Pathophysiological roles of ASK1-MAP kinase signaling pathways

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogenactivated protein kinase (MAPK) kinase kinase that activates JNK and p38 kinases. ASK1 is activated by various stresses, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, lipopolysaccharide (LPS) and calcium influx which are thought to be responsible for the pathogenesis or exacerbations of various human diseases. Recent studies revealed the involvement of ASK1 in ROS- or ER stressrelated diseases, suggesting that ASK1 may be a potential therapeutic target of various human diseases. In this review, we focus on the current findings for the relationship between pathogenesis and ASK1-MAPK pathways.     

The ASK1-MAP kinase pathways in immune and stress responses

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase which plays pivotal roles in stress and immune responses. This review is focused on three major subjects on ASK1: the regulatory mechanisms of the kinase activity, the pathophysiological roles in stress response and innate immunity, and the evolutionary perspectives.     

Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling

The intracellular redox state is a key determinant of cell fate, such as cell survival, proliferation, differentiation, and apoptosis. Redox imbalance is closely linked to a variety of human diseases, so that the intracellular redox condition should be tightly regulated. The redox state of the cell is a consequence of the precise balance between the levels of oxidizing and reducing equivalents, such as reactive oxygen species (ROS) and endogenous antioxidants. ROS are not only toxicants to the cell, but also second messengers in intracellular signal transduction, and control the action of several signaling pathways, including mitogen-activated protein (MAP) kinases. Apoptosis signal-regulating kinase 1 (ASK1) is a MAP kinase kinase kinase of the c-Jun N-terminal kinase (JNK) and p38 MAP kinase pathways, which is preferentially activated in response to various types of stress such as oxidative stress and plays pivotal roles in a wide variety of cellular responses. Recent studies have revealed that ASK1 is also required for innate immune response through ROS production. In this review, we focus on redox control of cell function by MAP kinase signaling, and provide the advanced mechanism of redox-regulated ASK1 activation and physiological roles of the ASK1-MAP kinase pathway in stress signaling.     

ER stress and neurodegenerative diseases

Endoplasmic reticulum (ER) stress is caused by disturbances in the structure and function of the ER with the accumulation of misfolded proteins and alterations in the calcium homeostasis. The ER response is characterized by changes in specific proteins, causing translational attenuation, induction of ER chaperones and degradation of misfolded proteins. In case of prolonged or aggravated ER stress, cellular signals leading to cell death are activated. ER stress has been suggested to be involved in some human neuronal diseases, such as Parkinson's disease, Alzheimer's and prion disease, as well as other disorders. The exact contributions to and casual effects of ER stress in the various disease processes, however, are not known. Here we will discuss the possible role of ER stress in neurodegenerative diseases, and highlight current knowledge in this field that may reveal novel insight into disease mechanisms and help to design better therapies for these disorders.     

Iron and ER stress in neurodegenerative disease

Neurodegenerative disease is a condition in which subpopulations of neuronal cells of the brain and spinal cord are selectively lost. A common event in many neurodegenerative diseases is the increased level of endoplasmic reticulum (ER) stress caused by accumulation and deposits of inclusion bodies that contain abnormal aggregated proteins. However, the basis of how ER stress contributes to the selective neuronal vulnerability and degeneration remain elusive. Iron accumulation in the central nerve system is consistently present in many neurodegenerative diseases. In the past 5?years we have begun to show a relationship between polymorphisms in the HFE (high iron) gene and the risk of neurodegenerative disorders. Recent findings have suggested a connection between ER stress and iron metabolism and neurodegeneration. Here we review how the different levels of chronic ER stress contribute to the different fates of neurons, namely the adaptive response and neuronal death. And, we discuss the roles of iron and HFE genotype in selective neuronal vulnerability and degeneration through modifying the ER stress level.     

Protein folding stress in neurodegenerative diseases: a glimpse into the ER

Several neurodegenerative diseases share common neuropathology, primarily featuring the presence in the brain of abnormal protein inclusions containing specific misfolded proteins. Recent evidence indicates that alteration in organelle function is a common pathological feature of protein misfolding disorders, highlighting perturbations in the homeostasis of the endoplasmic reticulum (ER). Signs of ER stress have been detected in most experimental models of neurological disorders and more recently in brain samples from human patients with neurodegenerative disease. To cope with ER stress, cells activate an integrated signaling response termed the unfolded protein response (UPR), which aims to reestablish homeostasis in part through regulation of genes involved in protein folding, quality control and degradation pathways. Here we discuss the particular mechanisms currently proposed to be involved in the generation of protein folding stress in different neurodegenerative conditions and speculate about possible therapeutic interventions.     

