Axin determines cell fate by controlling the p53 activation threshold after DNA damage

Cells can undergo either cell-cycle arrest or apoptosis after genotoxic stress, based on p53 activity(1-6). Here we show that cellular fate commitment depends on Axin forming distinct complexes with Pirh2, Tip60, HIPK2 and p53. In cells treated with sublethal doses of ultra-violet (UV) radiation or doxorubicin (Dox), Pirh2 abrogates Axin-induced p53 phosphorylation at Ser 46 catalysed by HIPK2, by competing with HIPK2 for binding to Axin. However, on lethal treatment, Tip60 interacts with Axin and abrogates Pirh2-Axin binding, forming an Axin-Tip60-HIPK2-p53 complex that allows maximal p53 activation to trigger apoptosis. We also provide evidence that the ATM/ATR pathway mediates the Axin-Tip60 complex assembly. An axin mutation promotes carcinogenesis in Axin(Fu)/+ (Axin-Fused) mice, consistent with a dominant-negative role for Axin(Fu) in p53 activation. Thus, Axin is a critical determinant in p53-dependent tumour suppression in which Pirh2 and Tip60 have different roles in triggering cell-cycle arrest or apoptosis depending on the severity of genotoxic stress.973 Program and 863 Program National Natural Science Foundation of China Ministry of Education of China National Basic Research Program of the Ministry of Science and Technology National Science Foundation of Fujian Provinc

Identification of Novel SNPs by Next-Generation Sequencing of the Genomic Region Containing the APC Gene in Colorectal Cancer Patients in China

We described an approach of identifying single nucleotide polymorphisms (SNPs) in complete genomic regions of key genes including promoters, exons, introns, and downstream sequences by combining long-range polymerase chain reaction (PCR) or NimbleGen sequence capture with next-generation sequencing. Using the adenomatous polyposis coli (APC) gene as an example, we identified 210 highly reliable SNPs by next-generation sequencing analysis program MAQ and Samtools, of which 69 were novel ones, in the 123-kb APC genomic region in 27 pair of colorectal cancers and normal adjacent tissues. We confirmed all of the eight randomly selected high-quality SNPs by allele-specific PCR, suggesting that our false discovery rate is negligible. We identified 11 SNPs in the exonic region, including one novel SNP that was not previously reported. Although 10 of them are synonymous, they were predicted to affect splicing by creating or removing exonic splicing enhancers or exonic splicing silencers. We also identified seven SNPs in the upstream region of the APC gene, three of which were only identified in the cancer tissues. Six of these upstream SNPs were predicted to affect transcription factor binding. We also observed that long-range PCR was better in capturing GC-rich regions than the NimbleGen sequence capture technique.MOST, Chin

Improved EEMD Denoising Method Based on Singular Value Decomposition for the Chaotic Signal

Chaotic data analysis is important in many areas of science and engineering. However, the chaotic signals are inevitably contaminated by complicated noise in the collection process which greatly interferes with the analysis of chaos identification. The chaotic vibration is extremely nonlinear and has a broad range of frequencies; linear filtering methods are not effective for chaotic signal noise reduction. Then an improved ensemble empirical mode decomposition (EEMD) based on singular value decomposition (SVD) and Savitzky-Golay (SG) filtering method was proposed. Firstly, the noise energy of first level intrinsic mode function (IMF) was estimated by “3σ” criterion, and then SVD was used to extract the signal details from first IMF, and the singular value was selected to reconstruct the IMF according to noise energy of the first IMF. Secondly, the remaining IMFs are divided into high frequency and low frequency components based on consecutive mean square error (CMSE), and the useful signals of high frequency components and low frequency components are extracted based on SVD and SG filtering method, respectively. The superiority of the proposed method is demonstrated with simulated signal, two-degree-of-freedom chaotic vibration signals, and the experimental signals based on double potential well theory

CDK5 activator p35 downregulates E-cadherin precursor independently of CDK5

Dysfunction of E-cadherins often results in metastasis of cancerous cells. Here we show that p35, a critical regulator of cyclin-dependent kinase 5 (CDK5), specifically depletes the precursor form of E-cadherin, but not the mature form, by using a precursor-specific antibody. Most intriguingly, this downregulation of precursor E-cadherin by p35 is unequivocally independent of CDK5. Moreover, we found that p35 forms complexes with E-cadherin proteins. We also found that p35 co-expression can target E-cadherin to lysosomes and that p35-triggered disappearance of E-cadherin precursor can be blocked specifically by lysosomal protease inhibitors, indicating that p35 induces endocytosis and subsequent degradation of precursor E-cadherin

An Improved Commutation Prediction Algorithm to Mitigate Commutation Failure in High Voltage Direct Current

