Mechanism and rate constants for complete series reactions of 19 fluorophenols with atomic H.

Fluorine-containing halogenated fluorophenol may have effect as intermediate species involved in the formation of polyfluorinated dibenzo-p-dioxin/dibenzofurans (PFDDs/Fs). The mechanism for the atomic H initiated reactions with complete series of nineteen fluorophenol congeners was studies using the density functional theory. At the MPWB1K/6-31+G(d,p) level, the geometries and frequencies of reactants, transition states, and products were obtained, and the accurate energetic values were acquired at the MPWB1K/6-311+G(3df,2p) level. The rate constants were evaluated by the canonical variational transition-state theory with the small curvature tunneling contribution over a wide temperature range of 600-1000 K. The study shows that the intramolecular hydrogen-bond in the ortho-substituted FPs as well as the inductive effect of the electron-withdrawing fluorine and steric repulsion of multiple substitutions may ultimately be responsible for the relative strength of the O-H bonds in FPs. The results can be used for further studies on PFDD/Fs formation mechanism.

Potential ecological risks of heavy metals and Cd accumulation characteristics of Suaeda salsa under different Cd input and water logging conditions in the Yellow River estuary, China.

To improve the remediation of heavy metal pollution by typical wetland vegetation and maintain the health of wetland ecosystems under the water-sediment regulation scheme (WSRS) application, we evaluated the potential ecological risk of heavy metals in surface sediment in the Yellow River estuary affected by the WSRS. The ranges of Cr, Cu, Zn, Cd, and Pb content in surface sediment were 52.44-100.80 mg·kg-1 dry weight (DW), 16.38-21.19 mg·kg-1 DW, 64.77-255.50 mg·kg-1 DW, 0.12-0.24 mg·kg-1 DW, and 5.40-8.63 mg·kg-1 DW, respectively, and potential ecological risk coefficients showed that Cd was associated with moderate potential risk. We further examined effects of Cd in a greenhouse experiment to explore the influence of short-term Cd input and water logging condition changes induced by WSRS on the Cd absorption characteristics of Suaeda salsa (L.) Pall in the Yellow River estuary. The results showed that total biomass decreased but Cd content in tissue of S. salsa increased with increasing Cd input and the accumulation factor reached maximum values at 100 µg·L-1 of Cd, indicating that S. salsa efficiently accumulated Cd. Water logging depth significantly affected S. salsa growth and Cd absorption with deeper water logging being detrimental to growth. The interaction effect of Cd input and water logging depth on Cd content and accumulation factor was significant. These results suggest that WSRS caused short-term heavy metal input and changes in water conditions affect wetland vegetation growth and heavy metal absorption in the downstream estuary.

Topoisomerase I Inhibition Radiosensitizing Hepatocellular Carcinoma by RNF144A-mediated DNA-PKcs Ubiquitination and Natural Killer Cell Cytotoxicity.

Background and Aims: Topoisomerase I (TOP1) participates the repair of DNA double-strand breaks (DSBs) upon radiation therapy (RT). RNF144A mediates ubiquitination of catalytic subunit of DNA protein kinase (DNA-PKcs), a critical factor in DSB repair. This study aimed to investigate the natural killer (NK) cell-mediated radiosensitization with TOP1 inhibition and the mechanism by DNA-PKcs/RNF144A. Methods: In vitro synergism with TOP1i or cocultured NK cells and RT were evaluated in human hepatocellular carcinoma (HCC) cell lines (Huh7/PLC5) by clonogenic survivals. Orthotopic xenografts were treated with Lipotecan and/or RT. Protein expression was analyzed by western blotting, immunoprecipitation, subcellular fractionation, and confocal microscopy. Results: Lipotecan/RT had a superior synergistic effect to RT on HCC cells. Combined RT/Lipotecan reduced the xenograft size by 7-fold than RT (p<0.05). Lipotecan caused more radiation-induced DNA damage and DNA-PKcs signaling. The expression of major histocompatibility complex class I-related chain A and B (MICA/B) on tumor cells is associated with the sensitivity to NK cell-mediated lysis. Cocultured NK and HCC cells with Lipotecan radiosensitized HCC cells/tissues with the expression of MICA/B. RNF144A increased more in Huh7 cells with combined RT/TOP1i, and reduced the prosurvival function of DNA-PKcs. The effect was reversed by inhibiting the ubiquitin/proteasome system. In comparison, RNF144A decreased through nuclear translocation with the cumulated DNA-PKcs and radio-resistance of PLC5 cells. Conclusions: TOP1i reinforces NK cell-activated anti-HCC effect of RT through RNF144A mediated DNA-PKcs ubiquitination. RNF144A provides a reason for differentiating radiosensitization effect between HCC cells.

