AP-1的研究进展

激活蛋白-1(activator protein-1,AP-1)是细胞内一类转录激活因子,主要由原癌基因编码的蛋白质Jun和Fos组成,以同源或异源二聚体复合物形式结合DNA靶序列,调控靶基因表达。AP-1通过调节靶基因表达来应对多种刺激(包括细胞因子、生长因子、压力及细菌和病毒感染等)对细胞的影响,参与调节细胞增殖、分化、凋亡以及炎症等多种细胞过程。该文就AP-1的结构特点、生物学功能、活性调控及其在医学研究中的应用作一综述。     

Enterovirus 71 induces COX-2 expression via MAPKs,NF-κB,and AP-1 in SK–N–SH cells: Role of PGE2 in viral replication

The enterovirus 71 (EV71) causes severe neurological diseases that were mediated through cyclooxygenase-2 (COX-2) expression in brain. However, the mechanisms underlying EV71-initiated intracellular signaling pathways leading to COX-2 expression remain unknown in neurons. Here we report that exposure of SK–N–SH cells to EV71 increased COX-2 expression and PGE₂ generation in a time- and virus titer-dependent manner, revealed by Western blot, real-time PCR, and PGE₂ analyses. These EV71-induced responses were mediated through activation of p42/p44 MAPK, p38 MAPK, JNK, NF-κB, and AP-1, revealed by using selective pharmacological inhibitors or transfection with respective siRNAs. Consistently, EV71-stimulated translocation of NF-κB into the nucleus and degradation of IκBα in the cytosol was blocked by pretreatment with the selective inhibitors of MEK1/2 (U0126) and NF-κB (Bay11-7085), respectively, suggesting that MEK1/2-p42/p44 MAPK cascade linking to NF-κB was involved in COX-2 expression. In addition, EV71-induced AP-1 subunits (c-jun and c-fos mRNA) expression was also attenuated by pretreatment with a selective JNK inhibitor SP600125, suggesting that JNK cascade linking to AP-1 was involved in COX-2 expression induced by EV71. These findings suggested that up-regulation of COX-2 associated with the release of PGE₂ from EV71-infected SK–N–SH cells which was mediated through activation of p38 MAPK, JNK, p42/p44 MAPK, NF-κB, and AP-1 pathways.     

Iron–sulfur protein folds,iron–sulfur chemistry,and evolution

An inventory of unique local protein folds around Fe–S clusters has been derived from the analysis of protein structure databases. Nearly 50 such folds have been identified, and over 90% of them harbor low-potential [2Fe–2S]^2+,+ or [4Fe–4S]^2+,+ clusters. In contrast, high-potential Fe–S clusters, notwithstanding their structural diversity, occur in only three different protein folds. These observations suggest that the extant population of Fe–S protein folds has to a large extent been shaped in the reducing iron- and sulfur-rich environment that is believed to have predominated on this planet until approximately two billion years ago. High-potential active sites are then surmised to be rarer because they emerged later, in a more oxidizing biosphere, in conditions where iron and sulfide had become poorly available, Fe–S clusters were less stable, and in addition faced competition from heme iron and copper active sites. Among the low-potential Fe–S active sites, protein folds hosting [4Fe–4S]^2+,+ clusters outnumber those with [2Fe–2S]^2+,+ ones by a factor of 3 at least. This is in keeping with the higher chemical stability and versatility of the tetranuclear clusters, compared with the binuclear ones. It is therefore suggested that, at least while novel Fe–S sites are evolving within proteins, the intrinsic chemical stability of the inorganic moiety may be more important than the stabilizing effect of the polypeptide chain. The discovery rate of novel Fe–S-containing protein folds underwent a sharp increase around 1995, and has remained stable to this day. The current trend suggests that the mapping of the Fe–S fold space is not near completion, in agreement with predictions made for protein folds in general. Altogether, the data collected and analyzed here suggest that the extant structural landscape of Fe–S proteins has been shaped to a large extent by primeval geochemical conditions on one hand, and iron–sulfur chemistry on the other.     

Calculation of the Three-Dimensional Structures of Two Antigenic Sequences, Pro–Pro–Pro–Pro–Asn–Pro–Asn–Asp–Pro and Pro–Pro–Pro–Pro–Asn–Pro–Asn–Asp–Pro–Pro–Pro, of the Circumsporozoite Protein From a Malaria-Causing Plasmodium

Using the chain build-up procedure based on the program ECEPP, we have computed the lowest energy structures for two terminally blocked subsequences from the antigenic circumsporozoite protein of Plasmodium berghei, that is known to cause malaria in animals. The full antigenic sequence is an octapeptide proline-rich tandem repeat, (Pro–Pro–Pro–Pro–Asn–Pro–Asn–Asp)₂. We computed the structures for the first octapeptide plus one Pro from the second octapeptide, terminally blocked CH₃CO–Pro–Pro–Pro–Pro–Asn–Pro–Asn–Asp–Pro–NHCH₃ as well as the first octpeptide with an additional three Pro residues from the adjoining unit, i.e., CH₃CO–Pro–Pro–Pro–Pro–Asn–Pro–Asn–Asp–Pro–Pro–Pro–NHCH₃. We find that the first sequence adopts a number of different low energy structures, the most probable of which has a probability of occurrence of 56 %. Addition of two more Pro residues results in the adoption a single, unique lowest energy structure that has a probability of occurrence of over 95 % without solvation effects and 86 % when solvation effects are included in the calculations. We predict that this structure may be the one recognized as a major antigenic determinant.     

