Mutation in the Drosophila melanogaster adenosine receptor gene selectively decreases the mosaic hyperplastic epithelial outgrowth rates in wts or dco heterozygous flies

Adenosine (Ado) is a ubiquitous metabolite that plays a prominent role as a paracrine homeostatic signal of metabolic imbalance within tissues. It quickly responds to various stress stimuli by adjusting energy metabolism and influencing cell growth and survival. Ado is also released by dead or dying cells and is present at significant concentrations in solid tumors. Ado signaling is mediated by Ado receptors (AdoR) and proteins modulating its concentration, including nucleoside transporters and Ado deaminases. We examined the impact of genetic manipulations of three Drosophila genes involved in Ado signaling on the incidence of somatic mosaic clones formed by the loss of heterozygosity (LOH) of tumor suppressor and marker genes. We show here that genetic manipulations with the AdoR, equilibrative nucleoside transporter 2 (Ent2), and Ado deaminase growth factor-A (Adgf-A) cause dramatic changes in the frequency of hyperplastic outgrowth clones formed by LOH of the warts (wts) tumor suppressor, while they have almost no effect on control yellow (y) clones. In addition, the effect of AdoR is dose-sensitive and its overexpression leads to the increase in wts hyperplastic epithelial outgrowth rates. Consistently, the frequency of mosaic hyperplastic outgrowth clones generated by the LOH of another tumor suppressor, discs overgrown (dco), belonging to the wts signaling pathway is also dependent on AdoR. Our results provide interesting insight into the maintenance of tissue homeostasis at a cellular level.

Electronic supplementary material

The online version of this article (doi:10.1007/s11302-014-9435-2) contains supplementary material, which is available to authorized users.     

CO2 激光联合胸腺五肽治疗尖锐湿疣的临床效果分析

目的:探讨CO2激光联合胸腺五肽治疗尖锐湿疣的临床疗效。方法:将我院2010年2月-2011年8月期间收治的82例尖锐湿疣患者随机分为两组,治疗组50例采用CO2激光器治疗联合胸腺五肽肌注;对照组32例单纯采用CO2激光器治疗;两组治疗疗程结束后观察临床疗效。结果:治疗组50例,一次治愈者46例,占92%;二次治愈者4例,占8%。对照组32例,一次治愈者19例,占59.4%;二次治愈者13例,占40.6%。两组一次治愈率比较差异明显,具有统计学意义(P<0.05)。两组术后局部轻度水肿和疼痛,无需处理1~3天缓解或痊愈。结论:CO2激光联合胸腺五肽治疗尖锐湿疣临床疗效好,并具有治疗简便,术后不良反应少,治愈率高等特点。     

Mob as tumor suppressor is activated at the cell membrane to control tissue growth and organ size in Drosophila

Growth inhibition mediated by Hippo (Hpo) signaling is essential for tissue growth and organ size control in Drosophila. However, the cellular mechanism by which the core components like Mob as tumor suppressor (Mats) and Warts (Wts) protein kinase are activated is poorly understood. In this work, we found that the endogenous Mats is located at the plasma membrane in developing tissues. Membrane targeting constitutively activates Mats to promote apoptosis and reduce cell proliferation, which leads to reduced tissue growth and organ size. Moreover, the ability of membrane-targeted Mats to inhibit tissue growth required the wts gene activity and Wts kinase activity was increased by the activated Mats in developing tissues. Consistent with the idea that Mats is a key component of the Hpo pathway, Mats is required and sufficient to regulate Yki nuclear localization. These results support a model in which the plasma membrane is an important site of action for Mats tumor suppressor to control tissue growth and organ size.     

