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Xianglin Shi

Publications and source records attributed to Xianglin Shi.

At least 91 records · Page 5Linked to original sources
PubMed2003

Effects of welding fumes of differing composition and solubility on free radical production and acute lung injury and inflammation in rats.

The goals of this study were to examine acute lung damage and inflammation, as well as free radical production, caused by welding fumes of different chemical compositions and solubilities. The fumes were from a gas metal arc welding using a mild-steel (GMA-MS) or stainless-steel electrode (GMA-SS) and a manual metal arc welding using a stainless-steel electrode (MMA-SS), which was further separated into soluble and insoluble fractions. The MMA-SS was the only fume to contain soluble chromium. Free radical production was observed only in suspensions of MMA-SS fume under various conditions. Male Sprague-Dawley rats were intratracheally instilled with either a welding fume suspension at 2 mg/rat or a saline vehicle, and various parameters of inflammation and damage were measured at 3 h and days 1, 3, and 6. Only the MMA-SS treatment caused a continued increase in lung weight until day 6 and elevated lipid peroxidation at day 3. All of the fumes caused increases in macrophages and neutrophils obtained by lavage, but the increased cellularity was extended through day 6 following the MMA-SS treatment only. Only the MMA-SS treatment led to an increased recovery of eosinophils and damage to the alveolar-capillary barrier. While all of the fumes produced increases in cytotoxicity, the MMA-SS treatment caused the maximal response at day 3. These findings indicate that different welding fumes caused varied responses in the lungs of rats, correlated to their metal composition and ability to produce free radicals. Additionally, both the soluble and insoluble fractions of the MMA-SS fume were required to produce most effects, indicating that the responses are not dependent exclusively on the soluble metals.

Acute Disease↗
PubMed2003

Role of reactive oxygen species and MAPKs in vanadate-induced G(2)/M phase arrest.

Cell growth arrest is an important mechanism in maintaining genomic stability and integrity in response to environmental stress. Using the human lung alveolar epithelial cancer cell line A549, we investigated the role of reactive oxygen species (ROS), extracellular signal-regulated protein kinase (ERK), and p38 protein kinase in vanadate-induced cell growth arrest. Exposure of cells to vanadate led to cell growth arrest at the G(2)/M phase and caused upregulation of p21 and phospho-cdc2 and degradation of cdc25C in a time- and dose-dependent manner. Vanadate stimulated mitogen-activated protein kinases (MAPKs) family members, as determined by the phosphorylation of ERK and p38. PD98059, an inhibitor of ERK, and SB202190, an inhibitor of p38, inhibited vanadate-induced cell growth arrest, upregulation of p21 and cdc2, and degradation of cdc25C. In addition to hydroxyl radical ((*)OH) formation, cellular reduction of vanadate generated superoxide radical (O(2)(*)(-)) and hydrogen peroxide (H(2)O(2)), as determined by confocal microscopy using specific dyes. Generation of O(2)(*)(-) and H(2)O(2) was inhibited by specific antioxidant enzymes, superoxide dismutase (SOD) and catalase, respectively. ROS activate ERK and p38, which in turn upregulate p21 and cdc2 and cause degradation of cdc25C, leading to cell growth arrest at the G(2)/M phase. Specific ROS affect different MAPK family members and cell growth regulatory proteins with different potencies.

Antioxidants↗
PubMed2003

The SH4-Unique-SH3-SH2 domains dictate specificity in signaling that differentiate c-Yes from c-Src.

c-Src and c-Yes are highly homologous members of the Src family of non-receptor tyrosine kinases. The overall sequence similarity between c-Src and c-Yes allows them to perform many overlapping functions. However, the phenotypes of the c-src and c-yes knockout mice, and cells derived from them, are quite different, indicating functional specificity between the two proteins. Specifically, c-src-/- cells are deficient in several processes that require dynamic regulation of the actin cytoskeleton. In order to begin to understand why c-Yes is unable to compensate for c-Src signaling, we used a series of Src/Yes chimeras in which the non-catalytic functional domains of Src527F were replaced by those of c-Yes. Using chicken embryo fibroblasts as a model system, our results indicate that the c-Yes N-terminal SH4-Unique domains are sufficient to inhibit the ability of Src527F to alter cell morphology, induce actin filament rearrangements or stimulate motility or invasive potential. The data also indicate that the SH4-Unique-SH3-SH2 domains of c-Yes work cooperatively and prevent activation of signaling proteins associated with Src527F transformation, including activation of phosphatidylinositol 3-kinase, phosphorylation of c-Raf and Akt and downregulation of RhoA-GTP. These data indicate that c-Yes may not modulate signals associated with c-Src-induced changes in actin filament integrity and may explain why c-Yes fails to compensate for c-Src signaling in src-/- cells.

