MAPK信号通路与脂肪细胞分化

促分裂原活化的蛋白激酶(MAPK)通路是真核细胞重要的信号转导通路,主要有ERK、p38和JNK三条途径,参与调控多种细胞应答和生理病理过程。该文重点讨论了MAPK对脂肪细胞分化的调控。其中ERK对脂肪细胞分化的调节具有多样性,随分化进程不同表现为不同的调控功能,p38和JNK也通过不同的机制对脂肪细胞分化发挥相异的调节作用。MAPK信号转导与脂肪分化的紧密联系,使其可能成为调控与脂分化密切相关的代谢疾病如肥胖、糖尿病等的一条关键通路。     

Global Regulation of a Differentiation MAPK Pathway in Yeast

Cell differentiation requires different pathways to act in concert to produce a specialized cell type. The budding yeast Saccharomyces cerevisiae undergoes filamentous growth in response to nutrient limitation. Differentiation to the filamentous cell type requires multiple signaling pathways, including a mitogen-activated protein kinase (MAPK) pathway. To identify new regulators of the filamentous growth MAPK pathway, a genetic screen was performed with a collection of 4072 nonessential deletion mutants constructed in the filamentous (Σ1278b) strain background. The screen, in combination with directed gene-deletion analysis, uncovered 97 new regulators of the filamentous growth MAPK pathway comprising 40% of the major regulators of filamentous growth. Functional classification extended known connections to the pathway and identified new connections. One function for the extensive regulatory network was to adjust the activity of the filamentous growth MAPK pathway to the activity of other pathways that regulate the response. In support of this idea, an unregulated filamentous growth MAPK pathway led to an uncoordinated response. Many of the pathways that regulate filamentous growth also regulated each other’s targets, which brings to light an integrated signaling network that regulates the differentiation response. The regulatory network characterized here provides a template for understanding MAPK-dependent differentiation that may extend to other systems, including fungal pathogens and metazoans.     

Feeding and Fasting Signals Converge on the LKB1-SIK3 Pathway to Regulate Lipid Metabolism in Drosophila

LKB1 plays important roles in governing energy homeostasis by regulating AMP-activated protein kinase (AMPK) and other AMPK-related kinases, including the salt-inducible kinases (SIKs). However, the roles and regulation of LKB1 in lipid metabolism are poorly understood. Here we show that Drosophila LKB1 mutants display decreased lipid storage and increased gene expression of brummer, the Drosophila homolog of adipose triglyceride lipase (ATGL). These phenotypes are consistent with those of SIK3 mutants and are rescued by expression of constitutively active SIK3 in the fat body, suggesting that SIK3 is a key downstream kinase of LKB1. Using genetic and biochemical analyses, we identify HDAC4, a class IIa histone deacetylase, as a lipolytic target of the LKB1-SIK3 pathway. Interestingly, we found that the LKB1-SIK3-HDAC4 signaling axis is modulated by dietary conditions. In short-term fasting, the adipokinetic hormone (AKH) pathway, related to the mammalian glucagon pathway, inhibits the kinase activity of LKB1 as shown by decreased SIK3 Thr196 phosphorylation, and consequently induces HDAC4 nuclear localization and brummer gene expression. However, under prolonged fasting conditions, AKH-independent signaling decreases the activity of the LKB1-SIK3 pathway to induce lipolytic responses. We also identify that the Drosophila insulin-like peptides (DILPs) pathway, related to mammalian insulin pathway, regulates SIK3 activity in feeding conditions independently of increasing LKB1 kinase activity. Overall, these data suggest that fasting stimuli specifically control the kinase activity of LKB1 and establish the LKB1-SIK3 pathway as a converging point between feeding and fasting signals to control lipid homeostasis in Drosophila.     

The MAPK Pathway Signals Telomerase Modulation in Response to Isothiocyanate-Induced DNA Damage of Human Liver Cancer Cells

