Contribution of receptor/G protein signaling to cell growth and transformation

While the effects of receptor/G protein systems on intermediary metabolism have been intensively studied, it has only recently been appreciated that G protein-coupled receptors and G proteins (heterotrimeric GTP-binding proteins) play important roles in the regulation of cell growth, differentiation and even transformation. Naturally occurring mutations both in G protein-coupled receptors and in G protein alpha-subunits lead to autonomous cell growth resulting in human disease. One mechanism to transduce mitogenic signals from the cell membrane to the nucleus is the engagement of the extracellular signal-regulated kinase (ERK)mitogen-activated protein kinase (MAPK) cascade. Multiple distinct signal transduction pathways have been characterized which link G proteins with the ERK cascade. Receptor and non-receptor tyrosine kinases play central roles in these pathways. Mitogenic signaling by receptor/G protein systems is realized as a complex interplay between signals emanating from different classes of cell surface receptors. The characterization of receptor-, G protein- and tyrosine kinase-specific contributions to mitogenic signaling in a particular cell may ultimately allow for the rational design and application of pharmaceuticals to treat diseases involving uncontrolled cell proliferation.     

Ras as a therapeutic target in hematologic malignancies

The RAS gene product is normally a membrane-localized G protein (N-Ras, K-Ras and H-Ras) of 21 kDa classically described as a molecular off/on switch. It is inactive when bound to guanosine diphosphate and active when bound to GTP. When mutated, the gene produces an abnormal protein resistant to GTP hydrolysis by GTPase, resulting in a constitutively active GTP-bound protein that stimulates a critical network of signal transduction pathways that lead to cellular proliferation, survival and differentiation. At least three downstream effector pathways have been described, including Raf/MEK/ERK, PI3K/AKT and RalGDS, but they are not completely understood. Ras pathways are also important downstream effectors of several receptor tyrosine kinases localized in the cell membrane, most notably the BCR-ABL fusion protein seen in patients with Philadelphia chromosome positive chronic myelogenous leukemia. An important consideration in designing strategies to block Ras stimulatory effect is that Ras proteins are synthesized in the cytosol, but require post-translational modifications and attachment to anchor proteins or membrane binding sites in the cell membrane to be biologically active. Farnesyl transferase inhibitors (FTIs) are probably the best-studied class of Ras inhibitors in hematologic malignancies. They block the enzyme farnesyl-transferase (FTase), which is essential for post-translational modification. However, it has been observed that the Ras proteins also can be geranylgeranylated in the presence of FTIs, thus allowing membrane localization and activation, which limits their effectiveness. It is now hypothesized that their mechanism of action may be through FTase inhibition involving other signal transduction pathways. S-trans, trans-farnesylthiosalicylic acid, which was first designed as a prenylated protein methyltransferase inhibitor, has shown in vitro activity against all activated Ras proteins by dislodging them from their membrane-anchoring sites. Here, Ras biology, its signaling pathways and its implications as a therapeutic target in hematologic malignancies are reviewed.     

Ras as a therapeutic target in hematologic malignancies

The RAS gene product is normally a membrane-localized G protein (N-Ras, K-Ras and H-Ras) of 21 kDa classically described as a molecular off/on switch. It is inactive when bound to guanosine diphosphate and active when bound to GTP. When mutated, the gene produces an abnormal protein resistant to GTP hydrolysis by GTPase, resulting in a constitutively active GTP-bound protein that stimulates a critical network of signal transduction pathways that lead to cellular proliferation, survival and differentiation. At least three downstream effector pathways have been described, including Raf/MEK/ERK, PI3K/AKT and RalGDS, but they are not completely understood. Ras pathways are also important downstream effectors of several receptor tyrosine kinases localized in the cell membrane, most notably the BCR-ABL fusion protein seen in patients with Philadelphia chromosome positive chronic myelogenous leukemia. An important consideration in designing strategies to block Ras stimulatory effect is that Ras proteins are synthesized in the cytosol, but require post-translational modifications and attachment to anchor proteins or membrane binding sites in the cell membrane to be biologically active. Farnesyl transferase inhibitors (FTIs) are probably the best-studied class of Ras inhibitors in hematologic malignancies. They block the enzyme farnesyl-transferase (FTase), which is essential for post-translational modification. However, it has been observed that the Ras proteins also can be geranylgeranylated in the presence of FTIs, thus allowing membrane localization and activation, which limits their effectiveness. It is now hypothesized that their mechanism of action may be through FTase inhibition involving other signal transduction pathways. S-trans, trans-farnesylthiosalicylic acid, which was first designed as a prenylated protein methyltransferase inhibitor, has shown in vitro activity against all activated Ras proteins by dislodging them from their membrane-anchoring sites. Here, Ras biology, its signaling pathways and its implications as a therapeutic target in hematologic malignancies are reviewed.     