Actin Cytoskeleton↗
PubMed2003

Intratracheal amiodarone administration to F344 rats directly damages lung airway and parenchymal cells.

Amiodarone (AD) is gaining support as a first-line antiarrhythmic drug despite its potentially fatal pulmonary toxicity involving inflammation and fibrosis. We previously reported a model for this amiodarone-induced pulmonary toxicity (AIPT) in which F344 rats were intratracheally (i.t.) instilled with AD (6.25 mg/kg) in sterile water on days 0 and 2, which led to transient pulmonary inflammation and lung damage and subsequent fibrosis. The goals of this study were to determine the direct effect of the drug in the lung damage occurring after i.t. AD administration, to identify its location, and to examine its potential mechanisms. Using bronchoalveolar lavage and laser-scanning confocal microscopy, it was discovered that AD instillation produces rapid and massive damage to the alveolar-capillary barrier and damage or death to lung airway and parenchymal cells. While AD in solution was found to be capable of generating hydroxyl radicals, protection from AD-induced damage could not be obtained by incorporating water-soluble antioxidants in the drug solution. However, damage induced by free-radicals could still occur after AD partitions into lipid membranes. AD could also be directly disrupting cellular membranes via its amphiphilic structure. It is not known if the mechanism(s) of damage following i.t. AD treatment are similar to the mechanisms that underlie human AIPT. Therefore these data suggest that investigators should use caution in extrapolating results from animal studies that utilize i.t. administration of AD to human AIPT.

Administration, Inhalation↗
PubMed2003

Hydrogen peroxide formation and actin filament reorganization by Cdc42 are essential for ethanol-induced in vitro angiogenesis.

This report focuses on the identification of the molecular mechanisms of ethanol-induced in vitro angiogenesis. The manipulation of angiogenesis is an important therapeutic approach for the treatment of cancer, cardiovascular diseases, and chronic inflammation. Our results showed that ethanol stimulation altered the integrity of actin filaments and increased the formation of lamellipodia and filopodia in SVEC4-10 cells. Further experiments demonstrated that ethanol stimulation increased cell migration and invasion and induced in vitro angiogenesis in SVEC4-10 cells. Mechanistically, ethanol stimulation activated Cdc42 and produced H(2)O(2) a reactive oxygen species intermediate in SVEC4-10 cells. Measuring the time course of Cdc42 activation and H(2)O(2) production upon ethanol stimulation revealed that the Cdc42 activation and the increase of H(2)O(2) lasted more than 3 h, which indicates the mechanisms of the long duration effects of ethanol on the cells. Furthermore, either overexpression of a constitutive dominant negative Cdc42 or inhibition of H(2)O(2) production abrogated the effects of ethanol on SVEC4-10 cells, indicating that both the activation of Cdc42 and the production of H(2)O(2) are essential for the actions of ethanol. Interestingly, we also found that overexpression of a constitutive dominant positive Cdc42 itself was sufficient to produce H(2)O(2) and to induce in vitro angiogenesis. Taken together, our results suggest that ethanol stimulation can induce H(2)O(2) production through the activation of Cdc42, which results in reorganizing actin filaments and increasing cell motility and in vitro angiogenesis.

Actins↗
PubMed2003

Vanadium-induced apoptosis and pulmonary inflammation in mice: Role of reactive oxygen species.