4-methylthiobutyl isothiocyanate (MTBITC), an aliphatic, sulphuric compound from Brassica vegetables, possesses in vitro and in vivo antitumor activity. Recently we demonstrated the potent growth inhibitory potential of the DNA damaging agent MTBITC in human liver cancer cells. Here we now show that MTBITC down regulates telomerase which sensitizes cells to apoptosis induction. This is mediated by MAPK activation but independent from production of reactive oxygen species (ROS). Within one hour, MTBITC induced DNA damage in cancer cells correlating to a transient increase in hTERT mRNA expression which then turned into telomerase suppression, evident at mRNA as well as enzyme activity level. To clarify the role of MAPK for telomerase regulation, liver cancer cells were pre-treated with MAPK-specific inhibitors prior to MTBITC exposure. This clearly showed that transient elevation of hTERT mRNA expression was predominantly mediated by the MAPK family member JNK. In contrast, activated ERK1/2 and P38, but not JNK, signalled to telomerase abrogation and consequent apoptosis induction. DNA damage by MTBITC was also strongly abolished by MAPK inhibition. Oxidative stress, as analysed by DCF fluorescence assay, electron spin resonance spectroscopy and formation of 4-hydroxynonenal was found as not relevant for this process. Furthermore, N-acetylcysteine pre-treatment did not impact MTBITC-induced telomerase suppression or depolarization of the mitochondrial membrane potential as marker for apoptosis. Our data therefore imply that upon DNA damage by MTBITC, MAPK are essential for telomerase regulation and consequent growth impairment in liver tumor cells and this detail probably plays an important role in understanding the potential chemotherapeutic efficacy of ITC.     

Axonal Signals and Oligodendrocyte Differentiation

Axons produce signals that regulate oligodendrocyte proliferation, survival, terminal differentiation, and myelinogenesis. We review here recent in vitro and in vivo experimental approaches that aim to characterize axonal signals to oligodendroglia and to identify molecular mediators that regulate differentiation of oligodendendrocytes. We propose that the promoters of myelin genes, whose activation during terminal differentiation is modulated by axonal signals, can provide a means to identify molecular mediators of axo-oligodendroglial signals.     

RhoA-p38MAPK信号转导通路及其进展

RhoA属于小G蛋白家族成员,p38MAPK属于丝/苏氨酸蛋白激酶家族成员.本文从巨噬细胞、肌肉细胞、成纤维细胞、神经元和肿瘤几个方面阐述RhoA-p38MAPK信号通路的研究进展,此信号通路在细胞骨架的改变和肿瘤的发生发展方面有望成为新的研究热点.     

RhoA—p38MAPK信号转导通路及其进展

RhoA属于小G蛋白家族成员,p38MAPK属于丝/苏氨酸蛋白激酶家族成员。本文从巨噬细胞、肌肉细胞、成纤维细胞、神经元和肿瘤几个方面阐述RhoA-p38MAPK信号通路的研究进展,此信号通路在细胞骨架的改变和肿瘤的发生发展方面有望成为新的研究热点。     

经MAPK信号转导通路介导的糖皮质激素的作用机制

糖皮质激素(GC)通过膜受体快速激活细胞内信号传导通路的机制,主要涉及ERK,JNK/SAPK和P38等MAPK家族的重要成员.GC在许多细胞中对ERK起抑制作用,在不同的细胞中,GC能激活JNK或抑制其活性,即具有一定的细胞特异性.GC还直接或间接地激活P38途径.GC激活MAPK介导的信号传导通路,产生一系列生物学效应,如抑制细胞的生长的繁殖,介导细胞的凋亡等.     

Notch信号通路对干细胞分化的影响

干细胞的增殖分化受到自身或外在、远程或近程多种信号通路的调控,而细胞之间的相互通讯在此过程中起到重要作用。Notch通路就是通过相邻细胞之间相互通讯调控细胞分化的重要信号通路之一,众多研究显示,该通路的活化在干细胞分化过程中发挥了重要调节作用,本文就此相关研究进展作一简要综述。     

FLASH Meets Nuclear Bodies: CD95 Receptor Signals via a Nuclear Pathway

The CD95 receptor signals via assembly of a multi-protein complex termed death-inducing signaling complex (DISC) which triggers activation of receptor-bound caspase-8/FLICE molecules. Most cells (type II cells) depend on a mitochondrial amplification pathway to commit apoptosis upon CD95 activation. The caspase-8-binding protein FLICE-associated huge protein (FLASH) has been previously implicated in the regulation of caspase-8 activation at the DISC. However, recent findings demonstrated that FLASH is a Cajal body component and regulates progression through S-phase of the cell cycle in the nucleus. Our recent work identified FLASH as binding partner of the PML nuclear body (PML NB) constituent Sp100 and demonstrated that FLASH partially localizes to PML NBs. Upon CD95 activation FLASH exits the nucleus and translocates to mitochondria where it meets caspase-8 to promote its activation. Our findings reconcile conflicting views on FLASH localization and its role in apoptosis regulation, and suggest that CD95 signals via a nuclear pathway. Potential implications of our findings for understanding FLASH function are discussed.     

