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BBS 2042 Cell signaling, activation, dual role in cancer regulation,…

- - - - classical steroid receptors
        
        e.g. glucocorticoid receptor, estrogen receptor
      - orphan receptors
        
        ligands are not natural
      - adopted orphan receptors
        
        orginally thought to be orphan receptors
        
        include PPAR and LXR
    - - domains: N- NTD - DBD - H - LBD - CTD - C
        
        NTD
        
        first transactivation domain
        
        DBD
        
        zinc fingers
        
        LBD
        
        second transactivation domain
        
        high affinity for NR co-activator proteins
        
        role in dimerization
    - - inactivated state: bound to heat shock proteins
      - different modes of action
        
        homodimers: endocrine: HPA axis
        
        heterodimers: autocrine or paracrine
        
        monomers: usually orphans: mediate regulated transcription changes
        
        ligand-dependent activation
        
        HAT activity
        
        ligand-dependent repression
        
        ligand-indepdent repression
        
        HDAC
    - - regulation
        
        truncated PPAR alpha: inhibition; misses LBD
        
        consensus sequence
        
        shows highly conserved nucleotides
        
        diffference in consensus sequence is mostly dependen on type of PPAR
  - - - Activation mechanism
        
        Src homology 2 (SH2) domains
        
        Diffrent ways
        
        Ligand dimerization
        
        Monomeric ligand binds to a crosslinking protein
        
        Clustered monomeric cell-surface ligand
      - RTK and GTPase
        
        Active Ras
        
        phosphorylation
  - - - Single polypeptide chain
      - Lipid bilayer
      - Heterotrimeric
        
        3 sublayer
        
        Alpha
        
        Atached to membrame by lipid anchors
        
        Beta
        
        Ganmma
    - - Second messwenger
        
        cAMP
        
        Action
        
        Production
        
        Regulation
        
        cAMP is turned off by Gi, an inhibitory protein.
        
        DAG
        
        IP3
        
        Gq
        
        Calcium
- - - - carries genetic info copied from DNA to ribosomes
      - specifies amino acid sequence
        
        each 3 bases code 1 amino acid
    - - helps form popypeptides
    - - forms ribosomes
    - - long non-coding RNA (lncRNA)
        
        200 nucleotides
      - small non-coding RNA (sncRNA)
        
        20-35 nucleotides
        
        micro RNA (miRNA)
        
        21-25 nucleotides
        
        control gene expression by:
        
        translational repression
        
        mRNA degradation
        
        endogenous (self-synthesized)
        
        encoded in introns (non-coding part DNA)
        
        signaling
        
        canonical pathway
        
        precursors: pri-miRNA
        
        processes in nucleus by microprocessor complex
        (consists of RNAse III enzyme Drosha & dsRNA-binding protien Pasha/DGCR8)
        
        1 more item...
        
        non-canonical pathway
        
        shRNA cleaved by microprocessor complex
        
        transport into cytoplasm via Exp5/RanGTP
        
        1 more item...
        
        small interfering RNA (siRNA)
        
        causes gene silencing
        
        made from dsRNA
        
        viral RNA
        
        processed into siRNA by RNAse II enzymes (Dicer, Drosha)
        
        forms either:
        
        RISC complex
        
        1 more item...
        
        RITS complex
        
        1 more item...
        
        23 nucleotides
        
        piwi-interacting RNA (piRNA)
        
        made in germline cells
        
        block movement of transposable elements
        
        transcriptionally silence transposon genes + destroy any RNA produced by them
        
        consist of sequence fragments of transposable elements that are transcribed and broken up
        
        24-32 nucleotides
        
        no Dicer
        
        longer sequence thatn miRNA/siRNA
        
        short/small hairpin RNA (shRNA)
        
        artificial
        
        silence gene expression
        
        expression by delivery of plasmids or vectors
        
        exogenous
  - - - result: reduction gene expression
    - - 1990s: discovery
        
        observations of transcriptional inhibition by antisense RNA expressed in plants
        
        1990: post-transcriptional gene silencing (PTGS)
        
        1992: quelling in neurospora
        
        1998-2001: RNAi in yeast, drosophila, plants, trypanosomes
        
        2001: succesful siRNA experiments in mammalian cells
        
        2002: science named RNAi "technology of the year"
        
        2002: recombinant Dicer generated siRNA
        
        1 more item...
        
        1998: "RNAi" in C. elegans
    - - protein kinase R (PKR)
        
        part in interferon antiviral defense pathway
        
        innate immunity
        
        2 main domains
        
        N-terminal domain
        
        C-terminal kinase domain
        
        gives PKR pro-apoptotic function
        
        mediates activation transcription factor NF-kB
        
        upregulation antiviral interferon cytokines
        
        activation tumor suppressor PP2A
        
        regulation cell cycle (growth and proliferation)
      - activation
        
        binding viral dsRNA to N-terminal domain
        
        autophosphorylation reactions
        
        activation PKR
      - cellular substrate: initiation factor eIF2-alpha
        
        phosphorylation inhibits proteins synthesis of virally-infected cells
    - - source: exogenous
      - synthetic siRNA/shRNA
      - function: experimental manipulation/therapeutic use
        
        has inhibitory effect on translation
- - - - nitric oxide (NO)
      - carbon monoxide (CO)
      - hydrogen sulfide (H2S)
  - - - internal receptors (cytoplasmic)
      - cell-surface receptors (transmembrane)
- - - - functions: communicating, occluding, anchoring
      - gap junction
        
        membrane protein: connecin
        
        located near basal end cells
        
        channel-fomring jucntions htat link cytoplasm of adjacent cells
      - tight junction
        
        membrane protein: Claudia, occludin
        
        cytoskeleton ifber: actin
        
        hold cells closely together near apex preventing leakage of molecules across epithelium
      - adherens junctions
        