Pulmonary exposure to metals and metal-containing compounds is associated with pulmonary inflammation, cell death, and tissue injury. The present study uses a mouse model to investigate vanadium-induced apoptosis and lung inflammation, and the role of reactive oxygen species (ROS) in this process. Aspiration of the pentavalent form of vanadium, V (V), caused a rapid influx of polymorphonuclear leukocytes into the pulmonary airspace with a peak inflammatory response at 6 h post-exposure and resolution by 72 h. During this period, the number of apoptotic lung cells which were predominantly neutrophils increased considerably with a peak response at 24 h accompanied by no or minimum necrosis. After 24 h when the V (V)-induced inflammation was in the resolution phase, an increased influx of macrophages and engulfment of apoptotic bodies by these phagocytes was observed, supporting the role of macrophages in apoptotic cell clearance and resolution of V (V)-induced lung inflammation. Electron spin resonance (ESR) studies using lavaged alveolar macrophages showed the formation of ROS, including O(2)(*-), H(2)O(2), and (*)OH radicals which were confirmed by inhibition with free radical scavengers. The mechanism of ROS generation induced by V (V) involved the activation of an NADPH oxidase complex and the mitochondrial electron transport chain. The ROS scavenger, catalase (H(2)O(2) scavenger), effectively inhibited both lung cell apoptosis and the inflammatory response, whereas superoxide dismutase (SOD) (O(2)(*-) scavenger) and the metal chelator, deferoxamine (inhibitor of (*)OH generation by Fenton-like reactions) had lesser effects. These results indicate that multiple oxidative species are involved in V (V)-induced lung inflammation and apoptosis, and that H(2)O(2) plays a major role in this process.

Administration, Inhalation↗
PubMed2003

Role of metal-induced reactive oxygen species generation in lung responses caused by residual oil fly ash.

Inhalation of residual oil fly ash (ROFA) increases pulmonary morbidity in exposed workers. We examined the role of reactive oxygen species (ROS) in ROFA-induced lung injury. ROFA was collected from a precipitator at Boston Edison Co., Everett, MA, USA. ROFA (ROFA-total) was suspended in saline, incubated for 24 h at 37 degrees C, centrifuged, and separated into its soluble (ROFA-sol.) and insoluble (ROFA-insol.) fractions. Sprague-Dawley rats were intratracheally instilled with saline or ROFA-total or ROFA-sol. or ROFA-insol. (1 mg/100 g body wt.). Lung tissue and bronchoalveolar lavage cells were harvested at 4, 24, and 72 h after instillation. Chemiluminescence (CL) of recovered cells was measured as an index of ROS production, and tissue-lipid-peroxidation was assessed to determine oxidative injury. Significant amounts of Al, Fe, and Ni were present in ROFA-sol., whereas ROFA-insol. contained Fe, V, and Al. Using electron spin resonance (ESR), significantly more hydroxyl radicals were measured in ROFA-sol. as compared to ROFA-insol. None of the ROFA samples had an effect on CL or lipid peroxidation at 4 h. Treatment with ROFA-total and ROFA-insol. caused significant increases in both CL (at 24 h) and lipid peroxidation (at 24 and 72 h) when compared to saline control value. ROFA-sol. significantly reduced CL production at 72 h after treatment and had no effect on lipid peroxidation at any time point. In summary, ROFA, particularly its soluble fraction, generated a metal-dependent hydroxyl radical as measured by a cell-free ESR assay. However, cellular oxidant production and tissue injury were observed mostly with the ROFA-total and ROFA-insol. particulate forms. ROS generated by ROFA-sol. as measured by ESR appear not to play a major role in the lung injury caused after ROFA exposure.

Air Pollutants↗
PubMed2002

Activation of JNK by vanadate induces a Fas-associated death domain (FADD)-dependent death of cerebellar granule progenitors in vitro.

Apoptosis is a highly regulated process that plays a critical role in neuronal development as well as the homeostasis of the adult nervous system. Vanadate, an environmental toxicant, causes developmental defects in the central nervous system. Here, we demonstrated that vanadate induced apoptosis in cultured cerebellar granule progenitors (CGPs). Treatment of cultured CGPs with vanadate activated ERKs and JNKs but not p38 MAPK and also induced c-Jun phosphorylation. In addition, vanadate induced FasL production, Fas (CD95) aggregation, and its association with the Fas-associated death domain (FADD), as well as the activation of caspase-8. Furthermore, vanadate generated reactive oxygen species (ROS) in CGPs; however, ROS was not involved in vanadate-mediated MAPK activation. Vanadate-induced FasL expression was ROS-dependent but JNK-independent. In contrast, vanadate-elicited Fas aggregation and Fas-FADD association, as well as caspase-8 activation, were dependent on JNK activation but were minimally regulated by ROS generation. The hydrogen peroxide scavenger, catalase, blocked vanadate-induced FasL expression and partially mitigated vanadate-induced cell death. On the other hand, dominant negative FADD and caspase-8 inhibitor completely eliminated vanadate-induced apoptosis. Thus, JNK signaling plays a major role in vanadate-mediated activation of the Fas-FADD-caspase-8 pathway that accounts for vanadate-induced apoptosis of CGPs.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Epidermal growth factor up-regulates the transcription of mouse lon homology ATP-dependent protease through extracellular signal-regulated protein kinase- and phosphatidylinositol-3-kinase-dependent pathways.