Theoretical evidence for the formation of perfluorocarboxylic acids form atmospheric oxidation degradation of fluorotelomer acrylates.

The atmospheric oxidation degradation of fluorotelomer acrylates (FTAcs) has been proposed as a potential source of perfluorocarboxylic acids (PFCAs) in remote locations. In this paper, detailed reactions of the main oxidant OH radicals with 4:2 FTAc in the atmosphere have been investigated by using density functional theory (DFT) calculation. All possible pathways involved in the oxidation process were presented and discussed. Based on the mechanism, transition state theory (TST) was used to predict the rate constants of the key elementary steps including the initial reactions of OH radical with n:2 FTAcs and the subsequent reactions of the main intermediates. Studies show that the reaction processes of OH radical addition to C = C bond are dominant and the fluorotelomer glyoxylate and formaldehyde are the major products. At 296 K, the calculated overall rate constant of 4:2 FTAc with OH radical is 1.19 × 10-11 cm3 molecule-1 s-1 with an atmospheric lifetime of 23.3 h. In the atmosphere, fluorotelomer glyoxylate will continue to be oxidized, which will lead to the formation of PFCAs ultimately. In addition, atmospheric reactions of more carbons FTAc (CnF2n+1CH2CH2OC(O)CH = CH2, n = 6, 8, 10) are also discussed in the presence of O2/NOx.

Influence of Potamogeton crispus harvesting on phosphorus composition of Lake Yimeng.

Harvesting is an important method used to control the overproduction of Potamogeton crispus in lakes. A three-year comparative field study was performed in a eutrophic lake (harvested area) and its connected lake (non-harvested area) to determine the effects of harvesting on the phosphorus (P) composition and environmental factors in the water and sediment. Results revealed that harvesting significantly reduced the dissolved total P and dissolved organic P (DOP) and increased the alkaline phosphatase activity and particulate P (PP) in the water. No significant differences were detected in the water total P (TP), soluble reactive P, chlorophyll-a, pH, and dissolved oxygen between the harvested and non-harvested areas. Sediment TP and organic P (OP) were significantly reduced in the harvested area. Harvesting changed the P composition in the water. In the non-harvested area, P was mainly formed by DOP (40%) in the water body, while in the harvested area, PP was the main water component (47%). Harvesting increased the proportion of inorganic P (IP) in the sediment and decreased the proportion of OP. In the water, the IP to TP ratio in the non-harvested and harvested areas were 58.26% and 63.51%, respectively. Our results showed that harvesting changed the P composition in the water and sediment. In the harvesting of submerged vegetation, our results can serve as a reference for the management of vegetation-rich lakes.

Nutrients and Environmental Factors Cross Wavelet Analysis of River Yi in East China: A Multi-Scale Approach.

The accumulation of nutrients in rivers is a major cause of eutrophication, and the change in nutrient content is affected by a variety of factors. Taking the River Yi as an example, this study used wavelet analysis tools to examine the periodic changes in nutrients and environmental factors, as well as the relationship between nutrients and environmental factors. The results revealed that total phosphorus (TP), total nitrogen (TN), and ammonia nitrogen (NH4+-N) exhibit multiscale oscillation features, with the dominating periods of 16-17, 26, and 57-60 months. The continuous wavelet transform revealed periodic fluctuation laws on multiple scales between nutrients and several environmental factors. Wavelet transform coherence (WTC) was performed on nutrients and environmental factors, and the results showed that temperature and dissolved oxygen (DO) have a strong influence on nutrient concentration fluctuation. The WTC revealed a weak correlation between pH and TP. On a longer period, however, pH was positively correlated with TN. The flow was found to be positively correct with N and P, while N and P were found to be negatively correct with DO and electrical conductance (EC) at different scales. In most cases, TP was negatively correlated with 5-day biochemical oxygen demand (BOD5) and permanganate index (CODMn). The correlation between TN and CODMn and BOD5 was limited, and no clear dominant phase emerged. In a nutshell, wavelet analysis revealed that water temperature, pH, DO, flow, EC, CODMn, and BOD5 had a pronounced influence on nutrient concentration in the River Yi at different time scales. In the case of the combination of environmental factors, pH and DO play the largest role in determining nutrient concentration.

