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1、.Complete List of Pathways Activation of cAMP-Dependent PKA cAMP (Cyclic Adenosine 3',5'-monophosphate) is the first identified second messenger, which has a fundamental role in the cellular response to many extracellular stimuli. The cAMP signaling pathway controls a diverse range of cellul

2、ar processes. Indeed, not only did cAMP provide the paradigm for the second messenger concept, but also provided the paradigm for signaling compartmentalization. The different receptors, chiefly the GPCRs (G-Protein Coupled Receptors), Alpha and Beta-ADRs (Adrenergic Receptors), Growth Factor recept

3、ors, CRHR (Corticotropin Releasing Hormone Receptor), GcgR (Glucagon Receptor) . AHR Pathway AHR (Aryl Hydrocarbon Receptor) is a member of the bHLH (basic Helix-Loop-Helix)- PAS (Per-ARNT-Sim) family of transcriptional regulators that control a variety of developmental and physiological events, inc

4、luding Neurogenesis, Tracheal and Salivary duct formation, Toxin metabolism, Circadian rhythms, response to Hypoxia and Hormone Receptor function. The unique feature of all bHLH-PAS proteins is the PAS domain, named after the first three proteins identified with this motif, the Drosophila Per, Human

5、 ARNT and Drosophila Sim. The PAS domain consists of 260 310 amino acids and incorporates two well-conserved hydrophobic re. Akt Signaling Akt (v-Akt Murine Thymoma Viral Oncogene)/ PKB (Protein Kinase- is a Serine/threonine Kinase that is involved in mediating various biological responses, such as

6、inhibition of Apoptosis and stimulation of cell proliferation. Three mammalian isoforms are currently known: Akt1/PKB- Alpha, Akt2/PKB-Beta and Akt3/PKB-Gamma. All three isoforms of Akt share a common structure of three domains. The N-terminus of the protein is a PH (Pleckstrin Homology) domain, whi

7、ch interacts with membrane lipid products such as PIP2 (Phosphatidylinositol-3,4-Bisphosphate) and PIP3 (Phosphatidylinositol-3,4,5-Triphosphate). All-trans-retinoic acid signaling Retinoic Acid, a lipophilic molecule and a metabolite of Vitamin-A (all-trans-Retinol), affects gene transcription and

8、modulates a wide variety of biological processes like Cell Proliferation, Differentiation, including Apoptosis. Retinoic Acid mediated gene transcription depends on the rate of transport of Retinoic Acid to target cells and the timing of exposure of Retinoic Acid to RARs (Retinoic Acid Receptors) in

9、 the target tissues. The all-trans-Retinoic Acid, the Carboxylic Acid form of Vitamin-A is of biological significance since it has high circulating levels than other isomers of Retinoic Acid. The targets of all-trans-Retinoic Acid and RARs include a multitude. Androgen Signaling Androgens mediate a

10、wide range of developmental and physiological responses and are especially important in male sexual differentiation and pubertal sexual maturation, the maintenance of spermatogenesis, and male gonadotropin regulation (Ref.1). The principle steroidal androgens, testosterone and its metabolite DHT (5-

11、Alpha-Dihydrotestosterone), mediate their biological effects predominantly through binding to the AR (Androgen Receptor), an androgen-inducible member of the nuclear receptor superfamily of transcription factors (Ref.2). Assembly of RNA Polymerase-II Initiation Complex The nuclei of all eukaryotic c

12、ells contain three different RNA Polymerases, designated I, II and III. Like the DNA Polymerase that catalyzes DNA replication, RNA Polymerases catalyze the formation of the phosphodiester bonds that link the nucleotides together to form a linear chain. The RNA Polymerase moves stepwise along the DN

13、A, unwinding the DNA helix just ahead of the active site for polymerization to expose a new region of the template strand for complementary base-pairing. In this way, the growing RNA chain is extended by one nucleotide at a time in the 5-to-3 direction. The substrates are nucleoside triphosphates. A

14、TM Pathway ATM (Ataxia Telangiectasia Mutated Protein) belongs to a family of Kinases that have sequence homology to PI3K (Phosphoinositide 3-Kinase). ATM is a key regulator of multiple signaling cascades which respond to DNA strand breaks induced by damaging agents IR (Ionizing Radiation), radiomet