        connect actin filament bundles --> link cytoskeletons adjacetn cells
      - desmosome
        
        membrane protein: cadherin
        
        cytoskeleton fiber: intermediate filaments and actin
        
        connect intermediate filaments --> link cytoskeletons adjacent cells
    - - function: anchoring
      - focal adhesion
        
        membrane protein: integrin
        
        cytoskeleton fiber: actin
        
        matrix protein: fibronectin
      - hemidesmosome
        
        membrane protein: integrin
        
        cytoskeleton fiber: keratin (intermediate filaments)
        
        matrix protein: laminin
        
        anchot intermediate filaments to matrix
  - - - cells produce signals that they themselves respond to
      - short-distance signaling
    - - by usage and secretion of hormones into bloodstream
        
        carried to target cells anywhere in the body
      - long-distance signaling
    - - local mediators
        
        act only on cell in local environment signaling cell
      - short-distance signaling
    - - many extracellular signal molecules remain bound to the surface of the signalingcell and influence only cells that contact it
      - short-distance signaling
    - - occurs via neurons
      - signal molecules: neurotransmitters
      - long-distance signaling
  - - - juxtacrine/contact-dependent
      - role in: embryonic development, angiogenesis, bone development, immune system
    - - role in somite formation embryos
      - signaling in intestine promotes proliferation of progenitor cells in intestinal crypts
      - paracrine signaling
    - - paracrine and autocrine signaling
      - sonic hedgehog (Shh)
        
        concentration and time exposure determine digit development
        
        digits V, IV, part of II derive directly from cells that express Shh
        
        autocrine
        
        digit II develops from cells that are exposed to moderate concentrations of extracellular Shh
- - - - stored in fat and liver
        
        accumulation symptoms
        
        metabolic disruption
        
        endocrine disruption
      - bind AhR
        
        inactive form
        
        heat shock protein 90, p23
    - - hard-plastic
      - can bind to estrogen receptors
        
        crosstalk
        
        AhR
        
        impact thyroid function
        
        reproductive effects
      - epigenetic changes
- - - - Mitochondria
        
        Oxidative Phosphorylation
        
        Fenton
        
        Haber-Weiss Reaction
        
        Electrons flow through four major multiprotein complexes (I-IV)
        
        The electron movement between complexes is mediated by either lipid-soluble molecule coenzyme Q (CoQ) or water-soluble molecule cytochrome C (cyt c)
        
        Three out of the four complexes use energy released from electrons to pump protons from matrix into intramembrane space
        
        NADH
        
        Succinate
      - Peroxisomes
        
        metabolizing long-chain fatty acids (LCFAs)
      - Enzymes
        
        Nitric Oxide synthase
        
        Synthesized from L-arginine and the reaction is catalyzed by nitric oxide synthase (NOS), using NADPH and O2.
        
        3 types
        
        NOS I (nNOS)
        
        found in neuronal cells (brain, spine, platelets)
        
        Ca2+ dependent
        
        NOS II (iNOS)
        
        expressed in most nucleated cells, especially in macrophages, is independent of Ca2+
        
        independent of Ca2+
        
        regulated by de novo synthesis
        
        NOS III (eNOS)
        
        present in vascular endothelial cells and neuronal cells
        
        Ca2+ dependent and regulate vasculature
        
        NADPH oxidase (NOX)
        
        Occurs during defence of phagocytes
        
        catalyze the formation of superoxide by
        transferring one electron to oxygen from NADPH.
        
        isoforms
        
        Xanthine oxidase
        
        can generate superoxide by reaction from hypoxanthine to xanthine
        
        Cyclooxygenase
        
        generation of superoxide
        
        Cytochrome P450
        
        Lipoxygenases
        
        dioxygenate polyunsaturated fatty acids in lipids
      - endoplasmic reticulum
        
        ER stress
    - - ● Hydroxyl radical (*OH)
      - ● Superoxide anion (O2-*)
      - ● Hydrogen peroxide (H2O2)
    - - Antioxidanr
        
        Non enzymatic
        
        Vitamin C
        
        Vitamin E
        
        Enzymatic
        
        GST
        
        dimer composed of identical
        Subunits of 23-29 kDa.
        
        Involved in phase II biotransformation.
        
        GST catalyzes the conjugation of gluthione to a harmful
        metabolite
        
        catalase
        
        SOD
        
        SOD catalyzes the conversion of superoxide (O2•) to hydrogen peroxide (H2O2)
  - - - ● Nitric oxide (*NO) (radical)
      - ● Peroxynitrite (ONOO-) (non-radical)
  - - - NRF2 pathway
        
        It is activated either through phosphorylation or ROS induced
        
        Nrf2 coordinately activates cytoprotective genes
        
        Defence
  - - - (B) Cancer cells generate higher levels of ROS that are essential for tumorigenesis.
        
        Genetic alterations leading to activation of oncogenes (PI3K, MAP kinase, HIFs, NF-κB) and loss of tumour suppressors (p53) coordinate an elevated redox state
        
        ROS is also generated by increased oxidative metabolism and hypoxia in rapidly expanding tumours
        
        Cancer cells express elevated levels of cellular antioxidants (SODs, GSH, GPx, and PRx), in part through NRF2, to protect against oxidative-stress-induced cell death.
        
        A. H2O2 is required for activation of a number of cellular pathways involved in cellular growth, survival and proliferation and in metabolism and angiogenesis, which are all hallmarks of cancer
      - Antioxidant role
        
        antioxidants might be beneficial by reducing ROS levels and thereby reducing DNA damage
        
        accelerate tumour formation
    - - The role of ATF4 in mitigating stress caused by ROS during cycling hypoxia
- - - - induce cell cycle arrest