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The Burnham Institute (formerly the La Jolla Cancer Research Foundation), La Jolla, California 92037
Keratins 8 (K8) and 18 (K18) are major components of intermediate filaments (IFs) of simple epithelial cells and tumors derived from such cells. Structural cell changes during apoptosis are mediated by
proteases of the caspase family. During apoptosis, K18
IFs reorganize into granular structures enriched for
K18 phosphorylated on serine 53. K18, but not K8, generates a proteolytic fragment during drug- and UV
light-induced apoptosis; this fragment comigrates with
K18 cleaved in vitro by caspase-6, -3, and -7. K18 is
cleaved by caspase-6 into NH2-terminal, 26-kD and
COOH-terminal, 22-kD fragments; caspase-3 and -7 additionally cleave the 22-kD fragment into a 19-kD
fragment. The cleavage site common for the three caspases was the sequence VEVD/A, located in the
conserved L1-2 linker region of K18. The additional
site for caspases-3 and -7 that is not cleaved efficiently
by caspase-6 is located in the COOH-terminal tail domain of K18. Expression of K18 with alanine instead of
serine at position 53 demonstrated that cleavage during apoptosis does not require phosphorylation of serine
53. However, K18 with a glutamate instead of aspartate
at position 238 was resistant to proteolysis during apoptosis. Furthermore, this cleavage site mutant appears to
cause keratin filament reorganization in stably transfected clones. The identification of the L1-2 caspase cleavage site, and the conservation of the same or very
similar sites in multiple other intermediate filament
proteins, suggests that the processing of IFs during apoptosis may be initiated by a similar caspase cleavage.
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