Expanded and fat regulate growth and differentiation in the Drosophila eye through multiple signaling pathways

Mutations in the expanded gene act as hyperplastic tumor suppressors, interfere with cell competition and elevate Dpp signaling. Unlike Dpp overexpression, ex causes few patterning defects. Our data suggest that patterning effects are partly masked by antagonistic roles of other signaling pathways that are also activated. ex causes proliferation of cells in the posterior eye disc that are normally postmitotic. ex mutations elevate Wg signaling, but Dpp signaling antagonizes patterning effects of Wg. By contrast, if Dpp signaling is blocked in ex mutant cells, the elevated Wg signaling preserves an immature developmental state and prevents retinal differentiation. An effect of ex mutations on vesicle transport is suggested by evidence for altered sterol distribution. Mutations in ft show effects on proliferation, Wg signaling and sterols very similar to those of ex mutations. During disc growth, ex was largely epistatic to ft, and the Warts pathway mutation hippo largely epistatic to ex. Our data suggest that ft and ex act partially through the Warts pathway.     

CO_2激光联合胸腺五肽治疗尖锐湿疣的临床效果分析

目的：探讨CO2激光联合胸腺五肽治疗尖锐湿疣的临床疗效。方法：将我院2010年2月-2011年8月期间收治的82例尖锐湿疣患者随机分为两组,治疗组50例采用CO2激光器治疗联合胸腺五肽肌注;对照组32例单纯采用CO2激光器治疗;两组治疗疗程结束后观察临床疗效。结果：治疗组50例,一次治愈者46例,占92%;二次治愈者4例,占8%。对照组32例,一次治愈者19例,占59.4%;二次治愈者13例,占40.6%。两组一次治愈率比较差异明显,具有统计学意义（P〈0.05）。两组术后局部轻度水肿和疼痛,无需处理1~3天缓解或痊愈。结论：CO2激光联合胸腺五肽治疗尖锐湿疣临床疗效好,并具有治疗简便,术后不良反应少,治愈率高等特点。     

Global gene methylation profiling of common warts caused by human papillomaviruses infection

Infection with the human papillomaviruses (HPV) often involves the epigenetic modification of the host genome. Despite its prevalence among the population, host genome methylation in HPV-induced warts is not clearly understood. In this study, genome-wide methylation profiling was carried out on paired healthy skin and wart samples in order to investigate the effects that benign HPV infection has on gene methylation status. To overcome this gap in knowledge, paired wart (n = 12) and normal skin (n = 12) samples were obtained from Arab males in order to perform DNA extraction and subsequent genome-wide methylation profiling on the Infinium Methylation EPIC Bead Chip microarray. Analysis of differential methylation revealed a clear pattern of discrimination between the wart and normal skin samples. In warts, the most differentially methylated (DM) genes included long non-coding RNAs (AC005884, AL049646.2, AC126121.2, AP001790.1, and AC107959.3), microRNAs (MIR374B, MIR596, MIR1255B1, MIR26B, and MIR196A2),snoRNAs (SNORD114-22, SNORD70, and SNORD114-31), pseudogenes (AC069366.1, RNU4ATAC11P, AC120057.1, NANOGP3, AC106038.2, TPT1P2, SDC4P, PKMP3, and VN2R3P), and protein-coding genes (AREG, GJB2, C12orf71, AC020909.2, S100A8, ZBED2, FABP7, and CYSLTR1). In addition, pathway analysis revealed that, among the most differentially methylated genes, STAT5A, RARA, MEF2D, MAP3K8, and THRA were the common regulators. It can be observed that HPV-induced warts involve a clear and unique epigenetic alteration to the host genome.     

Ce-wts-1 plays important roles in Caenorhabditis elegans development

The Hippo-Warts pathway defines a novel signaling cascade involved in organ size control and tumor suppression. However, the developmental function of this pathway is less understood. Here we report that the Caenorhabditis elegans homolog of Warts, Ce-wts-1, plays important roles during worm development. The null allele of Ce-wts-1 causes L1 lethality. Partial loss of Ce-wts-1 function by RNAi reveals that Ce-wts-1 is involved in many developmental processes such as larval development, growth rate regulation, gut granule formation, pharynx development, dauer formation, lifespan and body length control. Genetic analyses show that Ce-wts-1 functions synergistically with the TGF-β Sma/Mab pathway to regulate body length. In addition, CE-WTS-1::GFP is enriched near the inner cell membrane, implying its possible membrane-related function.