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Evolution of Functions within the p53/p63/p73 Family
Author(s) -
LAURENZI VINCENZO,
MELINO GERRY
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb05602.x
Subject(s) - mdmx , transactivation , biology , rna splicing , mdm2 , gene , alternative splicing , dna damage , genetics , cancer research , gene isoform , microbiology and biotechnology , transcription factor , dna , rna
A bstract : Even though the tumor suppressor gene p53 is highly important in human cancer, as indicated by the fact that it is mutated in about 50% of cases, up to a few years ago no similar proteins had been identified. Recently, two p53 homologues have been identified, p73 and p63, with high aminoacid identity suggesting similar functions. Indeed, like p53, p73 as well (i) can bind mdmx, mdm2, p300/CAF and adenovirus E4‐ORF6 proteins, (ii) can trigger several promoters including p21, bax, mdm2, gadd45, cyclin G, IGFBP3, 14–3–3σ, (iii) is able to trigger cell death, (iv) is involved in the DNA damage response, although through a different pathway. Here we analyze the data present in the literature in search of diverging pathways among the p53, p63, p73 family. Both p63 and p73 present two significant structural peculiarities: the presence of an extended non‐conserved C‐terminus containing a sterile alpha motive (SAM), typical of developmental proteins, and the presence of number of different splicing isoforms differing in the N‐terminus or in the absence of the transactivation domain (ΔN forms), acting as dominant negative. The mouse knockout of p63 and p73, unlike the ones for p53, shows developmental abnormalities; p63 and p73 are rarely mutated in human cancers; both genes are regulated in different differentiation models. This strongly suggests the involvement of p63 and p73 in development. A picture is emerging showing a gradient of function among p53, p73, p63 ranging from tumor suppression to development.