Gap junctions and cellular continuum
(Gap Junctional Intercellular Communication - GJIC)


Inhibition of GJIC - mechanism of tumor promotion
http://www.bioscience.org/1998/v3/d/trosko/fig5.jpg
from Trosko and Ruch 1998,
Frontiers in Bioscience 3:d208
•gap-junctional intercellular communication (GJIC)
- transfer of small signalling molecules via protein channels (gap junctions)
•
•regulation of proliferation, differentiation, apoptosis
•
•inhibition of GJIC -> proliferation ~ tumor promotion
•
•relevance: tumors in vivo have inhibited gap-junctions
Control cells
Inhibition of GJIC

http://www.bioscience.org/1998/v3/d/trosko/fig2.jpg
GJIC
AhR
ER
Oxidative Stress

PAHs as tumor promoters
- inhibition of GJIC -
Bláha et al. 2002 Toxicol Sci 65: 43
- Several PAHs inhibits GJIC
 within 30 min exposure
 (IC50 ~ 10-40 mM)
-
- Low MW and bay/bay-like regions promotes the effect
-Fluoranthene
          :non-mutagenic
          :non-AhR-inducing
          :tumor promoter in vivo (!)
-

Toxicity to membrane gradients and transport
l- Semipermeability of membranes:
several key functions
- cytoplasmic membrane:
signalling, neural cells Na+/K+ gradient
- mitochondrial membrane:
electrone flow -> ATP synthesis
- endoplasmatic reticulum
Ca2+ signalling
l
l- Membrane fusion / transport
neurotransmitter release

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Membrane gradient
disruption
lIon transfer ("ionofors") antibiotics
(K+, Ca2+, Mg2+)
l
l
l
l
l
l
l
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Ion Channel BLOCKERS / ACTIVATORS
lNeuromodulators (drugs)               Neurotoxins (cyanobacterial)
l
l
l
l
l
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Botulinum and Tetanus toxins
(Clostridium botulinum, Clostridium tetani)
Toxins = enzymes - proteases (!)
- cleavage of proteins involved in vesicle formation
- selective inhibition of neutrotransmitter release
neurotoxicity
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Cytoskeleton as target of toxicants
microtubules / actin-myosin
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Cytoskeleton – function
- intracellular transport
- cell replication and division (mitosis:chromosomes)
- muscle movement
- membrane (vesicles) fusion
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TOXINS: effects on (DE)POLYMERIZATION
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cytochalasin D
(fungal toxin)
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Phalloidin
(death cap - Amanita phalloides)

TOXINS: effects on (DE)POLYMERIZATION
Colchicine
taxol
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