Encoding Olfactory Signals via Multiple Chemosensory Systems

ABSTRACT

Most animals have evolved multiple olfactory systems to detect general odors as well as social cues. The sophistication and interaction of these systems permit precise detection of food, danger, and mates, all crucial elements for survival. In most mammals, the nose contains two well described chemosensory apparatuses (the main olfactory epithelium and the vomeronasal organ), each of which comprises several subtypes of sensory neurons expressing distinct receptors and signal transduction machineries. In many species (e.g., rodents), the nasal cavity also includes two spatially segregated clusters of neurons forming the septal organ of Masera and the Grueneberg ganglion. Results of recent studies suggest that these chemosensory systems perceive diverse but overlapping olfactory cues and that some neurons may even detect the pressure changes carried by the airflow. This review provides an update on how chemosensory neurons transduce chemical (and possibly mechanical) stimuli into electrical signals, and what information each system brings into the brain. Future investigation will focus on the specific ligands that each system detects with a behavioral context and the processing networks that each system involves in the brain. Such studies will lead to a better understanding of how the multiple olfactory systems, acting in concert, offer a complete representation of the chemical world.     

Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome,a RAS/MAPK Pathway Syndrome

RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.     

The Robustness of Proofreading to Crowding-Induced Pseudo-Processivity in the MAPK Pathway

Double phosphorylation of protein kinases is a common feature of signaling cascades. This motif may reduce cross-talk between signaling pathways because the second phosphorylation site allows for proofreading, especially when phosphorylation is distributive rather than processive. Recent studies suggest that phosphorylation can be pseudo-processive in the crowded cellular environment, since rebinding after the first phosphorylation is enhanced by slow diffusion. Here, we use a simple model with unsaturated reactants to show that specificity for one substrate over another drops as rebinding increases and pseudo-processive behavior becomes possible. However, this loss of specificity with increased rebinding is typically also observed if two distinct enzyme species are required for phosphorylation, i.e., when the system is necessarily distributive. Thus the loss of specificity is due to an intrinsic reduction in selectivity with increased rebinding, which benefits inefficient reactions, rather than pseudo-processivity itself. We also show that proofreading can remain effective when the intended signaling pathway exhibits high levels of rebinding-induced pseudo-processivity, unlike other proposed advantages of the dual phosphorylation motif.     

Signals Regulating Multiple Responses to Wounding and Herbivores

Damage inflicted by herbivore feeding necessitates multiple defense strategies in plants. The wound site must be sealed and defense responses mounted against the herbivore itself and against invading opportunistic pathogens. These defenses are controlled both in time and space by highly complex regulatory networks that themselves are modulated by interactions with other signaling pathways. In this review, we describe the signaling events that occur in individual wounded leaves, in systemic unwounded regions of the plant, and between the plant, and other organisms, and attempt to place these events in the context of a coordinated system. Key signals that are discussed include ion fluxes, active oxygen species, protein phosphorylation cascades, the plant hormones jasmonic acid, ethylene, abscisic acid and salicylic acid, peptide signals, glycans, volatile chemicals, and physical signals such as hydraulic and electrical signals. Themes that emerge after consideration of the published data are that glycans and peptide elicitors are likely primary triggers of wound-induced defense responses and that they function through the action of jasmonic acid, a central mediator of defense gene expression, whose effect is modulated by ethylene. In the field, wound signaling pathways are significantly impacted on by other stress response pathways, including pathogen responses that often operate through potentially antagonistic signals such as salicylic acid. However, gross generalisations are not possible because some wound and pathogen responses operate through common jasmonate- and ethylene-dependent pathways. Understanding the ways in which local and systemic wound signaling pathways are coordinated individually and in the context of the plants wider environment is a key challenge in the application of this science to crop-protection strategies.     

Soluble Signals from Cells Identified at the Cell Wall Establish a Developmental Pathway in Carrot

Cells in a plant differentiate according to their positions and use cell-cell communication to assess these positions. Similarly, single cells in suspension cultures can develop into somatic embryos, and cell-cell communication is thought to control this process. The monoclonal antibody JIM8 labels an epitope on cells in specific positions in plants. JIM8 also labels certain cells in carrot embryogenic suspension cultures. We have used JIM8 and secondary antibodies coupled to paramagnetic beads to label and immunomagnetically sort single cells in a carrot embryogenic suspension culture into pure populations. Cells in the JIM8(+) population develop into somatic embryos, whereas cells in the JIM8(-) population do not form somatic embryos. However, certain cells in JIM8(+) cultures (state B cells) undergo asymmetric divisions, resulting in daughter cells (state C cells) that do not label with JIM8 and that sort to JIM8(-) cultures. State C cells are competent to form somatic embryos, and we show here that a conditioned growth medium from a culture of JIM8(+) cells allows state C cells in a JIM8(-) culture to go on and develop into somatic embryos. JIM8 labels cells in suspension cultures at the cell wall. Therefore, a cell with a role in cell-cell communication and early cell fate selection can be identified by an epitope in its cell wall.