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Morphological changes and damage degrees of PPS can be tracked and detected by fluorescence during service. However, the functionalization of the main chain of PPS is limited. To explore its luminescent properties for fluorescence tracking, 1,6-dibromopyrene and 1,3,6,8-tetrabromopyrene were employed to construct Dbp-PPS (Dibromopyrene-PPS) and Tbp-PPS (Tetrabromopyrene-PPS) with fluorescence tracking, respectively. These two sets of copolymers were systematically designed, synthesized, and characterized by Uv–Vis, PL, FT-IR, TGA, DSC, and XRD. To sum up, both Dbp-PPS and Tbp-PPS displayed visible fluorescence. UV–vis spectra showed an absorption maximum at λabs = 262–411 nm. PL spectra demonstrated emission maximum at λem = 450–545 nm. Particularly, 0.25%Dbp-PPS emitted the most intense blue fluorescence with the emission maximum at 450 nm and the absolute quantum yield of Φf = 0.08. The fluorescence decay lifetime of 0.25%Dbp-PPS comprised two components with lifetimes of 0.43 and 1.17 ns, implying the formation of excimer. The IR and XRD spectra of Dbp-PPS and Tbp-PPS were in line with those of PPS. TGA measurements illustrated that introducing pyrene into PPS is favorable for improving thermal stability. The DSC analysis indicated their melting temperature ranged from 260.9 to 280.4 °C and Dbp-PPS exhibited a little better melting point (279.4–280.4 °C) than neat-PPS (278.4 °C). Meanwhile, the resultant copolymers possessed a flexural strength of 31.0–101.5 MPa and tensile strength of 69.2–96.7 MPa. Both the flexural and tensile strengths of only 0.25%Dbp-PPS (101.5 and 86.8 Mpa) were higher than that of neat-PPS (95.1 and 84.3 Mpa). Imparting the pyrene unit into the PPS backbone is an effective method to give the PPS fluorescence tracking function for inspecting or tracking the polymer during their application and keep the original high performance of the PPS. Importantly, the systematic studies for pyrene-containing PPS in the current work provide a practical polymer tracking strategy suitable for other aromatic polymers such as poly (ether ether ketone), poly (ether sulfone).

A joint subduction of the oceanic-continental plates exerts primary controls on the tectonomagmatic activities alongside trench-perpendicular ocean-continental transitional (OCT) belts (i.e., passive continental margin). Such OCT belts with a rheological boundary trigger substantial great crustal density contrast since lateral pressure gradients create where a mature oceanic lithosphere terminate against a thicker continental lithosphere. This study investigates the conjunction between the southernmost segment of the ~1500-km-long, NW–SE-trending Yushu–Yidun Arc Belt and the NE–SW trending Longmen Shan Fault system in southeastern Tibet, to explore the interaction of these two large-scale linear structures. A compilation of geological evidence reveals that an OCT belt previously defined the Longmen Shan Fault, separating the South China Continent from the Garze–Litang Ocean. During the southwestward subduction of the Garze-Litang oceanic lithosphere, this OCT belt which lies on the southeastern edge was reacted with the subduction of the oceanic lithosphere, and subsequently induced slab tearing of its subduction front causing the upwelling of the asthenosphere. This model interprets favorably the intriguing geology of the triangle-shaped Songpan–Garze–Hoh Xil terrane as well as the generation of the Late Triassic enriched mid-ocean ridge basalts or ocean island basalts (EOB) at the southernmost segment of the Yushu–Yidun Arc Belt, where the asthenosphere-sourced mafic lavas are tightly intercalated with normal arc-like igneous rocks in a continental arc.

The ~1500 km, N-NW-trending Yushu-Yidun arc magmatic belt delineate the configuration of the subducted Paleo-tethys oceanic lithosphere in the central-eastern Tibetan Plateau. In its southern termination, not only widespread Late Triassic arc-like rocks but also contemporary minor volume E-MORB/OIB-like basalts (EOB) and porphyry Cu (± Mo ± Au) deposits developed within northern of the southwest extension of the Longmenshan Fault (LF). Above special magmatic-tectonic- metallogenic coupling, combining with the contemporary dextral sliding deformation of the LF and the northeast-southwest striking granitic belt occurred in the northwest of its, is most likely related with the active proto-LF, which is considered as a weakened conservative plate boundary between the subducted Garze-Litang oceanic slab and Yangtze craton. Upwelling of asthenospheric mantle along the subducted conservative boundary experienced decompressive partial melting and formed the parental melts of EOB, which triggered to partial melting of the subducted-slab and the metasomatized mantle-wedge and formed the ore-bearing melts and the arc-like andesites, respectively.