Akt activation emulates Chk1 inhibition and Bcl2 overexpression and abrogates G2 cell cycle checkpoint by inhibiting BRCA1 foci.

Akt is perhaps the most frequently activated oncoprotein in human cancers. Overriding cell cycle checkpoint in combination with the inhibition of apoptosis are two principal requirements for predisposition to cancer. Here we show that the activation of Akt is sufficient to promote these two principal processes, by inhibiting Chk1 activation with concomitant inhibition of apoptosis. These activities of Akt cannot be recapitulated by the knockdown of Chk1 alone or by overexpression of Bcl2. Rather the combination of Chk1 knockdown and Bcl2 overexpression is required to recapitulate Akt activities. Akt was shown to directly phosphorylate Chk1. However, we found that Chk1 mutants in the Akt phosphorylation sites behave like wild-type Chk1 in mediating G2 arrest, suggesting that the phosphorylation of Chk1 by Akt is either dispensable for Chk1 activity or insufficient by itself to exert an effect on Chk1 activity. Here we report a new mechanism by which Akt affects G2 cell cycle arrest. We show that Akt inhibits BRCA1 function that induces G2 cell cycle arrest. Akt prevents the translocation of BRCA1 to DNA damage foci and, thereby, inhibiting the activation of Chk1 following DNA damage.

Mechanism and direct kinetics study on the homogeneous gas-phase formation of PBDD/Fs from 2-BP, 2,4-DBP, and 2,4,6-TBP as precursors.

This study investigated the homogeneous gas-phase formation of polybrominated dibenzo-p-dioxin/dibenzofurans (PBDD/Fs) from 2-BP, 2,4-DBP, and 2,4,6-TBP as precursors. First, density functional theory (DFT) calculations were carried out for the formation mechanism. The geometries and frequencies of the stationary points were calculated at the MPWB1K/6-31+G(d,p) level, and the energetic parameters were further refined by the MPWB1K/6-311+G(3df,2p) method. Then, the formation mechanism of PBDD/Fs was compared and contrasted with the PCDD/F formation mechanism from 2-CP, 2,4-DCP, and 2,4,6-TCP as precursors. Finally, the rate constants of the crucial elementary reactions were evaluated by the canonical variational transition-state (CVT) theory with the small curvature tunneling (SCT) correction over a wide temperature range of 600-1200 K. Present results indicate that only BPs with bromine at the ortho position are capable of forming PBDDs. The study, together with works already published from our group, clearly shows an increased propensity for the dioxin formations from BPs over the analogous CPs. Multibromine substitutions suppress the PBDD/F formations.

Mechanism and direct kinetic study of the polychlorinated dibenzo-p-dioxin and dibenzofuran formations from the radical/radical cross-condensation of 2,4-dichlorophenoxy with 2-chlorophenoxy and 2,4,6-trichlorophenoxy.

A direct density functional theory (DFT) kinetic calculation is carried out for the homogeneous gas-phase formation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) from the cross-condensation of 2,4-dichlorophenoxy radical (2,4-DCPR) with 2-chlorophenoxy radical (2-CPR) and 2,4,6-trichlorophenoxy radical (2,4,6-TCPR). The possible formation mechanism is investigated and compared with the PCDD/F formation mechanism from the self-condensation of 2,4-DCPR, 2-CPR, and 2,4,6-TCPR. The rate constants and their temperature dependence of the crucial elementary reactions are computed by the canonical variational transition-state theory with the small curvature tunneling contribution over the temperature range of 600-1200 K. This study shows that the multichlorine substitutions suppress the PCDD/F formations. Because of a lack of experimental kinetic data, the present theoretical results are expected to be useful and reasonable to estimate the kinetic properties, such as the pre-exponential factors, the activation energies, and the rate constants, of the elementary reactions involved in the formation of PCDD/Fs.

Dioxin formations from the radical/radical cross-condensation of phenoxy radicals with 2-chlorophenoxy radicals and 2,4,6-trichlorophenoxy radicals.

