model, the approach and results provide a glimpse into the power that these methods will achieve once the technology for obtaining the necessary data becomes readily available.

Bayes Theorem↗

PubMed2002

Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway.

The mechanism by which genotoxic stress induces IRF-1 and the signalling components upstream of this anti-oncogenic transcription factor during the response to DNA damage are not known. We demonstrate that IRF-1 and the tumour suppressor protein p53 are coordinately up-regulated during the response to DNA damage in an ATM-dependent manner. Induction of IRF-1 protein by either ionizing radiation (IR) or etoposide occurs through a concerted mechanism involving increased IRF-1 expression/synthesis and an increase in the half-life of the IRF-1 protein. A striking defect in the induction of both IRF-1 mRNA and IRF-1 protein was observed in ATM deficient cells. Although ATM deficient cells failed to increase IRF-1 in response to genotoxic stress, the induction of IRF-1 in response to viral mimetics remained intact. Re-expression of the ATM kinase in AT cells restored the DNA damage inducibility of IRF-1, whilst the PI-3 kinase inhibitor wortmannin inhibited IRF-1 induction by DNA damage in ATM-positive cells. The data highlight a role for the ATM kinase in orchestrating the coordinated induction and transcriptional cooperation of IRF-1 and p53 to regulate p21 expression. Thus, IRF-1 is controlled by two distinct signalling pathways; a JAK/STAT-signalling pathway in viral infected cells and an ATM-signalling pathway in DNA damaged cells.

Androstadienes↗

PubMed2005

[EGF-dependent signaling pathways are activated under heat stress in A431 carcinoma cells].

EGF receptor transactivation and activation of EGF-dependent signaling pathways under heat shock conditions were studied. Heating A431 cells at 42 degrees C induced both EGF receptor tyrosine phosphorylation and appearance of phosphorylated forms of key components of its downstream signaling pathways - phospholipase Cgamma1 (PLCgamma1), transcription factor STAT3, and EPK1/2. It is suggested that EGF receptor is transactivated under heat shock in A431 cells. Pretreatment of heat-shocked cells with a specific inhibitor of EGF receptor tyrosine kinase tyrphostin AG1478 does not prevent EGF receptor and EPK 1/2 tyrosine phosphorylation. In contrast, tyrphostin AG1478 abrogates tyrosine phosphorylation of PLCgamma1 and STAT3. This suggested that the intrinsic EGF receptor tyrosine kinase is not involved in EGF receptor transactivation, but is sufficient for PLCgamma1 and STAT3 activation in stress conditions. The effect of a conditioned medium of heated cells was investigated to check whether autocrine mechanism is involved in EGF receptor transactivation. The conditioned medium of heated cells induced both tyrosine phosphorylation of EFG receptor and ERK 1/2. Simultaneously, neither PLCgamma1, not STAT3 phosphorylation were detected. Here, for the first time, we demonstrated the involvement of autocrine mechanism in EGF receptor transactivation under heat stress in A431 carcinoma cells, but additional intracellular events are essential for activation of EGF receptor downstream signaling pathways.

Carcinoma↗

PubMed2005

Glucose sensing through the Hxk2-dependent signalling pathway.

In this work, we describe the hexokinase 2 (Hxk2) signalling pathway within the yeast cell. Hxk2 and Mig1 are the two major factors of glucose repression in Saccharomyces cerevisiae. The functions of both proteins have been extensively studied but there is no information about possible interactions among them in the repression pathway. Our results demonstrate that Hxk2 interacts directly with Mig1 in vivo and in vitro and that the ten amino acids motif between K6 and M15 is required for their interaction. This interaction has been detected at the DNA level both in vivo by chromatin immunoprecipitation experiments and in vitro using purified proteins and a DNA fragment containing the MIG1 site of the SUC2 promoter. This demonstrates that the interaction is of physiological relevance. Our findings show that the main role of Hxk2 in the glucose signalling pathway is the interaction with Mig1 to generate a repressor complex located in the nucleus of S. cerevisiae.

Cell Nucleus↗

PubMed2004

Oxalate inhibits renal proximal tubule cell proliferation via oxidative stress, p38 MAPK/JNK, and cPLA2 signaling pathways.