A joint subduction of the oceanic-continental plates exerts primary controls on the tectonomagmatism alongside trench-perpendicular ocean-continental transitional (OCT) belts. Such OCT belts trigger substantial crustal density contrasts since lateral pressure gradients create where a mature oceanic lithosphere terminates against a thicker continental lithosphere. This study investigates the conjunction between the southernmost Yushu–Yidun Arc belt and the Longmen Shan Fault system in northeastern Tibetan Plateau, exploring the interaction of these two large-scale linear structures. Geological evidences compiled reveals that an OCT belt previously defined the Longmen Shan Fault, separating the South China Continent from the Garze–Litang Ocean. This OCT belt lying on the southeastern edge reacted with the subducted Garze–Litang oceanic lithosphere with subsequently tearing of its subduction front causing the upwelling of asthenosphere. This model plausibly interprets the distinctive magmatism in the study region, where the asthenosphere-sourced mafic lavas are tightly intercalated with normal arc-like igneous rocks.

A carboxymethyl chitosan (CMC)-assisted method is developed for the preparation of a palladium (Pd) nanoparticles (NPs)/carbon nanotubes (CNTs) nanohybrid. The addition of a small amount of CMC to the reaction solution leads to the production of well-crystallised metallic Pd NPs with small diameter and uniformly dispersed on CNTs. The obtained Pd NPs supported on CNTs show enhanced catalytic activity and stability for the electrochemical oxidation of methanol in alkaline media. The as-developed Pd NPs/CNTs nanohybrid is a highly promising catalyst for use in fuel cell technology.

Tripartite motif 39 (Trim39) is a RING domain-containing E3 ubiquitin ligase able to inhibit the anaphase-promoting complex (APC/C) directly. Through analysis of Trim39 function in p53-positive and p53-negative cells, we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from disinhibition of the APC/C. Moreover, although Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knockdown in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, murine double minute 2 (MDM2), varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with WT p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis.

Trim39 inhibits the ability of APC/CCdh1 to ubiquitylate and promote the degradation of MOAP-1, leading to enhanced apoptosis., Proapoptotic Bcl-2 family members, such as Bax, promote release of cytochrome c from mitochondria, leading to caspase activation and cell death. It was previously reported that modulator of apoptosis protein 1 (MOAP-1), an enhancer of Bax activation induced by DNA damage, is stabilized by Trim39, a protein of unknown function. In this paper, we show that MOAP-1 is a novel substrate of the anaphase-promoting complex (APC/CCdh1) ubiquitin ligase. The influence of Trim39 on MOAP-1 levels stems from the ability of Trim39 (a RING domain E3 ligase) to directly inhibit APC/CCdh1-mediated protein ubiquitylation. Accordingly, small interfering ribonucleic acid–mediated knockdown of Cdh1 stabilized MOAP-1, thereby enhancing etoposide-induced Bax activation and apoptosis. These data identify Trim39 as a novel APC/C regulator and provide an unexpected link between the APC/C and apoptotic regulation via MOAP-1.

Mitochondria form an interconnected network that undergoes dynamin-related protein 1 (Drp1)-dependent fission during mitosis. We demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven through ubiquitylation of Drp1 by the (anaphase- promoting complex/cyclosome and its coactivator Cdh1) APC/CCdh1 complex. Inhibition Drp1 degradation prevents the normal regrowth of mitochondrial networks during G1 phase., Homeostatic maintenance of cellular mitochondria requires a dynamic balance between fission and fusion, and controlled changes in morphology are important for processes such as apoptosis and cellular division. Interphase mitochondria have been described as an interconnected network that fragments as cells enter mitosis, and this mitotic mitochondrial fragmentation is known to be regulated by the dynamin-related GTPase Drp1 (dynamin-related protein 1), a key component of the mitochondrial division machinery. Loss of Drp1 function and the subsequent failure of mitochondrial division during mitosis lead to incomplete cytokinesis and the unequal distribution of mitochondria into daughter cells. During mitotic exit and interphase, the mitochondrial network reforms. Here we demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven in part through ubiquitylation of Drp1, catalyzed by the APC/CCdh1 (anaphase-promoting complex/cyclosome and its coactivator Cdh1) E3 ubiquitin ligase complex. Importantly, inhibition of Cdh1-mediated Drp1 ubiquitylation and proteasomal degradation during interphase prevents the normal G1 phase regrowth of mitochondrial networks following cell division.

The anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi2 contains a destruction box (D-box) found in APC/C substrates, but does not appear to inhibit the APC/C by a “pseudosubstrate” mechanism. Rather, it inhibits transfer of ubiquitin from the E2 to substrates. The D-box promotes Emi2-APC/C association, but the zinc-binding region plays the critical role in APC/C inhibition., Vertebrate eggs are arrested at Metaphase II by Emi2, the meiotic anaphase-promoting complex/cyclosome (APC/C) inhibitor. Although the importance of Emi2 during oocyte maturation has been widely recognized and its regulation extensively studied, its mechanism of action remained elusive. Many APC/C inhibitors have been reported to act as pseudosubstrates, inhibiting the APC/C by preventing substrate binding. Here we show that a previously identified zinc-binding region is critical for the function of Emi2, whereas the D-box is largely dispensable. We further demonstrate that instead of acting through a “pseudosubstrate” mechanism as previously hypothesized, Emi2 can inhibit Cdc20-dependent activation of the APC/C substoichiometrically, blocking ubiquitin transfer from the ubiquitin-charged E2 to the substrate. These findings provide a novel mechanism of APC/C inhibition wherein the final step of ubiquitin transfer is targeted and raise the interesting possibility that APC/C is inhibited by Emi2 in a catalytic manner.

Ripening of banana ( Musa acuminate L.) fruit is concomitant with weakening of disease resistance. The aim of this research was to determine the patterns of expression of PR1 and chitinase genes during banana ripening. Northern blots show that the MaPR1 did not have expression in peel of young growing banana fruit, nor in harvested bananas until the onset of ripening. The chitinase gene ( MaChit ) had constitutive expression in bananas during development and after harvest. MaChit expression increased with time after harvest and reached the highest level at the onset of ripening when MaPR1 transcripts began to give detectable signals. Infection of the banana pathogen Colletotrichum musae did not induce MaPR1 but increased MaChit expression. The ethylene producer ethephon immediately induced MaPR1 , but benzothiadiazole (BTH) and methyl jasmonate (MeJA), when applied alone, did not. The combination of ethephon and BTH or MeJA treatment increased intensity of PR1 signals 12 h after treatment compared with ethephon alone, and in the combination treatments, the inoculation-related lesions were significantly ( P MaPR1 and MaChit transcripts decreased in distal uninfected areas, but in a combination treatment, it did not decrease. The triple combination of ethephon, BTH and diphenylene iodonium (DPI) reduced MaPR1 and MaChit expression compared with a double combination of ethephon and BTH, whereas when MeJA replaced BTH in the triple treatment, the expression of the two genes increased compared with the double treatment. This research suggests that MaPR1 could be involved in defense mechanisms of ripe bananas, while MaChit could more be involved in banana resistance to disease before ripening. The results also suggest that BTH and MeJA-induced systemic defense in banana fruit is ethylene-dependent, and H 2 O 2 might be necessary in BTH-induced SAR, but not in MeJA-induced systemic resistance. In the banana industry, MaPR1 could be used as a molecular indicator for monitoring banana ripening.