Epidermal growth factor (EGF) induces tumorigenic transformation of mouse epidermal cells (JB6 P(+)). We cloned a full-length EGF-responsive cDNA in JB6P(+) cells; EGF up-regulated mRNA expression of this gene 5- to 6-fold. The deduced amino acid sequence of this cDNA exhibited 84 and 96% homology with human and rat Lon homology ATP-dependent protease, respectively, and all conserved domains of Lon, such as ATPase/protease domains, are present in the mouse gene, indicating that this gene is mouse Lon. EGF increased the transcriptional rate without affecting the mRNA stability of m-Lon. The level of m-Lon in irreversibly transformed mouse epidermal cells (JB7) was 3.4-fold higher than that in parental JB6 P(+) cells. Similarly, human mammary epithelial cells overexpressing the proto-oncogene ErbB2 expressed significantly higher levels of Lon than normal mammary epithelial cells. EGF failed to regulate Lon expression in ERK-deficient JB6 P(-) cells or cells that expressed the dominant-negative p85 P13-K regulatory unit. Furthermore, selective chemical blockers for MEK1 and P13-K (PD98059 and LY294002) inhibited EGF-mediated induction. Mitochondria-localized Lon protease plays a critical role in the regulation of mitochondrial gene expression and genome integrity. Disruption of mitochondrial homeostasis is a general characteristic of tumorigenic transformation. Thus, the role of Lon in tumor promotion warrants further study.

ATP-Dependent Proteases↗
PubMed2002

Ultraviolet-induced phosphorylation of p70(S6K) at Thr(389) and Thr(421)/Ser(424) involves hydrogen peroxide and mammalian target of rapamycin but not Akt and atypical protein kinase C.

The p70 S6 kinase (p70(S6k)) is a Ser/Thr kinase that plays an important role in cell growth, transformation, and the transition of the cell cycle in mammalian cells. Because UV radiation has been reported to induce activation of p70(S6k), which is believed to play some role in the carcinogenic effects of sun exposure, the present study investigated the signaling pathways involved in this activation induced by UV radiation in mouse epidermal JB6 Cl41 cells. Exposure of cells to UV radiation led to marked increases in p70(S6k) activity and phosphorylation at Thr(389) and Thr(421)/Ser(424). UV radiation also generated reactive oxygen species as measured by electron spin resonance and by H(2)O(2) and O( minus sign, dot below )(2) fluorescence staining assays in JB6 Cl 41 cells. The scavenging of UV-generated H(2)O(2) by N-acety-L-cyteine (a general antioxidant) or catalase (a specific H(2)O(2) scavenger) inhibited p70(S6k) phosphorylation at Thr(389) and Thr(421)/Ser(424), whereas pretreatment of cells with sodium formate (an.OH radical scavenger) or superoxide dismutase (an O( minus sign, dot below )(2) radical scavenger) did not show any inhibitory effects. Importantly, UV-induced increases in p70(S6k) phosphorylation at Thr(389) and Thr(421)/Ser(424) were dramatically inhibited by pretreatment of cells with rapamycin, LY294002, or PD98059, whereas overexpression of dominant-negative mutants of PKClambda/iota and Akt1 did not inhibit p70(S6k) phosphorylation at Thr(389) and Thr(421)/Ser(424). These results demonstrated that H(2)O(2), phosphatidylinositol 3-kinase, and mammalian target of rapamycin were important players for UV-induced p70(S6k) phosphorylation at Thr(389) and Thr(421)/Ser(424), whereas Akt and atypical protein kinase C were not involved in this activation. The role of H(2)O(2) in p70(S6k) phosphorylation at Thr(389) and Thr(421)/Ser(424) was further supported by the findings that treatment of cells with H(2)O(2) also caused p70(S6k) phosphorylation at Thr(389) and Thr(421)/Ser(424).

