A common polymorphism acts as an intragenic modifier of mutant p53 behaviour.
The p73 protein, a homologue of the tumour-suppressor protein p53, can activate p53-responsive promoters and induce apoptosis in p53-deficient cells. Here we report that some tumour-derived p53 mutants can bind to and inactivate p73. The binding of such mutants is influenced by whether TP53 (encoding p53) codon 72, by virtue of a common polymorphism in the human population, encodes Arg or Pro. The ability of mutant p53 to bind p73, neutralize p73-induced apoptosis and transform cells in cooperation with EJ-Ras was enhanced when codon 72 encoded Arg. We found that the Arg-containing allele was preferentially mutated and retained in squamous cell tumours arising in Arg/Pro germline heterozygotes. Thus, inactivation of p53 family members may contribute to the biological properties of a subset of p53 mutants, and a polymorphic residue within p53 affects mutant behaviour.
Marin
M C
MC
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
Jost
C A
CA
Brooks
L A
LA
Irwin
M S
MS
O'Nions
J
J
Tidy
J A
JA
James
N
N
McGregor
J M
JM
Harwood
C A
CA
Yulug
I G
IG
Vousden
K H
KH
Allday
M J
MJ
Gusterson
B
B
Ikawa
S
S
Hinds
P W
PW
Crook
T
T
Kaelin
W G
WG
D000483:Alleles; D001120:Arginine / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D002460:Cell Line; D003062:Codon / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006580:Genetic Carrier Screening; D018095:Germ-Line Mutation; D006801:Humans; D046911:Macromolecular Substances; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D011110:Polymorphism, Genetic; D011392:Proline / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D025521:Tumor Suppressor Proteins
D003062:Codon; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D001120:Arginine; D011392:Proline