Arteriovenous-lymphatic endothelial cell fates are specified by the master regulators, namely, Notch, COUP-TFII, and Prox1. Whereas Notch is expressed in the arteries and COUP-TFII in the veins, the lymphatics express all 3 cell fate regulators. Previous studies show that lymphatic endothelial cell (LEC) fate is highly plastic and reversible, raising a new concept that all 3 endothelial cell fates may coreside in LECs and a subtle alteration can result in a reprogramming of LEC fate. We provide a molecular basis verifying this concept by identifying a cross-control mechanism among these cell fate regulators. We found that Notch signal down-regulates Prox1 and COUP-TFII through Hey1 and Hey2 and that activated Notch receptor suppresses the lymphatic phenotypes and induces the arterial cell fate. On the contrary, Prox1 and COUP-TFII attenuate vascular endothelial growth factor signaling, known to induce Notch, by repressing vascular endothelial growth factor receptor-2 and neuropilin-1. We show that previously reported podoplanin-based LEC heterogeneity is associated with differential expression of Notch1 in human cutaneous lymphatics. We propose that the expression of the 3 cell fate regulators is controlled by an exquisite feedback mechanism working in LECs and that LEC fate is a consequence of the Prox1-directed lymphatic equilibrium among the cell fate regulators.

Oligonucleotide probes on the sensor surface can be hybridized with single-strand DNA (ssDNA) that is formed from PCR products in ice bath after degeneration. Thus, detection of PCR products by piezoelectric sensors requires the participation of ssDNA PCR products in ice bath. When PCR products in ice bath are added into the buffer of the sensor well at room temperature, there will be a temperature change process during mixing. However, it still remains unclear whether the temperature change affects the frequency baseline stability of the sensor and the result judgment, which is the basic condition for detecting hybridization of nucleic acid. In this study, we detected the hybridization of HPV PCR products during temperature change process by a self-designed adjustable metal-clamping piezoelectric sensor. The study mainly involves sensor adjustment, probe immobilization and ice bath sample addition (at different concentrations and different volumes). The response curve of basic frequency in temperature change process showed three stages, i.e., increase, decrease to baseline, and continuous decrease to stability. The early increase of frequency and duration of the time can reach 55+/-7.4 Hz and 39 min when 40 microL sample (0-1 degrees C) was added into 110 microL buffer (25 degrees C). The frequency increase effect caused by temperature difference at early stage depends on the volume ratio of two liquids and on the temperature difference. The results indicate that we should pay more attention to possibly small volume of PCR products in ice bath and minor temperature difference of two liquids in operation.

Xenopus oocyte death is partly controlled by the apoptotic initiator, caspase-2. We reported previously that oocyte nutrient depletion activates caspase-2 upstream of mitochondrial cytochrome c release. Conversely, nutrient-replete oocytes inhibit caspase-2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that caspase-2 phosphorylated at S135 binds 14-3-3ζ, thus preventing caspase-2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1, which directly binds caspase-2. Although caspase-2 dephosphorylation is responsive to metabolism, neither PP1 activity nor binding is metabolically regulated. Rather, release of 14-3-3ζ from caspase-2 is controlled by metabolism and allows for caspase-2 dephosphorylation. Accordingly, a caspase-2 mutant unable to bind 14-3-3ζ is highly susceptible to dephosphorylation. Although this mechanism was initially established in Xenopus, we now demonstrate similar control of murine caspase-2 by phosphorylation and 14-3-3 binding in mouse eggs. These findings provide an unexpected evolutionary link between 14-3-3 and metabolism in oocyte death.

The pathogenic fungus Colletotrichum musae infects developing green bananas (Musa spp. AAA group), but remains latent until the fruit ripens. The aim of this research was to determine whether the appearance of disease symptoms is regulated by chitinase gene expression following treatment of fruit with benzothiadiazole (BTH) and methyl jasmonate (MeJA), and with physical (heat) and chemical (H2O2 and Ca2+-related) treatments. In bananas inoculated with C. musae, BTH and MeJA lowered disease severity and stimulated higher gene expression compared with the untreated controls during ripening. However, in naturally infected bananas, BTH and MeJA treatments slightly reduced transcription of the chitinase gene in green bananas, but they prolonged gene expression in ripe bananas and significantly reduced disease severity. The combination of H2O2 and the NADPH oxidase inhibitor, diphenylene iodonium, down-regulated chitinase gene expression and compromised disease resistance compared with H2O2 alone. Heat treatment (HT) or the combination of HT followed by CaCl2 reduced disease, but only the latter significantly upregulated chitinase gene expression. The combination of HT and a calcium ionophore (A23187) resulted in different disease indicies and different levels of gene expression depending upon the order of application: HT followed by A23187 induced higher gene expression and lower disease. The results suggest that disease resistance of green bananas could be related to high and prolonged levels of chitinase gene expression, and chitinase could be involved in harvested banana's anthracnose resistance activated by different defense pathway signals, such as BTH, MeJA, H2O2, and Ca2+.