Animals↗
PubMed2002

p38 Signaling-mediated hypoxia-inducible factor 1alpha and vascular endothelial growth factor induction by Cr(VI) in DU145 human prostate carcinoma cells.

Chromium(VI) (Cr(VI)) is widely used in industry and is a potent inducer of tumors in animals. The present study demonstrates that Cr(VI) induces hypoxia-inducible factor 1 (HIF-1) activity through the specific expression of HIF-1alpha but not HIF-1beta subunit and increases the level of vascular endothelial growth factor (VEGF) expression in DU145 human prostate carcinoma cells. To dissect the signaling pathways involved in Cr(VI)-induced HIF-1 expression, we found that p38 mitogen-activated protein kinase signaling was required for HIF-1alpha expression induced by Cr(VI). Neither phosphatidylinositol 3-kinase nor extracellular signal-regulated kinase activity was required for Cr(VI)-induced HIF-1 expression. Cr(VI) induced expression of HIF-1 and VEGF through the production of reactive oxygen species in DU145 cells. The major species of reactive oxygen species responsible for the induction of HIF-1 and VEGF expression is H(2)O(2). These results suggest that the expression of HIF-1 and VEGF induced by Cr(VI) may be an important signaling pathway in the Cr(VI)-induced carcinogenesis.

Antioxidants↗
PubMed2002

Vanadate-induced expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor through phosphatidylinositol 3-kinase/Akt pathway and reactive oxygen species.

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1 alpha and HIF-1 beta/aryl hydrocarbon nuclear translocator subunits. HIF-1 expression is induced by hypoxia, growth factors, and activation of oncogenes. In response to hypoxia, HIF-1 activates the expression of many genes including vascular endothelial growth factor (VEGF) and erythropoietin. HIF-1 and VEGF play an important role in angiogenesis and tumor progression. Vanadate is widely used in industry, and is a potent inducer of tumors in humans and animals. In this study, we demonstrate that vanadate induces HIF-1 activity through the expression of HIF-1alpha but not HIF-1 beta subunit, and increases VEGF expression in DU145 human prostate carcinoma cells. We also studied the signaling pathway involved in vanadate-induced HIF-1 alpha and VEGF expression and found that phosphatidylinositol 3-kinase/Akt signaling was required for HIF-1 and VEGF expression induced by vanadate, whereas mitogen-activated protein kinase pathway was not required. We also found that reactive oxygen species (ROS) were involved in vanadate-induced expression of HIF-1 and VEGF in DU145 cells. The major species of ROS responsible for the induction of HIF-1 and VEGF expression was H(2)O(2). These results suggest that the expression of HIF-1 and VEGF induced by vanadate through PI3K/Akt may be an important signaling pathway in the vanadate-induced carcinogenesis, and ROS may play an important role.

Antioxidants↗
PubMed2002

Vanadate-induced cell growth arrest is p53-dependent through activation of p21 in C141 cells.

Vanadium is widely used in industry. It is a potent toxic agent and carcinogen. The mechanisms involved in its toxicity and carcinogenesis are still unclear. Improper cell growth is believed to be involved in cancer development. The present study investigated the regulation of p53 on vanadate-induced cell growth arrest using both p53 wild type C141 cells and p53 deficient embryo fibroblasts (p53 -/-). On vanadate stimulation, C141 cells exhibited a dose- and time-dependent S phase arrest as determined by DNA content analysis. In contrast, vanadate was unable to increase the percentage of S phase in p53 -/- cells. Luciferase assay showed that vanadate induced p53 activation in a dose- and time-dependent manner in p53 wild type C141 cells. Addition of pifithrin-alpha (PFT), a specific inhibitor of p53, reduced the activation of p53 with a concomitant decrease in growth arrest at S phase. Western blotting analysis demonstrated that vanadate caused a dose- and time-dependent increase of p21 level in C141 cells. Pretreatment of C141 cells with PFT decreased p21 expression induced by vanadate while the p21 expression did not vary in vanadate stimulated p53 -/- cells. The results obtained from the present study suggest that vanadate is able to induce S phase arrest through p53- and p21-dependent pathway.

Animals↗
PubMed2002

Arsenite-induced Cdc25C degradation is through the KEN-box and ubiquitin-proteasome pathway.

