A novel protein with strong homology to the tumor suppressor p53

Abstract

The p53 tumor suppressor orchestrates a number of important genes involved in cell-cycle control and apoptosis. Mice de®cient for p53 show a high incidence of cancer but are developmentally normal suggesting that compensatory mechanisms exist in embryogenesis and dierentiation. The new KET protein is the ®rst mammalian protein with strong homology to p53 in all evolutionary conserved regions. This conservation makes a functional redundancy of the two proteins in cell-cycle control possible. KET is expressed during embryonic development and in certain adult tissues. Among all of the known p53 proteins of dierent species KET is most closely related to that found in squid. The relationship between KET and the invertebrate p53 protein sheds light on the evolutionary origin of p53. KET appears to be an ancestral p53-related protein in vertebrates with a possible role in development and dierentiation while the ubiquitously expressed p53 protein attained its general role as`guardian of the genome' during evolution.

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…They di er considerably at the C-terminus, with both p73 (Kaghad et al, 1997) and p63 (Schmale and Bamberger, 1997) having long extensions whereas p63 has in addition a 40 amino acid N-terminal extension. The ®nding of p53 homologs may explain the fact that p53-null mice develop mostly normally.…”

p53-dependent apoptosis is regulated by a C-terminally alternatively spliced form of murine p53

“…Generation of alternative pathways can also be mediated by cellular homologues. However, in the case of p53, although several such candidates were suggested (Jost et al, 1997;Kaghad et al, 1997;Schmale and Bamberger, 1997), none of them seemed to serve as an ideal p53 analogue. Interestingly, in these newly discovered`homologues' of the p53 protein, alternative splicing of mRNA is frequently observed.…”

PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73

“…Mutations in p53 occur in nearly half of all human tumors (Olivier et al, 2002). p63 and p73 share structural homology with p53, particularly in their DNA-binding domains, with >60% amino acid identity (Kaghad et al, 1997;Schmale and Bamberger, 1997;Osada et al, 1998;Trink et al, 1998;Yang et al, 1998;Zeng et al, 2001). All three proteins take part in the regulation of cell cycle progression and apoptosis, and are expressed as several different isoforms because of alternative promoter usage and splicing.…”