调控P-糖蛋白介导的肿瘤多药耐药的相关信号转导通路及其临床意义

多药耐药现象最初发现于肿瘤细胞,它是导致肿瘤药物化疗失败的最主要原因之一。在药物转运系统中,细胞膜上的外排转运体P-糖蛋白是外排细胞内药物从而导致肿瘤细胞多药耐药的最主要转运体之一。此外,某些信号转导通路参与了P-糖蛋白介导的肿瘤细胞多药耐药,例如丝裂原活化蛋白激酶信号转导通路、环核苷酸依赖性蛋白激酶信号转导途径、核因子XB信号通路、磷脂酰肌醇3激酶／蛋白激酶B信号通路和蛋白激酶c信号转导通路等等。本文对：参与调控P-糖蛋白介导肿瘤细胞多药耐药的相关信号转导通路及其临床意义进行综述。     

Therapeutic targets and biomarkers identified in cancer choline phospholipid metabolism

Choline phospholipid metabolism is altered in a wide variety of cancers. The choline metabolite profile of tumors and cancer cells is characterized by an elevation of phosphocholine and total choline-containing compounds. Noninvasive magnetic resonance spectroscopy can be used to detect this elevation as an endogenous biomarker of cancer, or as a predictive biomarker for monitoring tumor response to novel targeted therapies. The enzymes directly causing this elevation, such as choline kinase, phospholipase C and phospholipase D may provide molecular targets for anticancer therapies. Signal transduction pathways that are activated in cancers, such as those mediated by the receptor tyrosine kinases breakpoint cluster region-abelson (Bcr-Abl), c-KIT or epidermal growth factor receptor (EGFR), correlate with the alterations in choline phospholipid metabolism of cancers, and also offer molecular targets for specific anticancer therapies. This review summarizes recently discovered molecular targets in choline phospholipid metabolism and signal transduction pathways, which may lead to novel anticancer therapies potentially being monitored by magnetic resonance spectroscopy techniques.     

蛋白酪氨酸激酶信号转导途径与抗肿瘤药物

细胞信号转导(signal transduction)在细胞的代谢、分裂、分化、生物功能及死亡过程中起着重要作用，肿瘤的发生和发展与细胞信号转导过度激活有关。本文简要阐述了蛋白酪氨酸激酶(protein tyrosine kinases，PTKs)介导的信号转导途径，分别介绍了受体酪氨酸激酶介导的Ras/Raf/MAPK和PI-3K/Akt途径，非受体酪氨酸激酶介导的Src、Bcr-Abl和JAK/STAT途径。以此5条信号转导通路中参与的重要蛋白分子为靶点，统计和介绍了相关的已经上市或处于临床研究的抗肿瘤药物。     

Anticancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects

Synthetic anticancer alkylphospholipids (APLs), such as edelfosine, miltefosine and perifosine, are a group of structurally related lipids that act on cellular membranes rather than the DNA. APLs have essentially one long hydrocarbon chain that allows easy partitioning into membrane lipid bilayers, but they resist catabolic degradation. APLs therefore accumulate in cell membranes and can interfere with normal lipid metabolism and lipid-dependent signal transduction. This action, often leading to apoptosis, is most effective in metabolically active, proliferating cells, such as cancer cells, but not in quiescent normal cells. This review describes the general mechanisms of APL cellular uptake and action. Most important for their biological effect are the inhibition of phosphatidylcholine synthesis, the inhibition of the MAP-kinase/ERK proliferative and phosphatidylinositol 3-kinase/ Akt survival pathways and the stimulation of the Stress-activated protein kinase/JNK pathway, which may lead to apoptosis in cancer cells. APLs are most promising in combination with conventional cancer therapies. For example, ALPs increase the cancer cell sensitivity to radiotherapy in vitro and in vivo. We highlight the clinical potential of perifosine, an orally available APL.     

Gab2支架蛋白——新的抗癌药物靶点

接头蛋白或支架蛋白可以介导蛋白．蛋白之间的相互作用,并促进蛋白复合物的形成。Gab2作为中介分子,通过招募受体酪氨酸激酶等膜受体与其下游的效应蛋白如SHP2、P13K的p85亚基,PLCy、CRK、SHC和SHIP的结合来实现信号的传递。近年来,由于Gab2支架蛋白在信号转导过程中发挥着重要的作用,使得其在人类癌症特别是白血病、乳腺癌、卵巢癌及黑色素瘤中的角色备受关注。Gab2主要参与介导SHP2／RAS／ERK和P13K／AKT两条经典的信号通路。综述Gab2的结构与功能,调解的蛋白,在癌症中的作用以及其作为药物治疗靶点的潜力。     