Phase Behavior, Stability, and Mesomorphism of Monostearin–oil–water Gels

This paper is the characterization of a new material comprised of oil, water, monostearin and stearic acid, which can be used as a heart-friendly, low-saturate, trans fatty acid-free spreadable fat and shortening. Oil–water–monstearin mixtures formed a gel above 2% monostearin and 30% water and were stable over a month’s time. An increase in the storage modulus (G′), and peak melting temperature (T _m) was observed over time, which suggests a slow change in structure to a more solid form. Powder x-ray diffraction measurements at temperatures above the Krafft temperature of the monglyceride (57°C) indicated the existence of a lamellar liquid crystalline phase $ {\left( {L_{\alpha } } \right)} This paper is the characterization of a new material comprised of oil, water, monostearin and stearic acid, which can be used as a heart-friendly, low-saturate, trans fatty acid-free spreadable fat and shortening. Oil–water–monstearin mixtures formed a gel above 2% monostearin and 30% water and were stable over a month’s time. An increase in the storage modulus (G′), and peak melting temperature (T _m) was observed over time, which suggests a slow change in structure to a more solid form. Powder x-ray diffraction measurements at temperatures above the Krafft temperature of the monglyceride (57°C) indicated the existence of a lamellar liquid crystalline phase with a (001) reflection occurring at 50 ?. In addition to the 50 ? reflection at small angles, a wide angle reflection at 4.2 ? was observed upon cooling below 60°C, indicating a transition from the to the phase, which upon storage at 22°C for one day converted to the coagel, or β-gel phase.     

Phosphatidylinositol 3,4,5-trisphosphate Localization in Recycling Endosomes Is Necessary for AP-1B–dependent Sorting in Polarized Epithelial Cells

Polarized epithelial cells coexpress two almost identical AP-1 clathrin adaptor complexes: the ubiquitously expressed AP-1A and the epithelial cell–specific AP-1B. The only difference between the two complexes is the incorporation of the respective medium subunits μ1A or μ1B, which are responsible for the different functions of AP-1A and AP-1B in TGN to endosome or endosome to basolateral membrane targeting, respectively. Here we demonstrate that the C-terminus of μ1B is important for AP-1B recruitment onto recycling endosomes. We define a patch of three amino acid residues in μ1B that are necessary for recruitment of AP-1B onto recycling endosomes containing phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P₃]. We found this lipid enriched in recycling endosomes of epithelial cells only when AP-1B is expressed. Interfering with PI(3,4,5)P₃ formation leads to displacement of AP-1B from recycling endosomes and missorting of AP-1B–dependent cargo to the apical plasma membrane. In conclusion, PI(3,4,5)P₃ formation in recycling endosomes is essential for AP-1B function.     

Grandmothering in Cambridgeshire, 1770–1861

The effects of grandparent survival on child survival and mean interbirth interval, both independent of and relative to parent survival, were investigated in a historical population. Families for the data set were reconstituted from the parish and census records of Cambridgeshire, 1770–1861. In a logistic regression analysis, only the mother’s and the maternal grandmother’s survival were found to be significant predictors of child survival. Maternal grandmother’s survival was found to influence child survival both via maternal survival and independent of maternal survival. Grandparent survival was not found to influence mean interbirth interval. These findings are reviewed with respect to other studies of grandmothering, the Grandmother Hypothesis, and the evolutionary significance of human female postreproductive lifespan. Gillian Ragsdale is a postgraduate student at the Leverhulme Centre for Human Evolution Studies (LCHES), Cambridge University, UK, currently investigating the evolution of human social cognition. She was originally a molecular geneticist, and subsisted through the intervening years in educational publishing.     

AP-1在腋臭患者发病过程中的作用

目的：腋臭是美容整形外科的常见病,目前发病机制尚不明确,已证实人体大汗腺中的载脂蛋白D（ApoD）在腋臭患者大汗腺中高表达,并且与腋臭的发生密切相关。探明ApoD在大汗腺细胞中的信号转导通路,可以进一步明确其在腋臭发病过程中的作用机制。JNK信号转导通路与多种疾病的发生有关。课题组前期已经做了JNKl对ApoD调控作用的相关研究,证明了在腋臭发病过程中JNK1是通过调控ApoD的转录来上调ApoD的表达。本实验在课题组前期研究基础上,探讨JNKl下游转录因子AP-1是否在JNKl上调ApoD通路中发挥作用。方法：取腋臭志愿者腋区皮肤组织,进行汗腺细胞培养。把汗腺细胞分为5．二氢睾酮处理组、5-二氢睾酮联合姜黄素处理组和空白对照3个组,用姜黄素抑制AP-1的活性,通过Real．timePCR实验方法检测ApoD在姜黄素抑制下的表达变化。结果：在姜黄素的抑制下,ApoD表达明显降低。在体外培养汗腺细胞加入5．二氢睾酮联合姜黄素处理后,ApoD的表达量在mRNA水平低于单独的5-二氢睾酮处理组和正常对照组（P〈0．05）。结论：姜黄素抑制了AP．1的活化导致ApoD的表达降低。在腋臭的发病过程中,JNKl的下游转录因子AP-1对ApoD有明显的上调作用。AP-1可能在JNKl上调ApoD这条通路中扮演了很重要的角色,它可能是JNK1和ApoD的中间转录因子。