Catálogo de publicaciones - libros

Reactive oxygen species (ROS) are an intricate part of normal cellular physiology. In excess, however, ROS can damage all three major classes of macromolecules and compromise cell viability. We briefly discuss the physiology of ROS but focus on the mechanisms cells use to preserve redox homeostasis upon oxidative stress, with particular emphasis on glycolysis. ROS inhibits multiple glycolytic enzymes, including glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase M2, and phosphofructokinase-1. Consistently, glycolytic inhibition promotes flux into the oxidative arm of the pentose phosphate pathway to generate NADPH. NADPH is critically important, as it provides the reducing power that fuels the protein-based antioxidant systems and recycles oxidized glutathione. The unique ability of pyruvate kinase M2 inhibition to promote serine synthesis in the context of oxidative stress is also discussed.

Nuclear receptors (NRs) are a large family of ligand-dependent transcriptional regulators that control development, reproduction, metabolism, and inflammation. Cognate ligands include fatty acids, bile acids, steroids, vitamins A and D, and thyroid hormone, which enable NRs to sense lipophilic nutrients levels and control their respective flux and metabolism. While major metabolic outputs of some individual receptors are well studied, an integrated understanding of their contributions to systemic metabolic homeostasis is just starting to be revealed. In this chapter, we summarize recent advances in NR signaling in metabolism, with a focus on the emerging paradigm that positions NRs as hubs that translate environmental signals of a particular physiological state into daily metabolic rhythms. As NRs are a proven class of therapeutic targets, these novel findings provide insight into therapeutics for the metabolic syndrome.

Cancer will not be cured until we understand and target the unique alterations that distinguish tumor cells from normal cells. This chapter briefly describes four new approaches to anticancer therapy based on boosting the immune system’s response to tumor cells, countering the metabolic adaptations that allow tumor cells to thrive under conditions that kill normal cells, manipulating the increased oxidative stress associated with the tumor environment, and exploiting the aneuploidy characteristic of many advanced tumor cells. The long-term goal is to devise biomarkers and novel therapeutic agents able to more effectively fight aggressive cancers.

NF-κB is a transcription factor known to be involved in pleomorphic biological phenomena such as inflammation and immune responses. Abnormal activation of NF-κB has been reported in many pathological conditions, including malignant tumors. Therefore, the NF-κB activation pathway has been extensively studied and involvement of the ubiquitin conjugation system in the NF-κB activation pathways has been revealed. Although the ubiquitin conjugation system was discovered as a part of a protein degradation pathway, non-degradable roles of the ubiquitin system have been revealed recently. Several types of polyubiquitin chains exist in cells and the type of chain seems to determine how ubiquitinated proteins are regulated. We have identified that a new type of polyubiquitin chain, the linear polyubiquitin chain, plays a crucial role in regulating the NF-κB activation pathway in non-degradable manner. In this chapter, the discovery, roles in NF-κB activation, and involvement in the pathogenesis of cancers of linear ubiquitination will be discussed.

Neuroprotection would be a novel therapeutic strategy for the prevention or retardation of clinical manifestations of currently incurable eye diseases as well as neurodegenerative diseases. A decrease in cellular ATP levels may contribute to the pathologies of these diseases; therefore, stabilization of ATP levels may retard the disease progression. We created novel small compounds (Kyoto University Substances, KUSs) to inhibit the ATPase activity of VCP (valosin-containing protein), the most abundant soluble ATPase in the cell. KUSs did not apparently impair the reported cellular VCP functions. Nevertheless, they significantly suppressed the VCP-dependent decrease of cellular ATP levels. Moreover, KUSs as well as exogenous ATP or ATP-producing compounds suppressed endoplasmic reticulum (ER) stress, and indeed protected various types of cultured cells from cell death-inducing insults. We then examined the efficacies of KUSs in rd10, a mouse model of retinitis pigmentosa. KUSs not only prevented photoreceptor cell death but also preserved visual function. These results reveal an unexpected, crucial role of ATP consumption by VCP for the determination of cell fate in the pathological context, and point to a promising new neuroprotective strategy for currently incurable eye and neurodegenerative diseases.