ER stress and diseases

Proteins synthesized in the endoplasmic reticulum (ER) are properly folded with the assistance of ER chaperones. Malfolded proteins are disposed of by ER-associated protein degradation (ERAD). When the amount of unfolded protein exceeds the folding capacity of the ER, human cells activate a defense mechanism called the ER stress response, which induces expression of ER chaperones and ERAD components and transiently attenuates protein synthesis to decrease the burden on the ER. It has been revealed that three independent response pathways separately regulate induction of the expression of chaperones, ERAD components, and translational attenuation. A malfunction of the ER stress response caused by aging, genetic mutations, or environmental factors can result in various diseases such as diabetes, inflammation, and neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and bipolar disorder, which are collectively known as 'conformational diseases'. In this review, I will summarize recent progress in this field. Molecules that regulate the ER stress response would be potential candidates for drug targets in various conformational diseases.     

The roles of ASK family proteins in stress responses and diseases

The aim of palliative chemotherapy is to increase survival whilst maintaining maximum quality of life for the individual concerned. Although we are still continuing to explore the optimum use of traditional chemotherapy agents, the introduction of targeted therapies has significantly broadened the therapeutic options. Interestingly, the results from current trials put the underlying biological concept often into a new, less favorable perspective. Recent data suggested that altered pathways underlie cancer, and not just altered genes. Thus, an effective therapeutic agent will sometimes have to target downstream parts of a signaling pathway or physiological effects rather than individual genes. In addition, over the past few years increasing evidence has suggested that solid tumors represent a very heterogeneous group of cells with different susceptibility to cancer therapy. Thus, since therapeutic concepts and pathophysiological understanding are continuously evolving a combination of current concepts in tumor therapy and tumor biology is needed. This review aims to present current problems of cancer therapy by highlighting exemplary results from recent clinical trials with colorectal and pancreatic cancer patients and to discuss the current understanding of the underlying reasons.     

Melatonin oxidative stress and neurodegenerative diseases

Oxidative Stress is implicated as one of the primary factors that contribute to the development of neurodegenerative diseases like Alzheimer's Disease, Parkinsonism and neurological conditions like epileptic seizures, stroke, brain damage, neurotrauma etc. The increased formation and release of oxygen free radicals coupled with the rather low antioxidative potential of the central nervous system are the major reasons that account for the enhanced oxidative stress seen in neuronal cells. In addition to this, brain is also enriched with polyunsaturated fatty acids that render neuronal cells easily vulnerable to oxidative attack. The fact that there is increased incidence of neurodegenerative disorders in aged individuals, has prompted many investigators to search for a common factor whose progressive decline with increase in age could account for increased oxidative stress resulting in senescence and age associated degenerative diseases. Since melatonin, the hormone secreted from the pineal gland has a remarkable anti-oxidant property and whose rate of production declines with increase in age, has prompted many to suggest that this hormone plays a crucial role in the genesis of neurodegenerative diseases. Melatonin cannot only scavenges oxygen free radicals like super oxide radical (O2-), hydroxyl radical (*OH), peroxyl radical (LOO*) and peroxynitrite anion (ONOO-), but can also enhance the antioxidative potential of the cell by stimulating the synthesis of antioxidative enzymes like super oxide dismutase (SOD), glutathione peroxidase (GPX), and also the enzymes that are involved in the synthesis of glutathione. In many instances, melatonin increases the expression of m RNA's of the antioxidative enzymes. Melatonin administration has been shown to be effective in counteracting the neurodegenerative conditions both in experimental models of neurodegenerative diseases and in patients suffering from such diseases. A disturbance of melatonin rhythm and secretion also has been noted in patients suffering from certain neurodegenerative diseases. From all these, it is evident that melatonin has a neuroprotective role.     