15、ric agents or by normal processes. These responses involve the activation of cell cycle Chk factors (Checkpoints factors), DNA repair and Apoptosis. In addition, ATM appears to function as a 'caretaker', suppressing tumorigenesis in specific T cell lineages. Its downstream targets include Ch

16、k1 (Cell Cycle Checkpoint Kinase-1), Chk2 (Cell C. B-cell Receptor Pathway Lymphocytes are one of the five kinds of white blood cells or leukocytes, circulating in the blood. Although mature lymphocytes all look pretty much alike, they are extraordinarily diverse in their functions. The most abundan

17、t lymphocytes are: B-Lymphocytes (often simply called B-Cells) and T-Lymphocytes (likewise called T-Cells) (Ref.1). B-Cells are not only produced in the bone marrow but also mature there. Each B-Cell is specific for a particular antigen. The specificity of binding resides in the BCR (B-Cell receptor

18、) for antigen. They are integral membrane proteins. They are present in thousands of identical copies exp. BRCA1 Pathway The maintenance of genome integrity is essential to all life, but is particularly important to long-lived multicellular organisms, which are susceptible to cancer. DNA damage can

19、take the form of base modifications, strand breaks, interstrand cross-links and other lesions. To deal with many types of damage, genomes have evolved multiple cellular defense mechanisms, including DNA repair and cell cycle checkpoint processes. Different pathways exist for specific kinds of DNA da

20、mage and the cell must have ways to decide which mechanism to use for a given lesion. These requirements imply that signaling networks not only sense t. cAMP Pathway cAMP (Cyclic Adenosine 3',5'-monophosphate) is the first identified second messenger, which has a fundamental role in the cell

21、ular response to many extracellular stimuli. The cAMP signaling pathway controls a diverse range of cellular processes. Indeed, not only did cAMP provide the paradigm for the second messenger concept, but also provided the paradigm for signaling compartmentalization. The different receptors, chiefly

22、 the GPCRs (G-Protein Coupled Receptors), Alpha and Beta-ADRs (Adrenergic Receptors), Growth Factor receptors, CRHR (Corticotropin Releasing Hormone Receptor), GcgR (Glucagon Receptor), DCC. Caspase Cascade Caspases are a family of cysteine proteases that act in concert in a cascade triggered by apo

23、ptosis signaling. The culmination of this cascade is the cleavage of a number of proteins in the cell, followed by cell disassembly, cell death, and, ultimately, the phagocytosis and removal of the cell debris. The Caspase cascade is activated by two distinct routes: one from cell surface and the ot

24、her from mitochondria (Ref.1). The pathway leading to Caspase activation varies according to the apoptotic stimulus. Initiator Caspases (including 8, 9, 10 and 12) are closely coupled to pro-apototic signals. Pro-apoptotic stimuli include the FasL (Fas Ligand), TNF. CD40 Signaling CD40, a TNFR (Tumo

25、r Necrosis Factor Receptor) family member, conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death. First identified and functionally characterized on B-Cells, CD40 is expressed on a plethora of different cell types,

26、including B-Cells, macrophages, dendritic cells, endothelial cells, and fibroblasts, and this widespread expression accounts for the central role of CD40 in the regulation of immune response and host defense (Ref.1). Binding of CD40 with its counter receptor, CD154 (also termed CD40L CD40 ligand or

27、GP39), act. CDK5 Pathway CDKs (Cyclin-dependent kinases) are a group of serine/threonine protein kinases activated by binding to a regulatory subunit cyclin. These kinases are key regulators of the eukaryotic cell cycle progression. CDK5 (also known as Neuronal CDC2-Like Kinase, NCLK) is a unique me

28、mber of the CDK family, that does not act as a checkpoint kinase to regulate cell cycle progression, but acts as a regulatory kinase involved in other post-mitotic processes such as neuronal activity, neuronal migration during development and neurite outgrowth. Although the CDK5 protein is expressed

29、 at basal levels in most mammalian tissues, CDK5 activi. Cellular Apoptosis Pathway Apoptosis is a naturally occurring process by which a cell is directed to Programmed Cell Death. Apoptosis is based on a genetic program that is an indispensable part of the development and function of an organism. I