Loss of E-cadherin function has been reported to be associated with progression and poor prognosis of liver cancer. However, the precise role of E-cadherin in liver cancer development has not been elucidated. Thus, we generated liver-specific E-cadherin () knockout mice () by crossing mice with transgenic mice. Interestingly, mice developed spontaneous inflammation in the portal areas, and then developed periductal onion skin–like fibrosis, which resembled primary sclerosing cholangitis. Microarray analysis showed that expression of stem cell markers such as CD44 and Sox9, and inflammatory cytokines such as IL-6 and TNF-α, are increased in liver compared with liver. To investigate the role of E-cadherin in the liver tumorigenesis, we crossed mice with mice (). mice developed liver tumors at age 28 weeks (8/8, 100 %), whereas mice did not develop any tumors. Histologically, these tumors were hepatocellular carcinomas with a small proportion of ductal lesions and strongly positive for progenitor cell markers such as CD44 and Sox9. Interestingly, epithelial to mesenchymal transition (EMT) was found in the tumors of mice. We also found that diethylnitrosamine-induced tumorigenesis was significantly accelerated in mice. In summary, loss of E-cadherin in the liver leads to sclerosing cholangitis and promotes tumorigenesis. Its tumor-promoting function seemed to be caused by gain of stem cell properties as well as induction of EMT.

The Hippo pathway has the unique capacity to sense tissue architecture and the external forces that shape it, and dysregulation of this pathway leads to tumorigenesis. The study of mice bearing systemic or tissue-specific mutations of Hippo elements has driven huge progress in understanding this pathway’s role in normal physiology and disease. Here, we summarize how disruption of Hippo signaling relates to cancer, and we highlight the importance of this pathway as a new drug target for malignant tumors.

Activation of immune cells is regulated by positive and negative signals triggered by activating and inhibitory cell surface immunoreceptors, respectively. Inhibitory receptors are characterized by the immunoreceptor tyrosine-based inhibition motif (ITIM) in their cytoplasmic domains and play an important role in immune regulation by both lymphoid and myeloid cells. Mast cells express the high-affinity receptor for IgE (FcεRI) and toll-like receptors (TLR) on the cell surface, and play a central role in allergic and non-allergic inflammations. We identified novel inhibitory immunoglobulin-like receptors, Allergin-1 and CD300a, which are expressed on mast cells. Allergin-1 inhibits mast cell degranulation via suppression of FcεRI-mediated signaling. Allergin-1-deficient mice showed significantly exacerbated IgE-associated type 1 immediate hypersensitivity reactions. On the other hand, CD300a recognizes phosphatidylserine exposed on the plasma membrane of apoptotic cells and inhibits production of chemoattractants from mast cells in response to LPS stimulation. CD300a-deficient mice showed significantly prolonged survival after cecum ligation and puncture (CLP). Together, our results suggest that Allergin-1 and CD300a may be candidates as molecular targets for the treatment of mast cell-dependent inflammatory diseases.

Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. BP autoantibodies target two hemidesmosomal components, collagen XVII (COL17) and BP230, with autoimmunity to COL17 being mainly involved in the development of the disease. BP most commonly affects the elderly, and systemic corticosteroids are widely used to treat blisters on the entire body. Therefore, severe cases are sometimes fatal. Toward developing innovative, disease-specific therapies with fewer adverse effects, faithful disease models are essential. However, it has been challenging to reproduce BP in animals, because of inter-species differences in the amino acid sequences of pathological epitopes on human and mouse COL17. Human IgG autoantibodies from BP patients are unable to bind with mouse COL17; thus, the passive transfer of BP-IgG into mice fails to induce blistering disease. To overcome inter-species differences, we have generated genetically modified mice that express human but not mouse COL17 in skin. We call these “COL17-humanized mice”. Using these mice, we have produced different BP models to elucidate the BP pathomechanism and to produce novel BP therapies. Currently, another novel model is under development. Here, we introduce the BP models that we have developed by using a novel technique called “humanization of autoantigen”.

Immune aging results in a decreased competence of adaptive immunity with an increased risk for autoimmunity. However, the mechanistic links between the immune aging and autoimmunity remain elusive. We reported that a PD-1 memory phenotype (MP) CD4 T cell population is increased as normal mice age, termed senescence-associated (SA-) T cells. The SA-T cells show characteristic signs and features of cellular senescence and emerge as follicular T cells in spontaneous germinal centers (GCs) that occur in aged mice. Spontaneous development of GCs is a hallmark of systemic autoimmune diseases, and we found that the development of SA-T cells is robustly and prematurely accelerated in bona fide lupus-prone mice in association with spontaneous, auto-reactive GCs. A fraction of the SA-T cells defined by CD153 expression is activated by autologous GC B cells to produce a plethora of inflammatory factors in a TCR-dependent manner and contributes to the expansion of the GC reactions, although the remaining part of them is rendered TCR anergic in situ. The results uncover that accelerated T cell senescence underlies the development of autoimmunity in systemic lupus erythematosus.