Al. Kim et al., Conformational and molecular basis for induction of apoptosis by a p53 C-terminal peptide in human cancer cells, J BIOL CHEM, 274(49), 1999, pp. 34924-34931
A p53-derived C-terminal peptide induced rapid apoptosis in breast cancer c
ell lines carrying endogenous p53 mutations or overexpressed wild-type (wt)
p53 but was not toxic to nonmalignant human cell lines containing wt p53,
Apoptosis occurred through a Fas/APO-1 signaling pathway involving increase
d extracellular levels of Fas/FasL in the absence of protein synthesis, as
well as activation of a Fas/APO-1-specific protease, FLICE, The peptide act
ivity was p53-dependent, and it had no effect in three tumor cell lines wit
h null p53. Furthermore, the C-terminal peptide bound to p53 protein in cel
l extracts. Thus, p53-dependent, Fas/APO-1 mediated apoptosis can be induce
d in breast cancer cells with mutant p53 similar to the recently described
Fas/APO-1 induced apoptosis by wt p53. However, mutant p53 without p53 pept
ide does not induce a Fas/APO-1 activation or apoptosis, Docking of the com
puted low energy conformations for the C-terminal peptide with those for a
recently defined proline-rich regulatory region from the N-terminal domain
of p53 suggests a unique low energy complex between the two peptide domains
. The selective and rapid induction of apoptosis in cancer cells carrying p
53 abnormalities may lead to a novel therapeutic modality.