It is important to understand the role of phenol in the dioxin formations because it is present in the high amount in municipal waste incinerators (MWIs). The formation mechanism of dioxins from the cross-condensation of PhRs with 2-CPRs and 2,4,6-TCPRs was investigated by using hybrid density functional theory (DFT) and compared with the dioxin formation mechanism from the self-condensation of single chlorophenol precursors. The geometrical parameters were optimized at the MPWB1K level with the 6-31+G(d,p) basis set without symmetry constraints. Single-point energy calculations were carried out at the MPWB1K/6-311+G(3df,2p) level of theory. The rate constants were deduced by using canonical variational transition-state (CVT) theory with small curvature tunneling (SCT) contribution over the temperature range of 600-1200 K. The Arrhenius formulas were reported for the first time. Results show that phenol is responsible for the formation of dioxin congeners. This work, together with results already published from our group, provides a comprehensive investigation of the homogeneous gas-phase formation of dioxins from (chloro)phenol precursors and should help to clarify the formation mechanism of dioxins in real waste combustion and to develop more effective control strategies.

[Adaptation of Suaeda salsa to water/sediment conditions and nitrogen input in tidal flat wetlands in the Yellow River Delta, China]. / é»„æ²³ä¸‰è§’æ´²æ»¨å²¸æ½®æ»©æ¹¿åœ°ç¢±è“¬å¯¹æ°´æ²™æ¡ä»¶åŠæ°®è¾“å ¥çš„é€‚åº”æ€§.

The application of Water-Sediment Regulation Project provides abundant freshwater for the Yellow River Delta, changes water and sediment condition, as well as brings lots of exogenous substances. Using orthogonal test with three factors and four levels, we examined the effects of water condition, sediment burial depth and exogenous nitrogen input on the growth of wetland plant, Suaeda salsa. The results showed that sediment burial had great effect on protein content and SOD activity. Nitrogen input had great effect on POD activity. CAT activity was not affected by sediment burial, nitrogen input and water depth. The water depth manipulation had significant effect on leaf, stem and total dry weight. With the increases of water depth, leaf, stem and total dry weight showed a decreasing trend, with the maximum values (25.70, 40.86, 69.73 g) at the 2 cm water depth. There was no effect of nitrogen input and sediment burial on dry weight. The results of range analysis showed that the effect of water depth on leaf, stem, root and total dry weight was great, and followed by nitrogen input and sediment burial, with an optimal combination of 2 cm water depth +12 cm sediment burial + 9 g·m-2 nitrogen input. These findings suggested that water condition played a decisive role in affecting the growth of S. salsa. Consequently, more attention should be paid to the control of water depth in the process of water and sediment regulation.

Effects of Carbon Chain Length on the Perfluoroalkyl Acids-Induced Oxidative Stress of Erythrocytes in Vitro.

Perfluoroalkyl acids (PFAAs) have been found extensively in wildlife and human bodies by sources of drinking water and food. In this study, we investigated the effects of three PFAAs, perfluoropentanoic acid (PFPA), perfluorooctanoic acid (PFOA), and perfluorodecanoic acid (PFDA), on the antioxidative defense system and lipid peroxidation in erythrocytes separately. The results demonstrated that they could lead to significant decline trends in the glutathione (GSH) levels together with increases of malondialdehyde (MDA) content, suggesting that three PFAAs induced oxidative stress to erythrocytes. Also PFDA with a longer carbon chain length posed more of a threat than other two PFAAs. Furthermore, the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were also altered in the presence of PFAAs upon erythrocytes. The changes of oxidative stress markers and the concomitant alterations of antioxidant enzymes suggest the role of oxidative stress in PFAA-induced damage upon erythrocytes.

[Effects of Sediment Burial and Exogenous Cd Input on Biomass Allocation and Antioxidative Enzyme Activities of Suaeda salsa in the Coastal Wetland of the Yellow River Delta].

