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					Dysfunction of cell signaling and
      the related disease
Signal transduction



Signal transduction refers to the process in
which cells sense the extracellular stimuli
through membranous or intracellular receptors,
transduce the signals through intracellular
molecules, and thus regulate the biological
function of the cells.
Signals


Chemical signals
     hormones, neurotransmitters, neuropeptide,
     cytokines, exogenous drugs, toxins
Physical signals
     Mechanical stimuli, osmotic pressure change
Intercellular contact or contact between cell and
extracellular matrix
Receptors



Membranous receptors
Neuclear receptors (intracellular receptors)
Transmemtrane signal transduction
mediated by membranous receptors

Ionotropic receptor       neurotransmitters
G protein coupled receptor (GPCR)
    hormones, neurotransmitters, neuropeptide,
chemokines, PGs
Tyrosine kinase receptor insulin, growth factors
Tyrosine kinase coupled receptor cytokines
(interleukins, interferones)
Serine/threonine kinase recptor TGFβ
TNF/Fas receptor      TNF, FasL
Guanylyl cyclase (GC) receptor ANP, BNP, CNP, NO
GPCR      Gs   adenylate cyclase (AC)     cAMP-PKA
          Gq   PLCβ → PIP2 → IP3-Ca2+; DAG-PKC
          PI-3K-PKB

                                        IP3-Ca2+; DAG-PKC
Tyrosine kinase receptor                PI-3K-PKB
                                        Ras-Raf-MAPK (ERK)



Tyrosine kinase coupled receptor            JAK-STAT



Serine/threonine kinase recptor           TGF β-smad



Guanylyl cyclase (GC) receptor              cGMP-PKG
Nuclear receptors



 Steroid hormone
 Thyroxine
 Vitamin D
Ways to regulate target proteins



  Reversible phosphorylation
  Regulation mediated by G protein
  Regulation of gene expression
Termination of signal transduction


 Dissociation of ligand from receptors
 Degradation of receptors
 Convertion of GTP to GDP
 Dephosphorylation
Dysfunction of cell signaling in disease



Aberrant extracellur signals in disease
Aberrant receptors in disease
Aberrant intracellular signaling
Multiple signaling aberrations in disease
Aberrant extracellur signals in disease



Type 1 diabetes mellitus insulin↓ antibody to
insulin or destruction of β cells.
Central diabetes insipidus      ADH ↓
Aberrant receptors in disease

 Receptor defect
    Familial hypercholesterolaemia (FH)      LDL receptor defect
    Nephrogenic diabetes insipidus        ADH V2R defect
                                          Gs-cAMP-PKA-AQP2
    Androgen insensitivity syndrome (AIS)       AR defect
    Type 2 diabetes                              IR defect

 Excessve receptor activation

    Hyperthyroidism          TSHR    activation by mutation


 Autoimmune receptor disease          TSH receptor antibody

     Hyperthyroidism            stimulatory antibody
     Hypothyroidism             inhibitory antibody
Aberrant intracellular signaling

   cholera

     Activity of GTPase↓
     GTP can’t convert to GDP
     Continuous Gs-cAMP-PKA activation
     Secretion of chloride into the lumen↑
Multiple signaling aberrations in disease


  cancer


    Growth factors↑ FGF TGFα
    Growth factor receptors ↑ FGFR EGFR NGFR
    Aberrant activation of receptor    EGFR
    Aberrant intracellular signaling   Ras mutation
    TGFβ receptor mutation      SMAD4 mutation
Cell proliferation, differenciation
and the related disease



Cell proliferation and the related disease
Cell diffenciation and the related disease
Cell proliferation




 Cell proliferation refers to the increase in
 the cell numbers as a result of cell growth
 and cell division.
Cell cycle

  Cell cycle is comprised of a set of sequential
  phases which lasts from the end of last
  mitosis to the end of this mitosis.


