Yasuko Kitagishi

Roles of PI3K/AKT/GSK3/mTOR Pathway in Cell Signaling of Mental Illnesses

Several pharmacological agents acting on monoamine neurotransmission are used for the management of mental illnesses. Regulation of PI3K/AKT and GSK3 pathways may constitute an important signaling center in the subcellular integration of the synaptic neurotransmission. The pathways also modulate neuronal cell proliferation, migration, and plasticity. There are evidences to suggest that inflammation of neuron contributes to the pathology of depression. Inflammatory activation of neuron contributes to the loss of glial elements, which are consistent with pathological findings characterizing the depression. A mechanism of anti-inflammatory reactions from antidepressant medications has been found to be associated with an enhancement of heme oxygenase-1 expression. This induction in brain is also important in neuroprotection and neuroplasticity. As enzymes involved in cell survival and neuroplasticity are relevant to neurotrophic factor dysregulation, the PI3K/AKT/GSK3 may provide an important signaling for the neuroprotection in depression. In this paper, we summarize advances on the involvement of the PI3K/AKT/GSK3 pathways in cell signaling of neuronal cells in mental illnesses.

Alternative splicings on p53, BRCA1 and PTEN genes involved in breast cancer.

Alternative splicing is a major contributor to transcriptome and proteome diversity, which can lead to the deregulation of crucial cellular processes and have been associated with a variety of human diseases including cancer. As p53, BRCA1, and PTEN proteins have a key role in preventing breast cancer formation, cancer-associated splicing variants of these tumor suppressor genes are potential molecular markers and may contribute to the development of diagnostic and prognostic methods. In the present review, we summarize these tumor suppressor genes at a viewpoint of alternative splicing involved in breast cancer.

Roles for PI3K/AKT/PTEN Pathway in Cell Signaling of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome, which represents a range of fatty liver diseases associated with an increased risk of type 2 diabetes. Molecular mechanisms underlying how to make transition from simple fatty liver to nonalcoholic steatohepatitis (NASH) are not well understood. However, accumulating evidence indicates that deregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in hepatocytes is a common molecular event associated with metabolic dysfunctions including obesity, metabolic syndrome, and the NAFLD. A tumor suppressor PTEN negatively regulates the PI3K/AKT pathways through its lipid phosphatase activity. Molecular studies in the NAFLD support a key role for PTEN in hepatic insulin sensitivity and the development of steatosis, steatohepatitis, and fibrosis. We review recent studies on the features of the PTEN and the PI3K/AKT pathway and discuss the protein functions in the signaling pathways involved in the NAFLD. The molecular mechanisms contributing to the diseases are the subject of considerable investigation, as a better understanding of the pathogenesis will lead to novel therapies for a condition.

Dietary regulation of PI3K/ AKT /GSK-3β pathway in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by the formation of senile plaques and neurofibrillary tangles composed of phosphorylated Tau. Several findings suggest that correcting signal dysregulation for Tau phosphorylation in AD may offer a potential therapeutic approach. The PI3K/AKT/GSK-3β pathway has been shown to play a pivotal role in neuroprotection, enhancing cell survival by stimulating cell proliferation and inhibiting apoptosis. This pathway appears to be crucial in AD because it promotes protein hyper-phosphorylation in Tau. Understanding those regulations may provide a better efficacy of new therapeutic approaches. In this review, we summarize advances in the involvement of the PI3K/AKT/GSK-3β pathways in cell signaling of neuronal cells. We also review recent studies on the features of several diets and the signaling pathway involved in AD.

PI3K/AKT/PTEN Signaling as a Molecular Target in Leukemia Angiogenesis

PI3K/AKT/PTEN pathway is important in the regulation of angiogenesis mediated by vascular endothelial growth factor in many tumors including leukemia. The signaling pathway is activated in leukemia patients as well as leukemia cell lines together with a decrease in the expression of PTEN gene. The mechanism by which the signaling pathway regulates angiogenesis remains to be further elucidated. However, it has become an attractive target for drug therapy against leukemia, because angiogenesis is a key process in malignant cell growth. In this paper, we will focus on the roles and mechanisms of PI3K/AKT/PTEN pathway in regulating angiogenesis.