Exposure of renal proximal tubule cells to oxalate may play an important role in cell proliferation, but the signaling pathways involved in this effect have not been elucidated. Thus the present study was performed to examine the effect of oxalate on (3)H-labeled thymidine incorporation and its related signal pathway in primary cultured rabbit renal proximal tubule cells (PTCs). The effects of oxalate on [(3)H]thymidine incorporation, lactate dehydrogenase (LDH) release, Trypan blue exclusion, H(2)O(2) release, activation of mitogen-activated protein kinases (MAPKs), and (3)H-labeled arachidonic acid (AA) release were examined in primary cultured renal PTCs. Oxalate inhibited [(3)H]thymidine incorporation in a time- and dose-dependent manner. However, its analogs did not affect [(3)H]thymidine incorporation. Oxalate (1 mM) significantly increased H(2)O(2) release, which was blocked by N-acetyl-l-cysteine (NAC) and catalase (antioxidants). Oxalate significantly increased p38 MAPK and stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK) activity, not p44/42 MAPK. Oxalate stimulated [(3)H]AA release and translocation of cytosolic phospholipase A(2) (cPLA(2)) from the cytosolic fraction to the membrane fraction. Indeed, oxalate significantly increased prostaglandin E(2) (PGE(2)) production compared with control. Oxalate-induced inhibition of [(3)H]thymidine incorporation and increase of [(3)H]AA release were prevented by antioxidants (NAC), a p38 MAPK inhibitor (SB-203580), a SAPK/JNK inhibitor (SP-600125), or PLA(2) inhibitors [mepacrine and arachidonyl trifluoromethyl ketone (AACOCF(3))], but not by a p44/42 MAPK inhibitor (PD-98059). These findings suggest that oxalate inhibits renal PTC proliferation via oxidative stress, p38 MAPK/JNK, and cPLA(2) signaling pathways.

Animals↗

PubMed1993

Multiple signaling pathways in bovine chromaffin cells regulate tyrosine hydroxylase phosphorylation at Ser19, Ser31, and Ser40.

Intact bovine adrenal medullary chromaffin cells were preincubated with 32PO4, and the multiple-site phosphorylation of tyrosine hydroxylase (TH) was studied. Up to eight 32P-labeled peptides were produced by tryptic hydrolysis of TH; however, all of the tryptic phosphopeptides were derived from four phosphorylation sites--Ser8, Ser19, Ser31 and Ser40. In situ regulation of 32P incorporation into the latter three sites was demonstrated with a diverse set of pharmacological agents. 32P incorporation into Ser19 was preferentially increased by brief exposures to depolarizing secretagogues. Longer treatments also increased Ser31 and Ser40 phosphorylation. Nicotine, muscarine and vasoactive intestinal polypeptide--reflecting cholinergic and non-cholinergic components of sympatho-adrenal transmission--each produced different patterns of multiple-site phosphorylation of TH. Nicotine, bradykinin and histamine increased 32P incorporation at each of the three sites whereas muscarine, angiotensin II, endothelin III, prostaglandin E1, GABA and ATP selectively increased Ser31 phosphorylation. Nerve growth factor did not influence TH phosphorylation in chromaffin cells from adult adrenal glands but selectively increased Ser31 phosphorylation in chromaffin cells isolated from calf adrenal glands. 32P incorporation into Ser40 was selectively increased by forskolin and other cAMP-acting agents whereas vasoactive intestinal polypeptide increased Ser31 and Ser40 phosphorylation. Thus, the phosphorylation of TH in bovine chromaffin cells appears to be regulated at three sites by three separate intracellular signaling pathways--Ser19 via Ca2+/calmodulin-dependent protein kinase II; Ser31 via ERK (MAP2 kinases); and Ser40 via cAMP-dependent protein kinase. These signaling pathways, as well as the extracellular signals that were effective in stimulating them, are similar to those previously described for TH in rat pheochromocytoma cells. However, several of the pharmacological agents produced different patterns of multiple-site TH phosphorylation in the bovine chromaffin cells. These differences between tissues could be accounted for by differences in the coupling/access between the extracellular signal transduction systems and the intracellular signaling pathways as opposed to differences in the intracellular signaling pathways per se.

Adrenal Medulla↗

PubMed2004

[Transforming growth factor beta 1 modulates connective tissue growth factor expression via Smad2 signaling pathway in podocyte in vitro].