Arsenite is a known human carcinogen that induces tumorigenesis through either a genotoxic or an epigenetic mechanism. In this study, the effect of arsenite on cell cycle regulation and the mechanisms that contribute to this effect were investigated. Treatment of the cells with arsenite suppressed cell proliferation and reduced cell viability in a dose- or time-dependent manner. Analysis of cell cycle profile and cell cycle regulatory proteins indicated that arsenite arrested the cell cycle at G(2)/M phase, partially through induction of cell division cycle 25 (Cdc25) isoform C (Cdc25C) degradation via ubiquitin-proteasome pathways. Mutation of the putative KEN box within the region 151 to 157 of human Cdc25C or treatment of the cells with a peptide competitor encompassing the KEN box partially inhibited arsenite-induced ubiquitination of Cdc25C. Thus, these results indicate that the regulated ubiquitination of Cdc25C may be involved in the arsenite-induced proteolytic down-regulation of Cdc25C activity in the G(2)/M phase of the cell cycle and suggest a link between cell cycle and the carcinogenic effects of arsenite.

Acetylcysteine↗
PubMed2002

Intracellular signal transduction of cells in response to carcinogenic metals.

Epidemiological and animal studies suggest that several metals and metal-containing compounds are potent mutagens and carcinogens. These metals include chromium, arsenic, vanadium, nickel, and others. During the last two decades, chemical and cellular studies have contributed enormously to our understanding of the mechanisms of metal-induced pathophysiological processes. Although each of these metals is unique in its mechanism of action, some common signaling molecules, such as reactive oxygen species (ROS), may be shared by many of the carcinogenic metals. New techniques are now available to reveal the mechanisms of carcinogenesis in precise molecular terms. In this review, we focused our attentions on carcinogenic metal-induced signal transduction pathways leading to the activation of NF-kappaB, cell apoptosis and cell cycle progression, three crucial steps or events involved in the transformation and carcinogenesis. This review summarizes current knowledge and our recent studies concerning intracellular signal transduction pathways initiated by carcinogenic metals and the cross-talk that occurs among these pathways in cells in response to metals.

Animals↗
PubMed2002

Diseases caused by silica: mechanisms of injury and disease development.

While silica particles are considered to be fibrogenic and carcinogenic agents, the mechanisms responsible are not well understood. This article summarizes literature on silica-induced accelerated silicosis, chronic silicosis, silico-tuberculosis, bronchogenic carcinoma, and immune-mediated diseases. This article also discusses the generation of reactive oxygen species (ROS) that occurs directly from the interaction of silica with aqueous medium and from silica-stimulated cells, the molecular mechanisms of silica-induced lung injuries with focus on silica-induced NF-kappaB activation, including its mechanisms, possible attenuation and relationship to silica-induced generation of cyclooxygenase II and TNF-alpha. Silica-induced AP-1 activation, protooncogene expression, and the role of ROS in these processes are also briefly discussed.

Acute Disease↗
PubMed2002

MAPKs mediate S phase arrest induced by vanadate through a p53-dependent pathway in mouse epidermal C141 cells.

Mitogen-activated protein (MAP) kinases play an important role in mediation of the signal transduction pathway in cellular response to genotoxic stress. Cell growth arrest is considered as an early stage in response to the genotoxic stress. p53 is well-known as a tumor suppression gene involved in both cell growth arrest and apoptosis. The present study investigated the involvement of MAP kinases in vanadate-induced cell growth arrest and the relationship of p53. DNA content analysis showed that vanadate-induced S phase arrest is time- and dose-dependent in p53 wild-type C141 cells but not in p53-deficient C141 cells. Western blotting results indicated that vanadate caused an inactivation of p-cdk2 at Thr160, which is an important kinase for the progression of S phase, and an increase in expression of p21, which is a key for S phase arrest. In p53-deficient cells, vanadate did not induce any observable change in p21 or p-cdk2 level. In addition, vanadate up-regulated phospho-p38 and ERK, two members of MAP kinases. At the same time, vanadate increased the p53 activity as measured by luciferase assay. Addition of PD98059 and SB202190, inhibitors of ERK and p38, respectively, decreased vanadate-induced S phase arrest, reduced p21 levels, restored activation of p-cdk2, and decreased p53 activity. The study demonstrated that vanadate-induced S phase arrest is mediated by both ERK and p38 in a p53-dependent pathway.

Animals↗