Link between PI3K/AKT/PTEN Pathway and NOX Proteinin Diseases

Accumulating evidence has revealed that thePI3K/AKT/PTENpathway acts as a pivotal determinant of cell fate regarding senescence and apoptosis, which is mediated by intracellular reactive oxygen species (ROS) generation. NADPH oxidase (NOX) family of enzymes generates the ROS. The regulation of NOX enzymes is complex, with many members of this family exhibiting complexity in terms of subunit composition, cellular location, and tissue-specific expression. Cells are continuously exposed to the ROS, which represent mutagens and are thought to be a major contributor to several diseases including cancer and aging process. Therefore, cellular ROS sensing and metabolism are firmly regulated by a variety of proteins involved in the redox mechanism. In this review, the roles of oxidative stress in PI3K/AKT/PTEN signaling are summarized with a focus on the links between the pathways and NOX protein in several diseases including cancer and aging.

Roles of PI3K/AKT/PTEN Pathway as a Target for Pharmaceutical Therapy

Multiple enzymes participate in the phosphorylation of a group of phosphoinositide lipids. Because of their important role in signal transduction, the dysregulated metabolism of phosphoinositides represents a key step in many disease settings. Loss of their function has been demonstrated to occur as an early event a wide variety of carcinogenesis and has therefore been suggested as a biomarker for the premalignant disease. In addition, genetic alterations at multiple nodes in the pathway have been implicated in several other diseases. Accordingly, given this pervasive involvement in many diseases, the development of molecules that modulates this pathway has been initiated in studies. They have been the focus of extensive research and drug discovery activities. A better understanding of the molecular connections could uncover new targets for drug development.

Function and Characteristics of PINK1 in Mitochondria

Mutations in phosphatase and tensin homologue-induced kinase 1 (PINK1) cause recessively inherited Parkinsons disease, a neurodegenerative disorder linked to mitochondrial dysfunction. Studies support the notion of neuroprotective roles for the PINK1, as it protects cells from damage-mediated mitochondrial dysfunction, oxidative stress, and cell apoptosis. PARL is a mitochondrial resident rhomboid serine protease, and it has been reported to mediate the cleavage of the PINK1. Interestingly, impaired mitophagy, an important autophagic quality control mechanism that clears the cells of damaged mitochondria, may also be an underlying mechanism of disease pathogenesis in patients for Parkinsons disease with the PARL mutations. Functional studies have revealed that PINK1 recruits Parkin to mitochondria to initiate the mitophagy. PINK1 is posttranslationally processed, whose level is definitely regulated in healthy steady state of mitochondria. As a consequence, PINK1 plays a pivotal role in mitochondrial healthy homeostasis.

The tumor suppressor PTEN interacts with p53 in hereditary cancer (Review).

Numerous hereditary syndromes caused by mutations in multiple tumor suppressor genes can cause cancers. Germline mutations in PTEN and p53 tumor suppressor cause Cowden syndrome and Li-Fraumeni syndrome, respectively. There exists some phenotypic overlap in these syndromes, and they are associated with high risks of breast cancer. The tumor suppressor protein PTEN is a dual-specificity phosphatase which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream targets. PTEN gene is recognized as one of the most frequently mutated or mutated in many human cancers. Li-Fraumeni syndrome results from germline mutations of the tumor suppressor p53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. The p53 protein cooperates with PTEN and might be an essential blockage in development of mammary tumors. Many findings have demonstrated that PTEN as well as p53 plays a critical role in DNA damage response. This review summarizes the function of PTEN and p53 in carcinogenic cell signaling. In addition, we will discuss the role of PTEN signaling through its interaction with p53 and MDM2 pathways for the potential implications in hereditary cancer prevention and therapeutic intervention.

Functions and characteristics of PINK1 and Parkin in cancer.

Most of the Parkinson disease (PD) linked genes are also associated with cancers. In particular, phosphatase and tensin homologue-induced kinase 1 (PINK1) and Parkin, both of which are involved in recessively inherited familial forms of PD linked to mitochondrial dysfunction, appear to be abnormally expressed in cancers. Functional studies have revealed that PINK1 recruits Parkin to mitochondria to initiate mitophagy, an important autophagic quality control mechanism that rids the cell of damaged mitochondria. Although PD and cancer are obviously disparate human disorders, there is an evidence for low cancer rates in patients with PD. The relationship between cancer rates and PD might be related to the involvement of common pathways in both diseases. This paper provides a concise overview on the cellular functions of the PINK1 and Parkin.