Cell signaling and nuclear receptors: new opportunities for molecular pharmaceuticals in liver disease

Liver-enriched nuclear receptors (NRs) collectively function as metabolic and toxicological "sensors" that mediate liver-specific gene-activation in mammals. NR-mediated gene-environment interaction regulates important steps in the hepatic uptake, metabolism, and excretion of glucose, fatty acids, lipoproteins, cholesterol, bile acids, and xenobiotics. Hence, liver-enriched NRs play pivotal roles in the overall control of energy homeostasis in mammals. While it is well-recognized that ligand-binding is the primary mechanism behind activation of NRs, recent research reveals that multiple signal transduction pathways modulate NR-function in liver. The interface between specific signal transduction pathways and NRs helps to determine their overall responsiveness to various environmental and physiological stimuli. In general, phosphorylation of hepatic NRs regulates multiple biological parameters including their transactivation capacity, DNA binding, subcellular location, capacity to interact with protein-cofactors, and protein stability. Certain pathological conditions including inflammation, morbid obesity, hyperlipidemia, atherosclerosis, insulin resistance, and type-2 diabetes are known to modulate selected signal transduction pathways in liver. This review will focus upon recent insights regarding the molecular mechanisms that comprise the interface between disease-mediated activation of hepatic signal transduction pathways and liver-enriched NRs. This review will also highlight the exciting opportunities presented by this new knowledge to develop novel molecular and pharmaceutical strategies for combating these increasingly prevalent human diseases.     

Involvement of plasma membrane redox systems in hormone action

Reactive oxygen species (ROS) is the common name used to describe the partially reduced forms of molecular oxygen that may be generated in cells during oxidative metabolism. They are normally considered to be toxic, and cells possess various defence systems to protect themselves including antioxidant enzymes and low molecular weight antioxidants like vitamin C and vitamin E. However, it is now clear that small amounts of ROS also act as messenger molecules in cell signal transduction pathways; the plasma membrane of eukaryotic cells in particular contains a variety of different ROS-producing oxidases and reductases, of which the best characterized are the superoxide-producing NADPH oxidases. It has been known for many years that membrane redox activity can be changed rapidly by various hormones and growth factors, but the molecular mechanisms involved and the physiological importance of this phenomenon have only recently begun to be unveiled. This review summarizes the state of the art on plasma membrane-based ROS signalling in the pathways of insulin, steroid and thyroid hormones and growth factors. The apparent paradox of ROS being essential biomolecules in the regulation of cellular functions, but also toxic by-products of metabolism, may be important for the pharmacological application of natural and synthetic antioxidants.     

New paradigms in signal transduction

Signal transduction is a dynamic field in which established pathways evolve and new pathways emerge. The purpose of this commentary is to highlight new paradigms of signal transduction that have developed over the past few years. This discussion proposes a third member of the generic models of membrane receptors in addition to the 7-transmembrane pass receptor and the enzyme-linked receptor: the non-enzymatic nucleating receptor. Also discussed are the new paradigms of signal transduction by proteolysis which includes signaling by Notch, signaling through the Hedgehog and Wnt pathways, signaling through histidine phosphorylation, and reactive oxygen species in signal transduction.     

Protein tyrosine kinase inhibitors as anticancer agents

There are > 700 protein kinases and 100 protein phosphatases encoded within the human genome. By catalysing protein phosphorylation and dephosphorylation, they play a pivotal role in intracellular signalling and in the regulation of signal transduction pathways. Activation of oncogenes coding for such proteins can lead to the production of kinases that are continually active in the absence of a normal stimulus, leading to increased cell proliferation and/or decreased apoptosis. Receptor and non-receptor protein tyrosine kinases (PTKs) are essential enzymes in cellular signalling processes that regulate cell growth, differentiation, migration and metabolism. Their inhibition by specific inhibitors was recently shown to constitute a new modality for cancer treatment. A patent literature review comprising the years 2000 – 2003 is presented here, as the major drug houses are currently involved in the design and development of novel types of such compounds with applications as antitumour agents.     

