Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis

Tissue homeostasis of skin is sustained by epidermal progenitor cells localized within the basal layer of the skin epithelium. Post‐translational modification of the proteome, such as protein phosphorylation, plays a fundamental role in the regulation of stemness and differentiation of somatic stem cells. However, it remains unclear how phosphoproteomic changes occur and contribute to epidermal differentiation. In this study, we survey the epidermal cell differentiation in a systematic manner by combining quantitative phosphoproteomics with mammalian kinome cDNA library screen. This approach identified a key signaling event, phosphorylation of a desmosome component, PKP1 (plakophilin‐1) by RIPK4 (receptor‐interacting serine–threonine kinase 4) during epidermal differentiation. With genome‐editing and mouse genetics approach, we show that loss of function of either Pkp1 or Ripk4 impairs skin differentiation and enhances epidermal carcinogenesis in vivo. Phosphorylation of PKP1's N‐terminal domain by RIPK4 is essential for their role in epidermal differentiation. Taken together, our study presents a global view of phosphoproteomic changes that occur during epidermal differentiation, and identifies RIPK‐PKP1 signaling as novel axis involved in skin stratification and tumorigenesis.     

Structure of a Pancreatic ATP-Sensitive Potassium Channel

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多烯磷脂酰胆碱对β-淀粉样蛋白（Aβ 1—40）致阿尔茨海默病模型大鼠的治疗作用

目的：研究多烯磷脂酰胆碱（Polyene Phosphatiayl choline,PPC）对β-淀粉样蛋白（Apl-40）致阿尔茨海默病（Alzheimer＇s Dis．ease,AD）模型大鼠的治疗作用。方法：32只SD大鼠随机分为正常组、假手术组、模型组和处理组,海马内注射淀粉样蛋白（Aβ1—40）,制作大鼠阿尔茨海默病模型,处理组给予多烯磷脂酰胆碱。通过Moms水迷宫实验验检测各组大鼠认知行为学改变,海马组织学及免疫组化染色,观察多烯磷脂酰胆碱对阿尔茨海默病模型大鼠的影响,并进行统计学分析。结果：①Moms水迷宫实验,模型组与正常组、假手术组比较,学习和记忆潜伏期显著增加;处理组与模型组比较,学习和记忆潜伏期显著减少;组间比较差异有统计学意义（P〈0．05）,提示多烯磷脂酰胆碱使AD模型大鼠的认知行为学功能改善。（2）Nissl染色,模型组与正常对照组、假手术组组织学染色结果有显著性差异（P〈0．05）,PPC处理组与模型组比较有显著性差异（P〈0．05）,PPC处理组与正常组及假手术组比较也呈现出显著性差异（P〈0．05）;提示多烯磷脂酰胆碱可以减少神经元的凋亡。③β-淀粉样蛋白免疫组化染色,模型组与正常对照组、假手术组比较,Aβ沉积明显增加;PPC处理组与模型组比较,Aβ沉积范围明显缩小,PPC处理组与正常对照组、假手术组也呈现出显著性差。结论：多烯磷脂酰胆碱对淀粉样蛋白（Aβ1—40）致阿尔茨海默病模型大鼠有治疗作用。     

Synthesis, structure and magnetic properties of a two-dimensional manganese(II) complex with a maximum denticity of ethylenediaminetetraacetic ligand

A new Mn(II) complex, [Mn₂(edta)(H₂O)]_n·nH₂O (1) (H₄edta = ethylenediaminetetraacetic acid) has been synthesized by the reaction of MnCl₂·4H₂O and H₄edta under hydrothermal conditions, and was characterized by single-crystal X-ray diffraction study, variable temperature (1.8-300 K) magnetic measurement, and thermal gravity analysis. The result of X-ray crystallographic analysis reveals that complex 1 is the first two-dimensional (2D) Mn-edta coordination polymer with a grid-like (4,4)-topology, which is built from Mn-carboxylate chains and entirely deprotonated edta⁴⁻ ligands with a maximum denticity. The variable temperature magnetic data indicate that complex 1 exhibits strong antiferromagnetic couplings.     

Over-expression of human carcinoma-associated antigen in intrahepatic cholangiocellular carcinoma

Objective: To investigate the expression status of human carcinoma antigen (HCA) in human cholangiocellular carcinomas, and to determine the relationship between HCA and clinical features. Methods: Tissues from 60 intrahepatic cholangiocellular carcinoma (ICC) patients, and normal liver tissues from 20 hepatic hemangioma patients selected randomly were assayed for the expression of HCA by immunohistochemistry, and Western blots. Areas of poorly differentiated (n = 20), moderately-well differentiated (n = 30), highly differentiated tumors (n = 10) from different cases were evaluated. Results were recorded as positive (?5% of cells staining and staining intensity 2+ or 3+) or negative (<5% of cells staining and staining intensity <2+) and analyzed using the χ² test. Results: BCE075 and BDD048 antibodies showed similar staining patterns. The positive immunostaining of BCE075 was mainly localized in the cytoplasm and cell secretions. The staining was positive in 15% of poorly differentiated ICC, 72% of moderately-well differentiated, 100% of highly differentiated tumors. But, staining was not detected in adjacent normal tissue. The differences in HCA expression among these tissues were statistically significant. Also, we found expression of HCA to be closely associated with the degree of differentiation of ICC and tumor cell morphology. There was a correlation between expression of HCA and serum CA19-9. Conclusion: The data suggest that HCA is a potential marker for the diagnosis of cholangiocellular carcinoma.     

Hypoxia induces beta-amyloid in association with death of RGC-5 cells in culture

Beta-amyloid (Aβ) derived from amyloid precursor protein (APP) has been associated with retinal degeneration in Alzheimer’s disease (AD) and glaucoma. This study examined whether hypoxia exposure induces Aβ accumulation in RGC-5 cells. While levels of APP mRNA and protein significantly increased in the cells, elevated abundance of Aβ was also observed in cells and culture medium between 12 or 24 and 48 h after 5% O₂ hypoxia treatment. Additionally, there is a close relationship between induction of APP and Aβ and intracellular accumulation of ROS along with loss of mitochondrial membrane potential followed by the death of RGC-5 cells in culture under hypoxia. These results suggest a possible involvement of APP and Aβ in the death of RGCs challenged by hypoxia.     

Cellular repressor of E1A-stimulated genes regulates vascular endothelial cell migration by the ILK/AKT/mTOR/VEGF(165) signaling pathway

The migration of vascular endothelial cells plays a critical role in a variety of vascular physiological and pathological processes, such as embryonic development, angiogenesis, wound healing, re-endothelialization, and vascular remodeling. This study clarified the role and mechanism of a new vascular homeostasis regulator, Cellular repressor of E1A-stimulated genes (CREG), in the migration of primary human umbilical vein endothelial cells (HUVECs). A wound healing assay and transwell migration model showed that upregulation of CREG expression induced HUVEC migration and it was positively correlated with the expression of vascular endothelial growth factor. Furthermore, wild type integrin-linked kinase reversed the poor mobility of CREG knock-down HUVECs; in contrast, kinase-dead integrin-linked kinase weakened the migration of HUVECs. We also studied the effect of CREG on HUVEC migration by the addition of an mTOR inhibitor, recombinant vascular endothelial growth factor₁₆₅, neutralizing antibody of vascular endothelial growth factor₁₆₅ and AKT siRNA, and we concluded that CREG induces endothelial cell migration by activating the integrin-linked kinase/AKT/mTOR/VEGF₁₆₅ signaling pathway.