The Yellow River Delta has been facing the threat of functional degradation during the recent years. The Water-Sediment Regulation Project not only supplements abundant freshwater, but also alters the sediment burial and heavy metal levels, which affects vegetation growth. Thus, we selected the pioneer species Suaeda salsa, to study the effects of different sediment burial depths (0, 3, 6, 12 cm) and exogenous Cd inputs (0, 0.5, 1.0, 1.5 mg·kg-1) on biomass allocation and activities of antioxidative enzymes in the coastal wetlands of the Yellow River delta. The results showed that a shallow or moderate burial depth had a stimulatory effect on chlorophyll content, while an excessive burial depth inhibited the growth of Suaeda salsa and chlorophyll content. With increasing Cd input, chlorophyll content and dry mass decreased. At a lower Cd input and moderate burial depth, activities of CAT and SOD increased, and at high levels, SOD activities decreased, while activities of CAT at a 12 cm burial depth and 1.0 mg·kg-1, 1.5 mg·kg-1 Cd input were higher than those for the control (62.66% and 58.56%). CAT activities reached high values (15.76 U·mg-1) at a high Cd input (1.5 mg·kg-1) and burial depth (12 cm). Analysis of variance showed that Cd input had a significant effect on protein content, and CAT and SOD activities, and sediment burial depth had a significant effect on the protein content and SOD activities. Interaction between Cd input and sediment burial depth had a significant effect on CAT and SOD activities (P<0.05). These results demonstrated that sediment burial depth and Cd input had a great influence on the growth of Suaeda salsa, and to some extent, Suaeda salsa could change its biomass allocation and antioxidative enzyme activities to adapt to severe environments.

Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms.

Akt is frequently hyperactivated in human cancers and is targeted for cancer therapy. However, the physiological consequences of systemic Akt isoform inhibition were not fully explored. We showed that while combined Akt1 and Akt3 deletion in adult mice is tolerated, combined Akt1 and Akt2 deletion induced rapid mortality. Akt2(-/-) mice survived hepatic Akt1 deletion but all developed spontaneous hepatocellular carcinoma (HCC), which is associated with FoxO-dependent liver injury and inflammation. The gene expression signature of HCC-bearing livers is similar to aggressive human HCC. Consistently, neither Akt1(-/-) nor Akt2(-/-) mice are resistant to diethylnitrosamine-induced hepatocarcinogenesis, and Akt2(-/-) mice display a high incidence of lung metastasis. Thus, in contrast to other cancers, hepatic Akt inhibition induces liver injury that could promote HCC.

Systemic Akt1 Deletion after Tumor Onset in p53(-/-) Mice Increases Lifespan and Regresses Thymic Lymphoma Emulating p53 Restoration.

Akt is frequently activated in human cancers. However, it is unknown whether systemic inhibition of a single Akt isoform could regress cancer progression in cancers that are not driven by Akt activation. We systemically deleted Akt1 after tumor onset in p53(-/-) mice, which develop tumors independently of Akt activation. Systemic Akt1 deletion regresses thymic lymphoma in p53(-/-) mice emulating p53 restoration. Furthermore, pharmacological inhibition of Akt selectively kills thymic lymphoma cells and not primary thymocytes. Mechanistically, Akt1 inhibition in p53(-/-) thymic lymphoma inhibits Skp2 expression and induces FasL, which is the primary cause of cell death. Skp2 exerts resistance to cell death by antagonizing the induction of FasL and reducing FAS expression, which is linked to cyclin D1 expression. The results established a paradigm whereby systemic Akt1 inhibition is sufficient to regress tumors that are not driven by Akt activation and a mechanism of cell survival by Skp2.

PBCDD/F formation from radical/radical cross-condensation of 2-Chlorophenoxy with 2-Bromophenoxy, 2,4-Dichlorophenoxy with 2,4-Dibromophenoxy, and 2,4,6-Trichlorophenoxy with 2,4,6-Tribromophenoxy.

Quantum chemical calculations were carried out to investigate the homogeneous gas-phase formation of mixed polybrominated/chlorinated dibenzo-p-dioxins/benzofurans (PBCDD/Fs) from the cross-condensation of 2-chlorophenoxy radical (2-CPR) with 2-bromophenoxy radical (2-BPR), 2,4-dichlorophenoxy radical (2,4-DCPR) with 2,4-dibromophenoxy radical (2,4-DBPR), and 2,4,6-trichlorophenoxy radical (2,4,6-TCPR) with 2,4,6-tribromophenoxy radical (2,4,6-TBPR). The geometrical parameters and vibrational frequencies were calculated at the MPWB1K/6-31+G(d,p) level, and single-point energy calculations were performed at the MPWB1K/6-311+G(3df,2p) level of theory. The rate constants of the crucial elementary reactions were evaluated by the canonical variational transition-state (CVT) theory with the small curvature tunneling (SCT) correction over a wide temperature range of 600-1200K. Studies show that the substitution pattern of halogenated phenols not only determines the substitution pattern of the resulting PBCDD/Fs, but also has a significant influence on the formation mechanism of PBCDD/Fs, especially on the coupling of the halogenated phenoxy radicals.

