Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin. More than one-third of MCC patients will die from this cancer, making it twice as lethal as malignant melanoma. Despite the fact that MCC is still a very rare tumor, its incidence is rapidly increasing; the American Cancer Society estimates for 2008 almost 1 500 new cases in the USA. These clinical observations are especially disturbing as the pathogenesis of MCC is not yet fully understood; however, a number of recent reports contribute to a better understanding of its pathogenesis. Here we describe findings regarding the role of Wnt, MAPK and Akt signaling as well as possible aberrations in the p14ARF/p53/RB tumor suppressor network in MCC. Most important, and possibly with high impact on future therapeutic approaches is the demonstration that a polyomavirus has frequently integrated in the genome of the MCC cells prior to tumor development. Received 12 August 2008; received after revision 06 October 2008; accepted 22 October 2008     

Modulation of chemokine receptor activity through dimerization and crosstalk

Chemokines are small, secreted proteins that bind to the chemokine receptor subfamily of class A G protein-coupled receptors. Collectively, these receptor-ligand pairs are responsible for diverse physiological responses including immune cell trafficking, development and mitogenic signaling, both in the context of homeostasis and disease. However, chemokines and their receptors are not isolated entities, but instead function in complex networks involving homo- and heterodimer formation as well as crosstalk with other signaling complexes. Here the functional consequences of chemokine receptor activity, from the perspective of both direct physical associations with other receptors and indirect crosstalk with orthogonal signaling pathways, are reviewed. Modulation of chemokine receptor activity through these mechanisms has significant implications in physiological and pathological processes, as well as drug discovery and drug efficacy. The integration of signals downstream of chemokine and other receptors will be key to understanding how cells fine-tune their response to a variety of stimuli, including therapeutics. Received 19 October 2008; received after revision 7 November 2008; accepted 11 November 2008 C. L. Salanga, M. O’Hayre: These authors contributed equally.     

小G蛋白Rho/Rock信号转导通路与肾小管上皮细胞转分化

上皮细胞在特定生理和病理情况下向间充质细胞转分化的现象是肿瘤及慢性炎症性疾病中的重要细胞生物学现象。近年来研究发现，细胞内信号转导途径中的MAPK通路、RhoGTP酶/Rho激酶系统（Rho/Rock信号转导通路）、Src激酶、PI3激酶和Smad通路参与调控上皮细胞转分化过程。肾小管上皮细胞在病理条件下可转分化为肌成纤维细胞，其细胞内信号转导机制虽已有初步研究，但尚所知甚少。本文就Rho／Rock信号转导通路在肾小管上皮细胞转分化过程中的作用进行综述。     

支架蛋白对丝裂原活化蛋白激酶信号途径中震荡的抑制

通过一种两体支架蛋白参与的丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号转导模型,研究了支架蛋白参与的存在负反馈的MAPK信号转导途径.支架蛋白(scaffold protein)既可以促进信号过程,也可以抑制信号的转导.由系统中支架蛋白的浓度以及支架与信号分子的相互作用共同决定了增加支架浓度造成的不同结果.不仅如此,系统中支架蛋白浓度的增加,还会抑制负反馈系统中出现的持续震荡.     

头孢噻肟对人外周血淋巴细胞钙信号转导作用的研究

以人外周血淋巴细胞为模型,利用稳态荧光法研究该模型在外源药物头孢噻肟刺激下,细胞钙稳态的变化,同时考察了钙-ATP酶活性与钙稳态之间的关系.研究发现,在低浓度组的头孢噻肟钠(0.005 g/L)刺激下,淋巴细胞内钙离子浓度略有增加,而胞外的钙离子浓度几乎没有发生变化.当药物浓度继续增加,胞内钙离子浓度逐渐减少,药物浓度与胞内钙离子浓度呈现出一定的剂量效应关系.不同药物处理组的钙-ATP酶活性与对照组相比均降低,呈现出一定的剂量-效应关系.     

封闭Her—2蛋白拮抗碱性成纤维细胞生长因子对人肝癌细胞的粘连效应

目的：探索碱性成纤维细胞生长因子(basic fibroblast growth,bFGF）影响癌细胞粘连的信号传递途径,提供抗癌治疗的线索。方法：以人肝癌细胞系（HepG2）为靶子,明确靶细胞存在Her-2蛋白表达的同时,利用Her-2蛋白抗体封闭靶细胞Her-2蛋白来研究bFGF作为配体与否的细胞粘连效应性。结果：靶细胞HepG2确实具有Her-2蛋白表达;利用抗体封闭靶细胞Her-2蛋白时,靶细胞明显地呈现拮抗bFGF作为配体的细胞粘连加强效应。结论：bFGF对人肝癌细胞粘连性的影响与Her-2基因蛋白介导的信号传递作用有关。     

Presenilin-dependent regulated intramembrane proteolysis and γ-secretase activity

Inhibiting the production of amyloid-β by antagonising γ-secretase activity is currently being pursued as a therapeutic strategy for Alzheimer’s disease (AD). However, early pre-clinical studies have demonstrated that disruption of presenilin-dependent γ-secretase alters many presenilin-dependent processes, leading to early lethality in several AD model organisms. Subsequently, transgenic animal studies have highlighted several gross developmental side effects arising from presenilin deficiency. Partial knockdown or tissue-specific knockout of presenilins has identified the skin, vascular and immune systems as very sensitive to loss of presenilin functions. A more appreciative understanding of presenilin biology is therefore demanded if γ-secretase is to be pursued as a therapeutic target. Herein we review the current understanding of γ-secretase complexes; their regulation, abundance of interacting partners and diversity of substrates. We also discuss regulation of the γ-secretase complexes, with an emphasis on the functional role of presenilins in cell biology. Received 25 July 2008; received after revision 24 November 2008; accepted 10 December 2008     

Kank proteins: structure, functions and diseases

The Kank family of proteins, Kank1–Kank4, are characterized by their unique structure, coiled-coil motifs in the N-terminal region, and ankyrin-repeats in the C-terminal region, with an additional motif, the KN motif, at the N-terminus. Kank1 was obtained by positional cloning of a tumor suppressor gene in renal cell carcinoma, while the other members were found by homology search. The family is involved in the regulation of actin polymerization and cell motility through signaling pathways containing PI3K/Akt and/or unidentified modulators/effectors. Their relationship to diseases such as cancer, and to neuronal and developmental disorders, will be an important subject of future study.