Loss of cell division cycle 2 (Cdc2, also known as Cdk1) activity after cyclin B degradation is necessary, but not sufficient, for mitotic exit. Proteins phosphorylated by Cdc2 and downstream mitotic kinases must be dephosphorylated. We report here that protein phosphatase-1 (PP1) is the main catalyst of mitotic phosphoprotein dephosphorylation. Suppression of PP1 during early mitosis is maintained through dual inhibition by Cdc2 phosphorylation and the binding of inhibitor-1. Protein kinase A (PKA) phosphorylates inhibitor-1, mediating binding to PP1. As Cdc2 levels drop after cyclin B degradation, auto-dephosphorylation of PP1 at its Cdc2 phosphorylation site (Thr 320) allows partial PP1 activation. This promotes PP1-regulated dephosphorylation at the activating site of inhibitor-1 (Thr 35) followed by dissociation of the inhibitor-1-PP1 complex and then full PP1 activation to promote mitotic exit. Thus, Cdc2 both phosphorylates multiple mitotic substrates and inhibits their PP1-mediated dephosphorylation.

The transition of oocytes from meiosis I (MI) to meiosis II (MII) requires partial cyclin B degradation to allow MI exit without S phase entry. Rapid reaccumulation of cyclin B allows direct progression into MII, producing a cytostatic factor (CSF)-arrested egg. It has been reported that dampened translation of the anaphase-promoting complex (APC) inhibitor Emi2 at MI allows partial APC activation and MI exit. We have detected active Emi2 translation at MI and show that Emi2 levels in MI are mainly controlled by regulated degradation. Emi2 degradation in MI depends not on Ca2+/calmodulin-dependent protein kinase II (CaMKII), but on Cdc2-mediated phosphorylation of multiple sites within Emi2. As in MII, this phosphorylation is antagonized by Mos-mediated recruitment of PP2A to Emi2. Higher Cdc2 kinase activity in MI than MII allows sufficient Emi2 phosphorylation to destabilize Emi2 in MI. At MI anaphase, APC-mediated degradation of cyclin B decreases Cdc2 activity, enabling Cdc2-mediated Emi2 phosphorylation to be successfully antagonized by Mos-mediated PP2A recruitment. These data suggest a model of APC autoinhibition mediated by stabilization of Emi2; Emi2 proteins accumulate at MI exit and inhibit APC activity sufficiently to prevent complete degradation of cyclin B, allowing MI exit while preventing interphase before MII entry.

Before fertilization, vertebrate eggs are arrested in meiosis II by cytostatic factor (CSF), which holds the anaphase-promoting complex (APC) in an inactive state. It was recently reported that Mos, an integral component of CSF, acts in part by promoting the Rsk-mediated phosphorylation of the APC inhibitor Emi2/Erp1. We report here that Rsk phosphorylation of Emi2 promotes its interaction with the protein phosphatase PP2A. Emi2 residues adjacent to the Rsk phosphorylation site were important for PP2A binding. An Emi2 mutant that retained Rsk phosphorylation but lacked PP2A binding could not be modulated by Mos. PP2A bound to Emi2 acted on two distinct clusters of sites phosphorylated by Cdc2, one responsible for modulating its stability during CSF arrest and one that controls binding to the APC. These findings provide a molecular mechanism for Mos action in promoting CSF arrest and also define an unusual mechanism, whereby protein phosphorylation recruits a phosphatase for dephosphorylation of distinct sites phosphorylated by another kinase.