Advance research in apoptosis mediating by death receptor

Apoptosis is one of the main types of programmed cell deaths(PCD)and involves a series of biochemical events that lead to a variety of morphological changes and death.The initial and progress of apoptosis is precisely regulated.This review will summarize current knowledge of the signal transduction pathways of apoptosis.It is now well-established that the apoptotic signals generally involve the extrinsic or intrinsic pathways of apoptosis.The extrinsic pathway originates at the membrane and engages cell surface death receptors whereas the intrinsic pathway predominantly involves mitochondria.In the intrinsic pathway,the cell death signal induced changes of mitochondrial membrane permeability and the loss of membrane potential.Many proteins factors released,and then cytoplasmic cytochrome C and caspase-9 form of apoptosis.The activated caspase-9 cut caspase-3,then cell dead at last.In the case of extrinsic pathway,several death receptors exist including Fas,TNFR-1,DR3,DR4,DR5 and DR6.These death receptors contain an intracellular region of approximately 80 amino acids that is designated as "death domain".The death domain is an important structure that plays a key role in the transduction of apoptotic signals.The interaction between Fas and its ligand(FasL)triggers the formation of a death-inducing signaling complex(DISC),which subsequently recruits and activates caspase-8;this in turn activates other procaspases and culminates in the cleavage of cellular substrates and apoptosis.During the process of tumor cell lines apoptosis Inducted by chemotherapy.It is easy to see the increasing of the Fas receptors and inducing of FasL expression,it can inhibite apoptosis when the blocking Fas /FasL.Tumor necrosis factor(TNF)-related apoptosis-inducing ligand(TRAIL)is a type II transmembrane protein belonging to the TNF family of death ligands.TRAIL has been suggested as a safe and tumorselective anticancer agent with low toxicity to normal tissues,and is thought to play a role in tumor immune surveillance by NK,T cells and probably also cells of the innate immune system.The interaction between TNF and its ligand(TRAIL)recruits and activates caspases,TRAIL transmitting the signals through FADD,the probable mechanism is that:activated TRAIL combined with FADD through mutual recognition of Death domain,FADD combined MACH/FLICE(caspase-8),and then activates ICE/CED3 of caspase-8 and other proteins.The vast majority of cancer chemotherapy drug,mainly play a role through mitochondria-induced apoptosis pathway.TRAIL-induced apoptosis rely on the activation of caspase-8 and caspase-3.The mitochondrial membrane potential was reducted and the cytochrome C was released,leading to no damage of mitochondrial integrity after DNA cracking.Caspase is a specific type of acid cysteine protease,in apoptosis directly involved in the process of implementing the early start of apoptosis,signal transduction and apoptosis of late.Caspase-8 plays a key role in the death receptor-mediated apoptosis.     

肾上腺素能受体对心肌钠钾泵的亚基特异性调节

钠钾泵是镶嵌在哺乳动物细胞膜上的一种蛋白质,在维持细胞内离子平衡、能量代谢和信号传递中都发挥着重要作用。其功能的紊乱和调节异常会引起严重的病理生理变化。肾上腺素能受体是钠钾泵的一个重要调节因子。该文即对肾上腺素能受体对心肌钠钾泵的亚基特异性调节及研究进展进行的综述。     

活性氧对蛋白激酶和基因表达调节作用的研究进展

活性氧在维持血管稳态方面有着十分重要的生理和病理生理作用。活性氧的产生和代谢失衡与多种血管性疾病有着密切的关系。近年来的研究发现 ,活性氧对信号转导通路中氧化还原敏感的蛋白激酶有调节作用 ,通过影响这些氧化还原敏感蛋白酶的活性 ,最终调节基因的表达     

Aroclor 1254, a developmental neurotoxicant, alters energy metabolism- and intracellular signaling-associated protein networks in rat cerebellum and hippocampus

The vast literature on the mode of action of polychlorinated biphenyls (PCBs) indicates that PCBs are a unique model for understanding the mechanisms of toxicity of environmental mixtures of persistent chemicals. PCBs have been shown to adversely affect psychomotor function and learning and memory in humans. Although the molecular mechanisms for PCB effects are unclear, several studies indicate that the disruption of Ca²⁺-mediated signal transduction plays significant roles in PCB-induced developmental neurotoxicity. Culminating events in signal transduction pathways include the regulation of gene and protein expression, which affects the growth and function of the nervous system. Our previous studies showed changes in gene expression related to signal transduction and neuronal growth. In this study, protein expression following developmental exposure to PCB is examined. Pregnant rats (Long Evans) were dosed with 0.0 or 6.0 mg/kg/day of Aroclor-1254 from gestation day 6 through postnatal day (PND) 21, and the cerebellum and hippocampus from PND14 animals were analyzed to determine Aroclor 1254-induced differential protein expression. Two proteins were found to be differentially expressed in the cerebellum following PCB exposure while 18 proteins were differentially expressed in the hippocampus. These proteins are related to energy metabolism in mitochondria (ATP synthase, sub unit β (ATP5B), creatine kinase, and malate dehydrogenase), calcium signaling (voltage-dependent anion-selective channel protein 1 (VDAC1) and ryanodine receptor type II (RyR2)), and growth of the nervous system (dihydropyrimidinase-related protein 4 (DPYSL4), valosin-containing protein (VCP)). Results suggest that Aroclor 1254-like persistent chemicals may alter energy metabolism and intracellular signaling, which might result in developmental neurotoxicity.