Commutation failure is a common fault for line-commutated converters in the inverter. To reduce the possibility of commutation failure, many prediction algorithms based on alternating current (AC) voltage detection have already been implemented in high voltage direct current (HVDC) control and protection systems. Nevertheless, there are currently no effective methods to prevent commutation failure due to transformer excitation surge current. In this paper, an improved commutation failure prediction algorithm based on the harmonic characteristics of the converter bus voltage during transformer charging is proposed. Meanwhile, a sliding-window iterative algorithm of discrete Fourier transformation (DFT) is developed for detecting the voltage harmonic in real time. This method is proved to be an effective solution, which prevents commutation failure in cases of excitation surge current, through experimental analysis. This method is already implemented into TianShan-ZhongZhou (TianZhong) ± 800 kV ultra high voltage direct current (UHVDC) system

MDM2 Inhibits Axin-Induced p53 Activation Independently of its E3 Ligase Activity

<div><p>MDM2 plays a crucial role in negatively regulating the functions of tumor suppressor p53. Here we show that MDM2 can inhibit Axin-stimulated p53-dependent apoptosis by suppressing p53 phosphorylation at Ser 46 and apoptosis-related p53 transactivational activity. Interestingly, the ubiquitin E3 ligase activity of MDM2 is not required for this inhibitory effect. Mechanically, either wildtype MDM2 or its E3-dead mutant, disrupts the Axin-based HIPK2/p53 complex formation by blocking the binding of p53 and HIPK2 to Axin. MDM2Δp53, a deletion mutant that lacks p53 binding domain fails to exert the inhibitory effect, demonstrating that the interaction of MDM2 and p53, but not its E3 ligase activity toward p53 plays key role in suppressing Axin-stimulated p53 activation. Our results thus have revealed a novel aspect of the mechanism by which MDM2 regulates p53 activities.</p></div

The Drosophila tankyrase regulates Wg signaling depending on the concentration of Daxin

National Basic Research Program of China [2011CB943901, 2011CB943802]; National Natural Science Foundation of China [31030049]; Research Foundation for Advanced Talents of Wenzhou Medical University [QTJ08012]; Wenzhou Medical University research grant [XNK07005]; Programme of Introducing Talents of Discipline to Universities [B06016]; NIH [2R01 GM063891]The canonical Wnt signaling pathway plays critical roles during development and homeostasis. Dysregulation of this pathway can lead to many human diseases, including cancers. A key process in this pathway consists of regulation of beta-catenin concentration through an Axin-recruited destruction complex. Previous studies have demonstrated a role for tankyrase (TNKS), a protein with poly(ADP-ribose) polymerase, in the regulation of Axin levels in human cells. However, the role of TNKS in development is still unclear. Here, we have generated a Drosophila tankyrase (DTNKS) mutant and provided compelling evidence that DTNKS is involved in the degradation of Drosophila Axin (Daxin). We show that Daxin physically interacts with DTNKS, and its protein levels are elevated in the absence of DTNKS in the eye discs. In S2 cells, DTNKS suppressed the levels of Daxin. Surprisingly, we found that Daxin in turn down-regulated DTNKS protein level. In vivo study showed that DTNKS regulated Wg signaling and wing patterning at a high Daxin protein level, but not at a normal level. Taken together, our findings identified a conserved role of DTNKS in regulating Daxin levels, and thereby Wg/Wnt signaling during development (C) 2014 Published by Elsevier Inc

A simplified model depicting the mechanism how MDM2 inhibits Axin-induced p53 activation.

<p>When overexpressed, MDM2 competes the binding of both p53 and HIPK2 on Axin, and disrupts the Axin/p53/HIPK2 complex, leading to the inhibition of p53 activation and cell apoptosis.</p

MDM2 Inhibits Axin-Induced p53 Activation Independently of Its E3 Ligase Activity

973 program [2009CB522200]; Natural Science Foundation of China [31101014, 30871280]; Fundamental Research Funds for the Central Universities [2011]; project 111 [B06016]; [NCET-09-0675]MDM2 plays a crucial role in negatively regulating the functions of tumor suppressor p53. Here we show that MDM2 can inhibit Axin-stimulated p53-dependent apoptosis by suppressing p53 phosphorylation at Ser 46 and apoptosis-related p53 transactivational activity. Interestingly, the ubiquitin E3 ligase activity of MDM2 is not required for this inhibitory effect. Mechanically, either wildtype MDM2 or its E3-dead mutant, disrupts the Axin-based HIPK2/p53 complex formation by blocking the binding of p53 and HIPK2 to Axin. MDM2Dp53, a deletion mutant that lacks p53 binding domain fails to exert the inhibitory effect, demonstrating that the interaction of MDM2 and p53, but not its E3 ligase activity toward p53 plays key role in suppressing Axin-stimulated p53 activation. Our results thus have revealed a novel aspect of the mechanism by which MDM2 regulates p53 activities

Both MDM2 and MDM2(C464A) inhibit Axin-HIPK2 interaction.

<p>(A, B) HEK 293T cells were co-transfected with Axin, HA-HIPK2 and Myc-MDM2 or MDM2 (C464A) as indicated, followed by immunoprecipitation and western blotting analysis. (C) Both MDM2 and MDM2 (C464A) can disrupt the interaction between HIPK2Δp53 (a HIPK2 deletion mutant that fails to bind with p53) and Axin. HEK 293T cells were co-transfected with different combinations of plasmids as indicated, followed by immunoprecipitation and western blotting.</p