Calcium signaling and molecular mechanisms underlying neurodegenerative diseases

Calcium (Ca²⁺) is a ubiquitous second messenger that regulates various activities in eukaryotic cells. Especially important role calcium plays in excitable cells. Neurons require extremely precise spatial-temporal control of calcium-dependent processes because they regulate such vital functions as synaptic plasticity. Recent evidence indicates that neuronal calcium signaling is abnormal in many of neurodegenerative disorders such as Alzheimer’s disease (AD), Huntington’s disease (HD) and Parkinson’s disease (PD). These diseases represent a major medical, social, financial and scientific problem, but despite enormous research efforts, they are still incurable and only symptomatic relief drugs are available. Thus, new approaches and targets are needed. This review highlight neuronal calcium-signaling abnormalities in these diseases, with particular emphasis on the role of neuronal store-operated Ca²⁺ entry (SOCE) pathway and its potential relevance as a therapeutic target for treatment of neurodegeneration.     

Heteromeric complex formation of ASK2 and ASK1 regulates stress-induced signaling

Apoptosis signal-regulating kinase 2 (ASK2) is an interaction partner of the highly related ASK1. Here, we describe a regulatory function of ASK2 in stress signaling-induced cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Increased cleavage of caspase-3 and PARP was demonstrated by overexpression as well as knockdown of ASK2 after stress-induction by serum-starvation. We show that ectopically expressed ASK2 homo-oligomerized while endogenous ASK2 and ASK1 formed hetero-oligomers, which decreased upon serum-starvation. Co-expression of ASK2 and ASK1 stabilized these two proteins and reduced starvation-induced caspase-3 activation and degradation of PARP. Analysis of the intracellular localization of ASK2 exhibited a similar localization compared with ASK1 in the nucleus, cytoplasm, and in mitochondria. We propose that ASK2 regulates stress-induced caspase-3 and PARP cleavage in a dose-dependent manner by heteromeric complex formation with ASK1.     

SIRT1与神经变性疾病

SIRT1(silent mating type information regulation2homolog1)是Sirtuins脱乙酰基酶家族中的一员,是酵母沉默信息调节因子SIR2(silence information regulator)的同源物,因其能在许多生物体模型中作为寿命延长调节子调控细胞生命周期而受到特别关注。SIRT1蛋白存在于哺乳动物细胞质和细胞核中,是老化相关蛋白。SIRT1作用于基因转录因子能加强基因组的稳定性。神经系统发生变性疾病时SIRT1表达量上调,起到一定的神经保护作用。但有实验验证神经元损伤SIRT1过表达导致记忆缺失,并没有起到神经保护作用。SIRT1诱导剂,可以是Sirtuin的激动剂也可以是能量限制状态。目前在生命科学领域里SIRT1已经凸显其科学价值地位,该文就SIRT1及其与神经变性疾病之间的关系做一综述。     

Tumor necrosis factor receptor 2 signaling induces selective c-IAP1-dependent ASK1 ubiquitination and terminates mitogen-activated protein kinase signaling

TRAF2 and ASK1 play essential roles in tumor necrosis factor alpha (TNF-alpha)-induced mitogen-activated protein kinase signaling. Stimulation through TNF receptor 2 (TNFR2) leads to TRAF2 ubiquitination and subsequent proteasomal degradation. Here we show that TNFR2 signaling also leads to selective ASK1 ubiquitination and degradation in proteasomes. c-IAP1 was identified as the ubiquitin protein ligase for ASK1 ubiquitination, and studies with primary B cells from c-IAP1 knock-out animals revealed that c-IAP1 is required for TNFR2-induced TRAF2 and ASK1 degradation. Moreover, in the absence of c-IAP1 TNFR2-mediated p38 and JNK activation was prolonged. Thus, the ubiquitin protein ligase activity of c-IAP1 is responsible for regulating the duration of TNF signaling in primary cells expressing TNFR2.     

Cdk5: a multifaceted kinase in neurodegenerative diseases

Since the identification of cyclin-dependent kinase-5 (Cdk5) as a tau kinase and member of the Cdk family almost 20 years ago, deregulation of Cdk5 activity has been linked to an array of neurodegenerative diseases. As knowledge on the etiopathological mechanisms of these diseases evolved through the years, Cdk5 has also been implicated in additional cellular events that are affected under these pathological conditions. From the role of Cdk5 in the regulation of synaptic functions to its involvement in autophagy deregulation, significant insights have been obtained regarding the role of Cdk5 as a key regulator of neurodegeneration. Here, we summarize recent findings on the involvement of Cdk5 in the pathophysiological mechanisms underlying various neurodegenerative diseases.