Quantum chemical and direct dynamic study on homogeneous gas-phase formation of PBDD/Fs from 2,4,5-tribromophenol and 3,4-dibromophenol.

2,4,5-Tribromophenol (2,4,5-TBP) and 3,4-dibromophenol (3,4-DBP) have the minimum number of Br atoms needed to form 2,3,7,8-PBDD/Fs, which are the most toxic among all 210 PBDD/F isomers. A mechanistic understanding of the formation of PBDD/Fs is a prerequisite for minimizing their emissions. In this paper, the homogeneous gas-phase formation of PBDD/Fs from 2,4,5-TBP and 3,4-DBP as precursors was investigated theoretically by using the density functional theory (DFT) method. The mathematical model to predict the formation of PBDD/Fs places a high demand on accurate kinetic parameters. So, the rate constants of key elementary steps involved in the formation of PBDD/Fs were calculated by using canonical variational transition-state (CVT) theory with small curvature tunneling (SCT) contribution over a wide temperature range of 600-1200K. The pre-exponential factors and the activation energies are also reported. This might be the first to investigate the formation of 2,3,7,8-PBDD/Fs. The present study shows that the formation of PBDDs dominates over the formation of PBDFs. The meta bromine facilitates the dimerization of bromophenoxy radicals (BPRs), whereas the para and ortho bromines suppress the dimerization of BPRs.

Quantum chemical and kinetic study on dioxin formation from the 2,4,6-TCP and 2,4-DCP precursors.

This study focuses on the homogeneous gas-phase formation of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) from the 2,4,6-trichlorophenol (2,4,6-TCP) and 2,4-dichlorophenol (2,4-DCP) precursors, which were found both in the gas phase and in the fly ash samples as the dominating chlorophenol congeners in municipal waste incinerators (MWIs). Molecular orbital theory calculations have been performed for the formation mechanism. The geometrical parameters and vibrational frequencies of all the stationary points were calculated at the MPWB1K level with the 6-31+G(d,p) basis set. Single-point energy calculations were carried out at the MPWB1K/6-311+G(3df,2p) level of theory. Canonical variational transition-state (CVT) theory with small curvature tunneling (SCT) contribution was used to predict the rate constants of crucial elementary steps over the temperature range of interest (600-1200 K). The rate-temperature formulas were fitted for the first time. The pre-exponential factor, the activation energy, and the rate constants are reported. This study shows that at least one chlorine substituent in the ortho position is needed for the formation of PCDDs from the condensation of chlorophenols. The results presented here should help to clarify and detail the formation mechanism of PCDD/PCDFs (PCDD/Fs for short) from chlorophenol precursors in real waste combustion.

Phosphatidylinositide 3-kinase priming couples c-FLIP to T cell activation.

Cellular FLICE (FADD-like interleukin-1-beta-converting enzyme)-inhibitory protein (c-FLIP) inhibits death receptor-induced apoptosis by binding to FADD (Fas-associated death domain protein) and pro-caspase-8. c-FLIP has also been shown to transmit activation signals and to enhance interleukin (IL)-2 production. However, c-FLIP-mediated T cell activation is difficult to detect in most cells. We found that in DO11.10 T cells, c-FLIP expression led to inhibition of IL-2 production, in contrast to the readily detectable c-FLIP-induced activation in Jurkat cells. A direct comparison revealed that distinct signal pathways were regulated by c-FLIP in Jurkat cells and DO11.10 cells. We investigated whether constitutively activated phosphatidylinositide 3-kinase (PI3K) in Jurkat cells stimulated c-FLIP. Inhibition of PI3K in Jurkat cells abrogated a c-FLIP-mediated increase in IL-2 production. In addition, c-FLIP coordinated with active PI3K for ERK activation. Furthermore, introduction of PTEN back into Jurkat cells eliminated the stimulatory effect of c-FLIP on IL-2 production and ERK activation. Our results suggest that priming with PI3K promotes the coupling of c-FLIP to T cell activation.