30、n this process, cells that are no longer needed or that will be detrimental to an organism or tissue are disposed of in a neat and orderly manner; this prevents the development of an inflammatory response, which is often associated with Necrotic cell death. There are at least two broad pathways that

31、 lead to Apoptosis, an "Extrinsic" and an "Intrinsic" Pathway. In both pathways, signaling results in the activation of a family of Cys (Cysteine). Chemokine Signaling Chemokines, or chemotactic cytokines, are a large family of small (6-14 kDa), structurally related proteins that

32、 mediate a wide range of biological activities. As a part of normal immune system functions, chemokines are a critical component of basal leukocyte trafficking essential for immune system architecture and development, and immune surveillance. Chemokines also participate in the growth, differentiatio

33、n, and activation of leukocytes as well as stimulate various effector functions of these cells, such as integrin activation, chemotaxis, superoxide radical production and granule enzyme release. Four classes of chemokines. Chromatin Remodeling The condensation of DNA into an ordered chromatin struct

34、ure allows the cell to solve the topological problems associated with storing huge molecules of chromosomal DNA within the nucleus. DNA is packaged into chromatin in orderly repeating protein-DNA complexes called nucleosomes. Each nucleosome consists of approximately 146bp of dsDNA (double-stranded

35、DNA) wound 1.8 times around a histone octamer (Ref.1). Two molecules each of H2A, H2B, H3, and H4 comprise the histone ramp around which the DNA superhelix winds. Stretches of DNA upto 100bp separate adjacent nucleosomes. Circadian Clock in Mammals Circadian clocks are molecular time-keeping mechani

36、sms that reside in a diverse range of cell types in a variety of organisms. The primary role of these cell-autonomous clocks is to maintain their own 24-hour molecular rhythm and to drive the rhythmic expression of genes involved in physiology, metabolism and behavior. The ability of the clock to pe

37、rsist in the absence of environmental cues provides internal temporal organization so that rhythmic activities can occur at characteristic times during the circadian cycle. In addition, two other clock properties, entrainment (that is, setting the clock to local time with respec. CREB Pathway The pr

38、ocess of consolidating a new memory and the dynamic complexity of information processing within neuronal networks is greatly increased by activity-dependent changes in gene expression within individual neurons. A leading paradigm of such regulation is the activation of the nuclear transcription fact

39、or CREB (cAMP Responsive Element Binding Protein), and its family members the ATF (Activating Transcription Factor) and CREM (cAMP Response Element Modulator), which belong to bZIP (basic/leucine zipper) class of transcription factors that functions in vivo to regulate the proliferation of pituitary

40、 cells and thymocytes. Cyclins and Cell Cycle Regulation Progress in the eukaryotic cell cycle is driven by oscillations in the activities of CDKs (Cyclin-Dependent Kinases). CDK activity is controlled by periodic synthesis and degradation of positive regulatory subunits, Cyclins, as well as by fluc

41、tuations in levels of negative regulators, by CKIs (CDK Inhibitors), and by reversible phosphorylation. The mammalian cell cycle consists of four discrete phases: S-phase, in which DNA is replicated; M-phase, in which the chromosomes are separated over two new nuclei in the process of mitosis. These

42、 two phases are separated by two so called "Gap" phases, G1 and G2. Cytokine Network The immune system recognizes the presence of pathogens by several proteins that bind to molecules secreted by the pathogen or carried on their surface. The cells responsible for these immune responses incl

43、ude the B-Cells, T-Cells, macrophages, neutrophils, basophils, eosinophils, endothelial cells, or mast cells (Ref.1). These cells have distinct roles in the immune system, and communicate with other immune cells by cytokines, which control proliferation, differentiation and function of cells of the

44、immune system. Furthermore, they are involved in processes of inflammation and in the neuronal, haematopoietic and embryonal development of an organism. DNA Methylation and Transcriptional Repression Transcriptional repression is an essential mechanism in the precise control of gene expression. Tran

45、scriptional repressor proteins associate with their target genes either directly through a DNA-binding domain or indirectly by interacting with other DNA-bound proteins. To inhibit transcription in a selective manner, a repressor protein can (1) mask a transcriptional activation domain, (2) block in

