Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2

大多数真核生物的体细胞是二倍体，即仅含有两组染色体，分别遗传自父本和母本。而一些特定组织如心脏、肝脏等就含有多倍体细胞，特别是肝脏组织含有较高比例的四、八倍体等多倍体细胞。肝脏是人体的重要解毒器官，同时酒精、肝炎病毒等毒性物质或毒性代谢物容易诱发肝细胞的基因突变，多倍体被认为有利于提供代偿性的正常基因来维持肝脏稳态。然而肝脏受损后，多倍体细胞将会受胁迫进行增殖，再生修复受损的肝组织。因此研究机体调控多倍体细胞产生及多倍体细胞进行细胞分裂的调控机理对于理解肝癌的发病机理和肝癌的治疗至关重要。Hippo信号通路在调节组织成体干细胞的分化和增殖，调控器官再生与尺寸大小中具有重要作用。深入研究发现, Hippo信号通路下游效应分子YAP通过AKT-SKP2信号促进二倍体细胞向多倍体转化及多倍体细胞的生长增殖。本项研究阐明了Hippo缺失及YAP激活促进多倍体细胞产生及增殖作为肝癌发生发展中的一个重要机制，为肝癌诊疗提供了新的策略。 周大旺，博士，厦门大学生命科学学院教授、副院长、国家杰出青年基金获得者。【Abstract】Polyploidy can lead to aneuploidy and tumorigenesis. Here, we report that the Hippo pathway effector Yap promotes the diploid-polyploid conversion and polyploid cell growth through the Akt-Skp2 axis. Yap strongly induces the acetyltransferase p300-mediated acetylation of the E3 ligase Skp2 via Akt signaling. Acetylated Skp2 is exclusively localized to the cytosol, which causes hyper-accumulation of the cyclin-dependent kinase inhibitor p27, leading to mitotic arrest and subsequently cell polyploidy. In addition, the pro-apoptotic factors FoxO1/3 are overly degraded by acetylated Skp2, resulting in polyploid cell division, genomic instability, and oncogenesis. importantly, the depletion or inactivation of Akt or Skp2 abrogated Hippo signal deficiency-induced liver tumorigenesis, indicating their epistatic interaction. Thus, we conclude that Hippo-Yap signaling suppresses cell polyploidy and oncogenesis through Skp2.该研究工作获得了国家自然科学基金委、国家重点基础研究发展计划(973)项目、青年千人计划和中央高校基本科研基金的资助。 The Yap (S127A) transgenic mice were kindly provided by Dr. Fernando Camargo from Harvard Medical School, Boston, MA. D.Z. and L.C. were supported by the National Natural Science Foundation of China (31625010,U1505224, and J1310027 to D.Z.; 81422018, U1405225, and 81372617 to L.C.; 81472229 to L.H.), the National Basic Research Program (973) of China (2015CB910502 to L.C.), the Fundamental Research Funds for the Central Universities of China-Xiamen University (20720140551 to L.C. and 2013121034 and 20720140537 to D.Z.)

Hippo信号通路通过调控Skp2活性从而抑制细胞多倍体产生及肝癌发生

文章简介在这项研究中,课题组揭示了Hippo信号通路在限制肝脏细胞的染色体由两倍体向多倍/非整倍体转变过程中起关键作用,该机制异常将导致基因组不稳定继而诱发肝癌的发生发展。课题组通过对Hippo信号通路重要成员(WW45,Mst1/2,Lats1/2)肝脏特异性敲除和过表达国家自然科学基金委;;国家重点基础研究发展计划(973)项目;;青年千人计划;;中央高校基本科研基金的资

Distribution of Polycyclic Aromatic Hydrocarbons in Sunken Oils in the Presence of Chemical Dispersant and Sediment

The formation of sunken oils is mainly dominated by the interaction between spilled oils and sediments. Due to their patchiness and invisibility, cleaning operations become difficult. As a result, sunken oils may cause long-term and significant damage to marine benthonic organisms. In the present study, a bench experiment was designed and conducted to investigate the quantitative distribution of polycyclic aromatic hydrocarbons (PAHs) in sunken oils in the presence of chemical dispersant and sediment. The oil sinking efficiency (OSE) of 16 priority total PAHs in the sediment phase was analyzed with different dosages of dispersant. The results showed that the synergistic effect of chemical dispersant and sediment promoted the formation of sunken oils, and the content of PAHs partitioned in the sunken oils increased with the increase of dispersant-to-oil ratios (DORs). Furthermore, with the addition of chemical dispersant, due to the solubility and hydrophobicity of individual PAHs, the high molecular weight (HMW) PAHs with 4–6 rings tended to partition to sediment compared with low molecular weight (LMW) PAHs with 2–3 rings. The synergistic effect of chemical dispersant and sediment could enhance the OSE of HMW PAHs in sunken oils, which might subsequently cause certain risks for marine benthonic organisms

Direct evidence for efficient scattering of suprathermal electrons by whistler mode waves in the Martian magnetosphere

Whistler mode waves are critical emissions in magnetized plasmas that usually influence the electron dynamics in a planetary magnetosphere. In this paper, we present a unique event in the Martian magnetosphere in which enhanced whistler mode waves (~10−11 V2/m2/Hz) with frequency of 0.1 fce–0.5 fce occurred, based on MAVEN data, exactly corresponding to a significant decrease of suprathermal electron fluxes. The diffusion coefficients are calculated by using the observed electric field wave spectra. The pitch angle diffusion coefficient can approach 10−2 s−1, which is much larger, by ~100 times, than the momentum diffusion coefficient, indicating that pitch angle scattering dominates the whistler–electron resonance process. The current results can successfully explain the dropout of the suprathermal electrons in this event. This study provides direct evidence for whistler-driven electron losses in the Martian magnetosphere

Effects of simvastatin-loaded polymeric micelles on human osteoblast-like MG-63 cells

<p id="spar0015">To develop an optimized simvastatin (SV) delivery device for bone regeneration, SV-loaded poly(ethylene glycol)-poly(ɛ-caprolactone) (PECL) micelles were constructed. The micelles had an average size of 80&nbsp;nm. The <em>in vitro</em> release behavior of SV from the micelles showed prolonged release compared to the free SV. The following four groups were tested in a cytologic experiment: a free SV group, a SV-loaded micelle group with SV concentrations ranging from 2.5&nbsp;&times;&nbsp;10^&minus;6 to 2.5&nbsp;&times;&nbsp;10^&minus;10&nbsp;M, a drug-free micelle group and a blank control group. The effect of SV-loaded micelles on osteoblast-like MG-63 cells was determined <em>via</em> analysis of cell proliferation, alkaline phosphatase activity, and cell calcification. In addition, the mRNA and protein expression of the BMP-2 gene were determined with real-time fluorescence quantitative polymerase chain reaction and western blot techniques, respectively. The results show that SV-loaded PECL micelles cause effective suppression of the osteoblast early proliferation inhibition, stimulation of osteoblast differentiation and mineralization, and stimulation of the BMP-2 expression. Therefore, SV-loaded PECL micelles are predicted to have great potential in bone regeneration applications.</p><!--VALIDHTML--><hr /