OBJECTIVE: To assess the expression of connective tissue growth factor (CTGF), and the signaling pathway for the regulation of CTGF by transforming growth factor beta1 (TGF beta(1)) in podocytes. METHODS: In this study, we observed the effects of three potent profibrotic growth factors-TGF beta(1), Platelet-derived growth factor (PDGF), and Angiotensin II (AngII) on the expression of CTGF protein by Western blot analysis in cultured mouse podocytes, which is one of the most important cell construction of glomerular filter barrier, and we also investigated the underlying ERK and Smads signaling pathway through which TGF beta(1) regulates CTGF expression. The levels of CTGF mRNA were assayed by RT-PCR. RESULTS: Basal levels of CTGF protein were observed in cultured podocytes, treatment with 20 ng/ml PDGF and 10(-6) mol/L Ang. II for 24 h did not stimulate the expression of CTGF protein compared with control (P > 0.05), but significantly increase in levels of CTGF protein were seen in 1 ng/ml TGF beta(1) treated cells compared with with control (P < 0.05), and the levels of CTGF were up-regulated in a TGF beta(1) dose-dependent manner; The level of CTGF mRNA was also stimulated by 1 ng/ml TGF beta(1) at 12 h. 1 ng/ml TGF beta(1) induced phosphorylation of Smad(2) and ERK(1/2), and both reached the peak at 30 min; suppression of phosphorylation of Smad(2) with Staurosporine, a Serine/Threonine kinase inhibitor, diminished TGF beta(1)-triggered expression of CTGF protein, while blockade of phosphorylation of ERK(1/2) with PD98059, a specific ERK(1/2) activation inhibitor, did not decrease the TGF beta(1)-triggered expression of CTGF protein. CONCLUSION: TGF beta(1) stimulated the expression of CTGF protein via Smad(2)-dependent and ERK(1/2)-independent signaling pathway in podocyte in vitro.

Angiotensin II↗

PubMed2006

Transcriptional profiling implicates TGFbeta/BMP and Notch signaling pathways in ductular differentiation of fetal murine hepatoblasts.

Bile duct morphogenesis involves sequential induction of biliary specific gene expression, bilayer generation, cell proliferation, remodeling and apoptosis. HBC-3 cells are a model system to study differentiation of hepatoblasts along the hepatocytic or bile ductular lineage in vitro and in vivo. We used microarray to define molecular pathways during ductular differentiation in response to Matrigel. The temporal pattern of expression of marker genes induced was similar to that observed during bile duct formation in vivo. Notch, HNF1beta, Polycystic kidney disease 2, Bicaudal C 1 and beta-catenin were up regulated during the time course. Functional clustering analysis revealed significant up regulation of clusters of genes involved in extracellular matrix remodeling, ion transport, vacuoles, lytic vacuoles, pro-apoptotic and anti-apoptotic genes, transcription factors and negative regulators of the cell proliferation, while genes involved in the cell cycle were significantly down regulated. Notch signaling pathway was activated by treatment with Matrigel. In addition, TGFbeta/BMP signaling pathway members including the type I TGFbeta receptor and Smads 3, 4 and 5 were significantly up regulated, as were several TGFbeta/BMP responsive genes including Hey 1, a regulator of Notch pathway signaling. SMADS 3, 4 and 5 were present in the nuclear fraction of HBC-3 cells during ductular differentiation in vitro, but not during hepatocyte differentiation. SMAD 5 was preferentially expressed in hepatoblasts undergoing bile duct morphogenesis in the fetal liver, while the TGFbeta/BMP signaling antagonist chordin, was expressed throughout the liver suggesting a mechanism by which TGFbeta/BMP signaling is limited to hepatoblasts that contact portal mesenchyme in vivo.

Animals↗

PubMed2006

Signaling pathways involved in the inhibition of epidermal growth factor receptor by erlotinib in hepatocellular cancer.

AIM: To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma (HCC). METHODS: Erlotinib-induced alterations in gene expression were evaluated using cDNA array technology; changes in protein expression and/or protein activation due to erlotinib treatment as well as IGF-1-induced EGFR transactivation were investigated using Western blotting. RESULTS: Erlotinib treatment inhibited the mitogen activated protein (MAP)-kinase pathway and signal transducer of activation and transcription (STAT)-mediated signaling which led to an altered expression of apoptosis and cell cycle regulating genes as demonstrated by cDNA array technology. Overexpression of proapoptotic factors like caspases and gadds associated with a down-regulation of antiapoptotic factors like Bcl-2, Bcl-X(L) or jun D accounted for erlotinib's potency to induce apoptosis. Downregulation of cell cycle regulators promoting the G1/S-transition and overexpression of cyclin-dependent kinase inhibitors and gadds contributed to the induction of a G1/G0-arrest in response to erlotinib. Furthermore, we displayed the transactivation of EGFR-mediated signaling by the IGF-1-receptor and showed erlotinib's inhibitory effects on the receptor-receptor cross talk. CONCLUSION: Our study sheds light on the under-standing of the mechanisms of action of EGFR-TK-inhibition in HCC-cells and thus might facilitate the design of combination therapies that act additively or synergistically. Moreover, our data on the pathways responding to erlotinib treatment could be helpful in predicting the responsiveness of tumors to EGFR-TKIs in the future.

Antineoplastic Agents↗