46、teraction of an activator with other components of the transcription machinery, or (3) displace an activator from the DNA. Furthermore, DNA response elements can exert allosteric effects on transcriptional regulators. DNA Repair Mechanisms Cells are constantly under threat from the cytotoxic and mut

47、agenic effects of DNA damaging agents. Environmental DNA-damaging agents include UV light and ionizing radiation, as well as a variety of chemicals encountered in foodstuffs, or as air- and water-borne agents. Endogenous damaging agents include metabolites that can act as alkylating agents and the R

48、OS (Reactive Oxygen Species) that arise during respiration. DNA repair enzymes continuously monitor chromosomes to correct damaged nucleotide residues generated by these exogenous and endogenous agents and exposure to carcinogens and cytotoxic compounds. EGF Pathway EGF (Epidermal Growth Factor) is

49、a small 53 amino acid residue protein that is involved in normal cell growth, oncogenesis, and wound healing. This protein shows both strong sequential and functional homology with hTGF-Alpha (human type-Alpha Transforming Growth Factor), which is a competitor for EGF receptor sites. EGF binds to a

50、specific high-affinity, low-capacity receptor on the surface of responsive cells known as EGFR (Epidermal growth factor receptor). EGFR is a member of the ErbB (Erythroblastic Leukemia Viral Oncogene Homolog) family receptors, a subfamily of four closely related receptor tyrosine kinases. eNOS Signa

51、ling NO (Nitric Oxide) is a short-lived free radical gas involved in diverse physiological and pathological processes. It is produced along with L-Citrulline by the oxidation of L-Arginine and catalyzed by three different isoforms of NOS (NO Synthase). Type-I nNOS (neuronal NOS) and Type-III eNOS (e

52、ndothelial NOS) are constitutively expressed as latent enzymes and require a higher concentration of Ca2+ for the enzyme activity. In contrast, Type-II iNOS (inducible NOS) is Ca2+ independent because it s high affinity for Ca2+/Calm (Calmodulin) renders the enzyme active even at basal levels of int

53、racellular Ca2+ (Ref.1 & 2). The ca. Ephrin-EphR Signaling In numerous processes that are vital for the development and maintenance of organism function, cells must communicate crucial information to respond appropriately to the changing environment. As such, RTKs (Receptor Tyrosine Kinases) are

54、 transmembrane proteins, which, on receiving an external stimulus, respond by transmitting a signal to the inside of the cell. Of all the RTKs that are found in the human genome, the Eph Receptor family and their ligands the Ephrins, constitutes the largest family. Epithelial Tight Junctions Epithel

55、ia in multicellular organisms constitute the frontier that separates the individual from the environment. Epithelia are sites of exchange as well as barriers, for the transit of ions and molecules from and into the organism. Epithelial cells achieve this by providing cellular borders that cover exte

56、rnal and internal surfaces throughout the body. Complexes between adjacent cells include Gap Junctions, Desmosomes, Adherens Junctions (AJs) and Tight Junctions (TJs). Such junctions are quite essential for the modulation of paracellular permeability in various epithelia. Vertebrate epithelial cells

57、 exhibit Tight Junction. ErbB Family Pathway The ErbB (Erythroblastic Leukemia Viral Oncogene Homolog) or EGF (Epidermal Growth Factor) family of transmembrane RTKs (Receptor Tyrosine Kinases) plays an important role during the growth and development of a number of organs including the heart, the ma

58、mmary gland, and the central nervous system. In addition, ErbB overexpression is associated with tumorigenesis of the breast, ovaries, brain, and prostate gland. The ErbB family includes four members, EGFR (EGF Receptor)/ErbB1/Her1 (Heregulin-1), ErbB2/Her2 (Heregulin-2), ErbB3/Her3 (Heregulin-3), a

59、nd ErbB4/Her4 (Heregulin-4) (Ref.1). Two of the family members, ErbB1 and E. ERK Signaling The MAPK (Mitogen-Activated Protein Kinase) pathway is one of the primordial signaling systems that nature has used in several permutations to accomplish an amazing variety of tasks. It exists in all eukaryotes, and controls such fundamental cellular processes as Proliferation, Differentiation, Survival and Apoptosis. Mammalian MAPK can