Summary Background Vertebrate oocytes are arrested in metaphase II of meiosis prior to fertilization by cytostatic factor (CSF). CSF enforces a cell-cycle arrest by inhibiting the anaphase-promoting complex (APC), an E3 ubiquitin ligase that targets Cyclin B for degradation. Although Cyclin B synthesis is ongoing during CSF arrest, constant Cyclin B levels are maintained. To achieve this, oocytes allow continuous slow Cyclin B degradation, without eliminating the bulk of Cyclin B, which would induce release from CSF arrest. However, the mechanism that controls this continuous degradation is not understood. Results We report here the molecular details of a negative feedback loop wherein Cyclin B promotes its own destruction through Cdc2/Cyclin B-mediated phosphorylation and inhibition of the APC inhibitor Emi2. Emi2 bound to the core APC, and this binding was disrupted by Cdc2/Cyclin B, without affecting Emi2 protein stability. Cdc2-mediated phosphorylation of Emi2 was antagonized by PP2A, which could bind to Emi2 and promote Emi2-APC interactions. Conclusions Constant Cyclin B levels are maintained during a CSF arrest through the regulation of Emi2 activity. A balance between Cdc2 and PP2A controls Emi2 phosphorylation, which in turn controls the ability of Emi2 to bind to and inhibit the APC. This balance allows proper maintenance of Cyclin B levels and Cdc2 kinase activity during CSF arrest.

Apoptosis ensures tissue homeostasis in response to developmental cues or cellular damage. Recently reported genome-wide RNAi screens have suggested that several metabolic regulators can modulate caspase activation in Drosophila. Here, we establish a previously unrecognized link between metabolism and Drosophila apoptosis by showing that cellular NADPH levels modulate the initiator caspase Dronc through its phosphorylation at S130. Depletion of NADPH removed this inhibitory phosphorylation, resulting in the activation of Dronc and subsequent cell death. Conversely, upregulation of NADPH prevented Dronc-mediated apoptosis upon DIAP1 RNAi or cycloheximide treatment. Furthermore, this CaMKII-mediated phosphorylation of Dronc hindered Dronc activation, but not its catalytic activity. Blockade of NADPH production aggravated the death-inducing activity of Dronc in specific neurons, but not in the photoreceptor cells of the eyes of transgenic flies; similarly, non-phosphorylatable Dronc was more potent than wild type in triggering specific neuronal apoptosis. Our observations reveal a novel regulatory circuitry in Drosophila apoptosis, and, as NADPH levels are elevated in cancer cells, also provide a genetic model to understand aberrations in cancer cell apoptosis resulting from metabolic alterations.

Summary Background In response to DNA damage, cells undergo either cell-cycle arrest or apoptosis, depending on the extent of damage and the cell's capacity for DNA repair. Cell-cycle arrest induced by double-stranded DNA breaks depends on activation of the ataxia-telangiectasia (ATM) protein kinase, which phosphorylates cell-cycle effectors such as Chk2 and p53 to inhibit cell-cycle progression. ATM is recruited to double-stranded DNA breaks by a complex of sensor proteins, including Mre11/Rad50/Nbs1, resulting in autophosphorylation, monomerization, and activation of ATM kinase. Results In characterizing Aven protein, a previously reported apoptotic inhibitor, we have found that Aven can function as an ATM activator to inhibit G2/M progression. Aven bound to ATM and Aven overexpressed in cycling Xenopus egg extracts prevented mitotic entry and induced phosphorylation of ATM and its substrates. Immunodepletion of endogenous Aven allowed mitotic entry even in the presence of damaged DNA, and RNAi-mediated knockdown of Aven in human cells prevented autophosphorylation of ATM at an activating site (S1981) in response to DNA damage. Interestingly, Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. Conclusions These results identify Aven as a new ATM activator and describe a positive feedback loop operating between Aven and ATM. In aggregate, these findings place Aven, a known apoptotic inhibitor, as a critical transducer of the DNA-damage signal.

Notch signaling plays an important role in arterial-venous specification during embryogenesis. However, the role of Notch signaling in lymphatic development is poorly understood. Here, we show that...

Trim39 is a RING domain-containing E3 ubiquitin ligase able to directly inhibit the anaphase promoting complex (APC/C). Through analysis of Trim39 function in p53-positive and p53-negative cells we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from dis-inhibition of the APC/C. Moreover, while Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knock-down in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, MDM2, varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with wild type p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis. Citation Format: Liguo Zhang, Chen Chen, Naijia Huang, Wanli Tang, Sally Kornbluth. Ubiquitination of p53 by Trim39. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2480. doi:10.1158/1538-7445.AM2014-2480