Four phases:

   G1 phase: presynthesis gap phase
   S phase: DNA synthesis phase
   G2 phase: postsynthesis phase
   M phase: mitotic phase
G0 phase cell


    Cell that is not actively dividing may be
    temporarily removed from the cycle by
    entering a resting state difined as G0 phase
    cell.
    Hepatocyte, fibroblast

Terminal differenciation cell

     Cell that is permanently removed from the
     cycle is difined as terminal differenciation cell.
     Neutrocyte and cardiomyocyte
Regulation of cell cycle


   Cyclin
   CDK (cyclin dependent kinase
   CKI (CDK inhibitor)



Cyclins refer to proteins presented in cell cycle
with periodical concentration change due to
synthesis and degradation.
Cyclin/CDK compound


  cyclinD-CDK4/CDK6    G1phase
  cyclinE-CDK2         S phase
  cyclinA-CDK2         G2phase
  cyclinB1-CDK1        M phase

CKI

   Cip/Kip family   p21, p27, p57
   INK4 family      p16, p15, p18, p19
       cyclinD-CDK4/6
              ↓
     Phosphorylate pRb
             ↓
  Release transcriptor E2F to
  translocate into the nucleus
             ↓
Promote Traget protein expression,
such as cyclinE
             ↓
      G1phase→S phase
Check point

  Cell cycle progression is strictly overseen by
  several checkpoints, which are quality controllers
  that monitor the condition of DNA throughout cell
  cycle and protect genomic integrity and the
  fidelity of chromosome seperation.


 p53

   DNA damage →upregulation of p21 by p53
   →arresting cell cycle →DNA repair
   When DNA fails to be repired, p53 initiates
   cell apoptosis
Dysregulation of cell cycle and tumor




   Cyclin overexpression
   pRb mutation and downregulation
   p16 mutation and downregulation
   p53 mutation and downregulation
Cell differenciation



Cell differenciation means the process
whereby relatively unspetialized cells, such as
embryonic or regenerative cells, acquaire
spetialized structural , functional and
biochemical features.
Regulation of cell differenciation


 Transcriptional regulation
 Post-transcriptional regulation
 Extracellular regulation
          extracellular matrix
          extracellular signal molecules
Dysregulation of cell differenciation and
disease




 Acute myeloid leukemia, AML
Apoptosis

 Apoptosis is commonly viewed as an energy-
 dependent process and a genetically regulated
 death form characterized by a series of intracellar
 molecular events.
 Programmed cell death (PCD)

Importance


 Maitaining normal development
 Maintaining homeostasis
Characteristics
      Morphological characteristics
           chromatin condensation
           nuclear fragmentation
           plasma membrane blebbing
           cell shrinkage
           formation of apoptotic body

       Biochemical characteristics

           Activation of endonuclease degradation of
           DNA ladder pattern nucleosome
           Activation of caspase (cysteine-containing
           asparate-specific protease)
caspase



 Initiator   caspase 8, 9, 10
 Effector    caspase 3, 6, 7
Apoptosis-related gene



 Fas (CD95, apo-1)
       death receptor
 Bcl-2 (B cell lymphoma/leukemia-2)
       the first gene found to inhibit apoptosis
 P53
       induce apoptosis
Signal transduction in apoptosis


 Death receptor pathway
         Fas, TNFR-1 bingding the correspongding
 ligand →caspase8 →caspase3


 Mitochondria pathway
         AIF(apoptosis inducing factor)
         cytochrome C (cyt C)
         apoptotic protease activating factor-1(Apaf-1)
         → caspase9 →caspase3
Mechanism

 Mitochondrial damage
         permeability transition pore (PTP)
 Oxidative stress
         ROS (reactive oxygen species)
 Calcium dyshomeostasis
         activation of endonuclease, calcium-
         dependent protease and phospholipase


                    cross-talk
Apoptosis-related disease


 Defect in apoptosis        tumors
 Excessive apoptosis        Alzheimer disease (AD)
                            Parkinson disease
                            AIDS
 Both of above              atherosclerosis
                   excessive endothial cell apoptosis
                   defect in SMC apoptosis

				
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posted:4/26/2011
language:English
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